Breast Cancer

This summary discusses primary epithelial breast cancers in women. The breast is rarely affected by other tumors such as lymphomas, sarcomas, or melanomas.

Breast cancer also affects men and children and may occur during pregnancy, although it is rare in these populations.

Clinical Evaluation   Staging   Treatment   Localized/Operable   Locally Advanced/Inflammatory   Locoregional/Recurrent   Metastatic   Ductal Carcinoma In Situ   Systemic therapy overview  

Incidence and Mortality

Estimated new cases and deaths from breast cancer (women only) in the United States in 2018:
•New cases: 268,670. •Deaths: 41,400.

Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 63,960 cases of in situ disease and 266,120 cases of invasive disease in 2018. Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 70,500 American women will die of lung cancer in 2018. Men account for 1% of breast cancer cases and breast cancer deaths.

Widespread adoption of screening increases breast cancer incidence in a given population and changes the characteristics of cancers detected, with increased incidence of lower-risk cancers, premalignant lesions, and ductal carcinoma in situ (DCIS). (Refer to the Ductal Carcinoma In Situ section in the Breast Cancer Diagnosis and Pathology section in the PDQ summary on Breast Cancer Screening for more information.) Population studies from the United States and the United Kingdom demonstrate an increase in DCIS and invasive breast cancer incidence since the 1970s, attributable to the widespread adoption of both postmenopausal hormone therapy and screening mammography. In the last decade, women have refrained from using postmenopausal hormones, and breast cancer incidence has declined, but not to the levels seen before the widespread use of screening mammography.


Protective Factors

Protective factors and interventions to reduce the risk of female breast cancer include the following:

•Estrogen use (after hysterectomy).
•Exercise.
•Early pregnancy.
•Breast feeding.
•Selective estrogen receptor modulators (SERMs).
•Aromatase inhibitors or inactivators.
•Risk-reducing mastectomy.
•Risk-reducing oophorectomy or ovarian ablation.

Risk Factors

Increasing age is the most important risk factor for most cancers. Other risk factors for breast cancer include the following:
•Family health history.
•Major inheritance susceptibility.
    •Germline mutation of the BRCA1 and BRCA2 genes and other breast cancer susceptibility genes.
•Alcohol intake.
•Breast tissue density (mammographic).
•Estrogen (endogenous).
    •Menstrual history (early menarche/late menopause).
    •Nulliparity.
    •Older age at first birth.
•Hormone therapy history.
    •Combination estrogen plus progestin hormone replacement therapy.
•Obesity (postmenopausal).
•Personal history of breast cancer.
•Personal history of benign breast disease (BBD) (proliferative forms of BBD).
•Radiation exposure to breast/chest.

Age-specific risk estimates are available to help counsel and design screening strategies for women with a family history of breast cancer.

Of all women with breast cancer, 5% to 10% may have a germline mutation of the genes BRCA1 and BRCA2. Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry. The estimated lifetime risk of developing breast cancer for women with BRCA1 and BRCA2 mutations is 40% to 85%. Carriers with a history of breast cancer have an increased risk of contralateral disease that may be as high as 5% per year. Male BRCA2 mutation carriers also have an increased risk of breast cancer.

Mutations in either the BRCA1 or the BRCA2 gene also confer an increased risk of ovarian cancer or other primary cancers. Once a BRCA1 or BRCA2 mutation has been identified, other family members can be referred for genetic counseling and testing. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Breast Cancer Prevention; and Breast Cancer Screening for more information.)

(Refer to the PDQ summary on Breast Cancer Prevention for more information about factors that increase the risk of breast cancer.)

 

Screening

Clinical trials have established that screening asymptomatic women using mammography, with or without clinical breast examination, decreases breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Screening for more information.)


Diagnosis

Patient evaluation
When breast cancer is suspected, patient management generally includes the following:
•Confirmation of the diagnosis.
•Evaluation of the stage of disease.
•Selection of therapy.

The following tests and procedures are used to diagnose breast cancer:
•Mammography.
•Ultrasound.
•Breast magnetic resonance imaging (MRI), if clinically indicated.
•Biopsy.

Contralateral disease
Pathologically, breast cancer can be a multicentric and bilateral disease. Bilateral disease is somewhat more common in patients with infiltrating lobular carcinoma. At 10 years after diagnosis, the risk of a primary breast cancer in the contralateral breast ranges from 3% to 10%, although endocrine therapy decreases that risk. The development of a contralateral breast cancer is associated with an increased risk of distant recurrence. When BRCA1/BRCA2 mutation carriers were diagnosed before age 40 years, the risk of a contralateral breast cancer reached nearly 50% in the ensuing 25 years.

Patients who have breast cancer will undergo bilateral mammography at the time of diagnosis to rule out synchronous disease. To detect either recurrence in the ipsilateral breast in patients treated with breast-conserving surgery or a second primary cancer in the contralateral breast, patients will continue to have regular breast physical examinations and mammograms.

The role of MRI in screening the contralateral breast and monitoring women treated with breast-conserving therapy continues to evolve. Because an increased detection rate of mammographically occult disease has been demonstrated, the selective use of MRI for additional screening is occurring more frequently despite the absence of randomized, controlled data. Because only 25% of MRI-positive findings represent malignancy, pathologic confirmation before treatment is recommended. Whether this increased detection rate will translate into improved treatment outcome is unknown.

Prognostic and Predictive Factors

Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy. Prognosis and selection of therapy may be influenced by the following clinical and pathology features (based on conventional histology and immunohistochemistry):

• Menopausal status of the patient.
•Stage of the disease.
•Grade of the primary tumor.
•Estrogen receptor (ER) and progesterone receptor (PR) status of the tumor.
•Human epidermal growth factor type 2 receptor (HER2/neu) overexpression and/or amplification.
•Histologic type. Breast cancer is classified into a variety of histologic types, some of which have prognostic importance. Favorable histologic types include mucinous, medullary, and tubular carcinomas.

The use of molecular profiling in breast cancer includes the following:

•ER and PR status testing.
•HER2/neu receptor status testing.
•Gene profile testing by microarray assay or reverse transcription-polymerase chain reaction (e.g., MammaPrint, Oncotype DX).

On the basis of ER, PR, and HER2/neu results, breast cancer is classified as one of the following types:
•Hormone receptor positive.
•HER2/neu positive.
•Triple negative (ER, PR, and HER2/neu negative).

ER, PR, and HER2 status are important in determining prognosis and in predicting response to endocrine and HER2-directed therapy. The American Society of Clinical Oncology/College of American Pathologists consensus panel has published guidelines to help standardize the performance, interpretation, and reporting of assays used to assess the ER/PR status by immunohistochemistry and HER2 status by immunohistochemistry and in situ hybridization.

Gene profile tests

Gene profile tests include the following:
•MammaPrint: The first gene profile test to be approved by the U.S. Food and Drug Administration was the MammaPrint gene signature. Its prognostic utility primarily targets adjuvant therapy−decision making in women aged 61 years and younger with stage I/II lymph node–negative breast cancer 5 cm or smaller. The MINDACT trial (NCT00433589) will help determine if the assay should be used to decide whether adjuvant chemotherapy may benefit a patient.
•Oncotype DX: The Oncotype DX 21 gene assay is the gene profile test with the most extensive clinical validation thus far, albeit in a prospective–retrospective fashion. A 21-gene recurrence score (RS) is generated based on the level of expression of each of the 21 genes:
•RS <18: low risk.
•RS ≥18 and <31: intermediate-risk.
•RS ≥31: high risk.

The following trials describe the prognostic and predictive value of multigene assays:

1.The prognostic ability of the Oncotype DX 21-gene assay was assessed in two randomized trials. •The National Surgical Adjuvant Breast and Bowel Project (NSABP B-14Exit Disclaimer) trial randomly assigned patients to receive tamoxifen or placebo; the results favoring tamoxifen changed clinical practice in the late 1980s. Formalin-fixed, paraffin-embedded tissue was available for 668 patients. The 10-year distant recurrence risk for patients treated with tamoxifen was 7% for those with a low RS, 14% for those with an intermediate RS, and 31% for those with high RS (P < .001).
•A community-based, case-control study examined the prognostic ability of the RS to predict breast cancer deaths after 10 years in a group of tamoxifen-treated patients and observed a similar prognostic pattern to that seen in patients from NSABP B-14.

2.Prediction of benefit from chemotherapy in patients with node-negative, ER-positive breast cancer was assessed by the tamoxifen alone (n = 227) and the combination arms (n = 424) of the NSABP B-20Exit Disclaimer trial. Patients in the NSABP B-20 trial were randomly assigned to receive tamoxifen alone or tamoxifen concurrently with methotrexate and 5-fluorouracil (MF) or cyclophosphamide with MF (CMF).
•The 10-year distant disease-free survival (DFS) improved from 60% to 88% by adding chemotherapy to tamoxifen in the high-risk group, while no benefit was observed in the low RS group.

3.Similar findings were reported in the prospective-retrospective evaluation of Southwestern Oncology Group (SWOG-8814) trial in lymph node-positive patients treated with tamoxifen with or without cyclophosphamide, doxorubicin, and fluorouracil (CAF). However, the sample size in this analysis was small, follow-up was only 5 years, and the prognostic impact of having positive nodes needs to be taken into consideration.
•Of note, both analyses (NSABP B-20 and S8814) were underpowered for any conclusive predictive analysis among patients identified as having an intermediate RS.

4.Results from the TAILORx (NCT00310180) trial may help provide recommendations for those with ER/PR-positive and node-negative disease with an intermediate RS. In this study, a low-risk score was defined as less than 11, intermediate score was 11 to 25, and high-risk score was greater than 25. These cut points differ from those described above.
Patients in this study with a low-risk score were found to have very low rates of recurrence at 5 years with endocrine therapy. Primary endpoint results from this study are awaited.

•Rate of invasive DFS was 93.8%.
•Rate of freedom from recurrence of breast cancer at a distant site was 99.3%.
•Rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7%.
•Rate of overall survival was 98.0%.

Results from the RxPONDER (NCT01272037) trial will help to determine if there is a benefit from adjuvant chemotherapy in patients with ER-positive, node-positive early breast cancer treated with endocrine therapy, and a RS below 25.

Many other gene-based assays may guide treatment decisions in patients with early breast cancer (e.g., Predictor Analysis of Microarray 50 [PAM50] Risk of Recurrence [ROR] score, EndoPredict, Breast Cancer Index).

Although certain rare inherited mutations, such as those of BRCA1 and BRCA2, predispose women to develop breast cancer, prognostic data on BRCA1/BRCA2 mutation carriers who have developed breast cancer are conflicting. These women are at greater risk of developing contralateral breast cancer. (Refer to the Prognosis of BRCA1- and BRCA2-related breast cancer section of the PDQ Genetics of Breast and Gynecologic Cancers summary for more information.)

 

Posttherapy Considerations

Hormone replacement therapy
After careful consideration, patients with severe symptoms may be treated with hormone replacement therapy. For more information, refer to the following PDQ summaries:
•Breast Cancer Prevention
•Hot Flashes and Night Sweats



Related Summaries

Other PDQ summaries containing information related to breast cancer include the following:
•Breast Cancer Prevention
•Breast Cancer Screening
•Breast Cancer Treatment During Pregnancy
•Genetics of Breast and Gynecologic Cancers
•Male Breast Cancer Treatment
•Unusual Cancers of Childhood Treatment (breast cancer in children)

 

Types of breast cancer

Breast cancer can be invasive or noninvasive. Invasive breast cancer is cancer that spreads into surrounding tissues. Noninvasive breast cancer does not go beyond the milk ducts or lobules in the breast. Most breast cancers start in the ducts or lobes and are called ductal carcinoma or lobular carcinoma:
• Ductal carcinoma. These cancers starts in the cells lining the milk ducts and make up the majority of breast cancers.
        • Ductal carcinoma in situ (DCIS). This is cancer that is located only in the duct.
        • Invasive or infiltrating ductal carcinoma. This is cancer that has spread outside of the duct.
• Lobular carcinoma. This is cancer that starts in the lobules.
        • Lobular carcinoma in situ (LCIS). LCIS is located only in the lobules. LCIS is not considered cancer. However, LCIS is a risk factor for developing invasive breast cancer in both breasts.

Less common types of breast cancer include:
• Medullary • Mucinous • Tubular • Metaplastic • Papillary breast cancer
• Inflammatory breast cancer is a faster-growing type of cancer that accounts for about 1% to 5% of all breast cancers.
• Paget’s disease is a type of cancer that begins in the ducts of the nipple. Although it is usually in situ, it can also be an invasive cancer.

Breast cancer subtypes
Breast cancer is not a single disease, even among the same type of breast cancer. There are 3 main subtypes of breast cancer that are determined by doing specific tests on a sample of the tumor. These tests will help your doctor learn more about your cancer and recommend the most effective treatment plan.

Testing the tumor sample can find out if the cancer is:

• Hormone receptor-positive. Breast cancers expressing estrogen receptors (ER) and/or progesterone receptors (PR) are called “hormone receptor-positive.” Tumors that have estrogen receptors are called “ER-positive.” Tumors that have progesterone receptors are called “PR-positive.”
Only 1 of these receptors needs to be positive for a cancer to be called hormone receptor positive. This type of cancer may depend on the hormones estrogen and/or progesterone to grow. Hormone receptor-positive cancers can occur at any age, but may be more frequent in women who have gone through menopause. About 60% to 75% of breast cancers have estrogen and/or progesterone receptors. Cancers without these receptors are called “hormone receptor-negative.”

• HER2-positive. About 20% to 25% of breast cancers depend on the gene called human epidermal growth factor receptor 2 (HER2) to grow. These cancers are called “HER2-positive” and have excessive numbers of HER2 receptors or copies of the HER2 gene. The HER2 gene makes a protein that is found on the cancer cell and is important for tumor cell growth. This type of cancer may grow more quickly. HER2-positive cancers can be either hormone receptor-positive or hormone receptor-negative. Cancers that do not express HER2 are called “HER2-negative.”

• Triple-negative. If a tumor does not express ER, PR, and/or HER2, the tumor is called “triple-negative.” Triple-negative breast cancer makes up about 15% of invasive breast cancers. Triple-negative breast cancer seems to be more common among younger women, particularly younger black women. Triple-negative cancer is also more common in women with a mutation in the breast cancer genes 1 and 2, commonly called BRCA1 and BRCA2 genes. Experts recommend that all people with triple-negative breast cancer be tested for BRCA gene mutations.

Histopathologic Classification of Breast Cancer

Histologic classification of breast cancer based on tumor location.
Infiltrating or invasive ductal cancer is the most common breast cancer histologic type and comprises 70% to 80% of all cases.

Tumor Location and Related Histologic Subtype

Tumor Location --- Histologic Subtype

Carcinoma, NOS ---

Ductal --- •Intraductal (in situ), •Invasive with predominant component, •Invasive, NOS, •Comedo, •Inflammatory, •Medullary with lymphocytic infiltrate, •Mucinous (colloid), •Papillary, •Scirrhous, •Tubular, •Other

Lobular --- •Invasive with predominant in situ component, •Invasive

Nipple --- •Paget disease, NOS •Paget disease with intraductal carcinoma, •Paget disease with invasive ductal carcinoma

Other --- •Undifferentiated carcinoma, •Metaplastic

*NOS = not otherwise specified.

The following tumor subtypes occur in the breast but are not considered typical breast cancers:
•Phyllodes tumor •Angiosarcoma •Primary lymphoma.

Breast Anatomy

 

Stage Information for Breast Cancer

The AJCC staging system provides a strategy for grouping patients with respect to prognosis. Therapeutic decisions are formulated in part according to staging categories but primarily according to the following:

•Tumor size.
•Lymph node status.
•Estrogen-receptor and progesterone-receptor levels in the tumor tissue.
•Human epidermal growth factor receptor 2 (HER2/neu) status.
•Menopausal status.
•General health of the patient.

Definitions of TNM and AJCC Stage Groupings
The AJCC has designated staging by tumor, node, and metastasis (TNM) classification to define breast cancer. When this system was modified in 2002, some nodal categories that were previously considered stage II were reclassified as stage III. As a result of the stage migration phenomenon, survival by stage for case series classified by the new system will appear superior to those using the old system.

Primary Tumor (T)
TX - Primary tumor cannot be assessed.
T0      -       No evidence of primary tumor.
Tis - Carcinoma in situ.
Tis(DCIS) - DCIS.       [DCIS = ductal carcinoma in situ]
Tis(LCIS) - LCIS.       [LCIS = lobular carcinoma in situ. *Information about LCIS is not included in this summary.]

Tis(Paget) - Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.

T1 - Tumor ≤20 mm in greatest dimension.
T1mi - Tumor ≤1 mm in greatest dimension.
T1a - Tumor >1 mm but ≤5 mm in greatest dimension.
T1b - Tumor >5 mm but ≤10 mm in greatest dimension.
T1c - Tumor >10 mm but ≤20 mm in greatest dimension.
T2 - Tumor >20 mm but ≤50 mm in greatest dimension.
T3 - Tumor >50 mm in greatest dimension.

T4 - Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules). &nsbp; &nsbp; &nsbp; &nsbp; [Invasion of the dermis alone does not qualify as T4.]

T4a - Extension to the chest wall, not including only pectoralis muscle adherence/invasion.
T4b - Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the skin, which do not meet the criteria for inflammatory carcinoma.
T4c - Both T4a and T4b.
T4d - Inflammatory carcinoma.

The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both. Size should be measured to the nearest millimeter. If the tumor size is slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of 1.1 mm is reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the subscript c or p modifier to indicate whether the T classification was determined by clinical (physical examination or radiologic) or pathologic measurements, respectively. In general, pathologic determination should take precedence over clinical determination of T size.

Regional Lymph Nodes (N) - Clinical
Clinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic examination. Confirmation of clinically detected metastatic disease by fine-needle aspiration without excision biopsy is designated with an (f) suffix, for example, cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, for example, cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine-needle aspiration, core biopsy, or sentinel lymph node biopsy. Pathologic classification (pN) is used for excision or sentinel lymph node biopsy only in conjunction with a pathologic T assignment.

NX - Regional lymph nodes cannot be assessed (e.g., previously removed).
N0 - No regional lymph node metastases.
N1 - Metastases to movable ipsilateral level I, II axillary lymph node(s).

N2 - Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted.
        OR
Metastases in clinically detectedb ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases.

N2a - Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures.
N2b - Metastases only in clinically detectedb ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph node metastases.
N3 - Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement.
        OR
Metastases in clinically detectedb ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node metastases.
        OR
Metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement.

N3a - Metastases in ipsilateral infraclavicular lymph node(s).
N3b - Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s).
N3c - Metastases in ipsilateral supraclavicular lymph node(s).

Clinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic examination. Confirmation of clinically detected metastatic disease by fine-needle aspiration without excision biopsy is designated with an (f) suffix, for example, cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, for example, cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine-needle aspiration, core biopsy, or sentinel lymph node biopsy. Pathologic classification (pN) is used for excision or sentinel lymph node biopsy only in conjunction with a pathologic T assignment.

Pathologic (pN)
pNX - Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study).
pN0 - No regional lymph node metastasis identified histologically.

Note: ITCs are defined as small clusters of cells ≤0.2 mm, or single tumor cells, or a cluster of <200 cells in a single histologic cross-section. ITCs may be detected by routine histology or by IHC methods. Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated.

pN0(i–) - No regional lymph node metastases histologically, negative IHC.
pN0(i+) - Malignant cells in regional lymph node(s) ≤0.2 mm (detected by H&E or IHC including ITC).
pN0(mol–) - No regional lymph node metastases histologically, negative molecular findings (RT-PCR).
pN0(mol+) - Positive molecular findings (RT-PCR), but no regional lymph node metastases detected by histology or IHC.
pN1 - Micrometastases.
        OR
Metastases in 1–3 axillary lymph nodes.
        AND/OR
Metastases in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected.

pN1mi - Micrometastases (>0.2 mm and/or >200 cells but none >2.0 mm).
pN1a - Metastases in 1–3 axillary lymph nodes, at least one metastasis >2.0 mm.
pN1b - Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.
pN1c - Metastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.

pN2 - Metastases in 4–9 axillary lymph nodes.
        OR
Metastases in clinically detectedd internal mammary lymph nodes in the absence of axillary lymph node metastases.

pN2a - Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit >2 mm).
pN2b - Metastases in clinically detectedd internal mammary lymph nodes in the absence of axillary lymph node metastases.

pN3 - Metastases in ≥10 axillary lymph nodes.
        OR
Metastases in infraclavicular (level III axillary) lymph nodes.
        OR
Metastases in clinically detectedc ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary lymph nodes.
        OR
Metastases in >3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.
        OR
Metastases in ipsilateral supraclavicular lymph nodes.
pN3a - Metastases in ≥10 axillary lymph nodes (at least 1 tumor deposit >2.0 mm).
        OR
Metastases to the infraclavicular (level III axillary lymph) nodes.
pN3b - Metastases in clinically detectedd ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes.
        OR
Metastases in >3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.
pN3c - Metastases in ipsilateral supraclavicular lymph nodes.

Posttreatment ypN

– Posttreatment yp N should be evaluated as for clinical (pretreatment) N methods above. The modifier SN is used only if a sentinel node evaluation was performed after treatment. If no subscript is attached, it is assumed that the axillary nodal evaluation was by AND.

– The X classification will be used (ypNX) if no yp posttreatment SN or AND was performed.
– N categories are the same as those used for pN.

AND = axillary node dissection; H&E = hematoxylin and eosin stain; IHC = immunohistochemical; ITC = isolated tumor cells; RT-PCR = reverse transcriptase/polymerase chain reaction.

Classification is based on axillary lymph node dissection with or without sentinel lymph node biopsy. Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node dissection is designated (SN) for "sentinel node," for example, pN0(SN).

Not clinically detected is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination.

Clinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic examination.

Distant Metastases (M)
M0 - No clinical or radiographic evidence of distant metastases.

cM0(i+) - No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional nodal tissue that are ≤0.2 mm in a patient without symptoms or signs of metastases.

M1 - Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven >0.2 mm.

 

Anatomic Stage / Prognostic Groups

Stage T N M
0 Tis N0 M0
IA T1 N0 M0
IB T0 N1mi M0
T1 N1mi M0
IIA T0 N1 M0
T1 N1 M0
T2 N0 M0
IIB T2 N1 M0
T3 N0 M0
Stage T N M
IIIA T0 N2 M0
T1 N2 M0
T2 N2 M0
T3 N1 M0
T3 N2 M0
IIIB T4 N0 M0
T4 N1 M0
T4 N2 M0
IIIC Any T N3 M0
IV Any T Any N M1

 

Note:
T1 includes T1mi.
T0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB.
– M0 includes M0(i+).
– The designation pM0 is not valid; any M0 should be clinical.
– If a patient presents with M1 prior to neoadjuvant systemic therapy, the stage is considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.
– Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided that the studies are carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received neoadjuvant therapy.
– Postneoadjuvant therapy is designated with yc or yp prefix. No stage group is assigned if there is a complete pathologic response (CR) to neoadjuvant therapy, for example, ypT0ypN0cM0.

 

 

Treatment overview for Breast Cancer

The biology and behavior of breast cancer affects the treatment plan. Some tumors are smaller but grow fast, while others are larger and grow slowly.
Treatment options and recommendations are very personalized and depend on several factors, including:
• The tumor’s subtype, including hormone receptor status (ER, PR) and HER2 status
• The stage of the tumor
• Genomic markers, such as Oncotype DX™ (if appropriate)
• The patient’s age, general health, menopausal status, and preferences
• The presence of known mutations in inherited breast cancer genes, such as BRCA1 or BRCA2

Even though the breast cancer care team will specifically tailor the treatment for each patient and the breast cancer, there are some general steps for treating early-stage and locally advanced breast cancer.

For both DCIS and early-stage invasive breast cancer, doctors generally recommend surgery to remove the tumor. To make sure that the entire tumor is removed, the surgeon will also remove a small area of healthy tissue around the tumor. Although the goal of surgery is to remove all of the visible cancer, microscopic cells can be left behind, either in the breast or elsewhere. In some situations, this means that another surgery could be needed to remove remaining cancer cells.

For larger cancers, or those that are growing more quickly, doctors may recommend systemic treatment with chemotherapy or hormonal therapy before surgery, called neoadjuvant therapy. There may be several benefits to having other treatments before surgery:
• Women who may have needed a mastectomy could have breast-conserving surgery (lumpectomy) if the tumor shrinks before surgery.
• Surgery may be easier to perform.
• Your doctor may find out if certain treatments work well for the cancer.
• Women may also be able to try a new treatment through a clinical trial.

After surgery, the next step in managing early-stage breast cancer is to lower the risk of recurrence and to get rid of any remaining cancer cells. These cancer cells are undetectable but are believed to be responsible for recurrences of cancer as they can grow over time. Treatment given after surgery is called adjuvant therapy.
Adjuvant therapies may include radiation therapy, chemotherapy, targeted therapy, and/or hormonal therapy.

Whether adjuvant therapy is needed depends on the chance that any cancer cells remain in the breast or the body and the chance that a specific treatment will work to treat the cancer. Although adjuvant therapy lowers the risk of recurrence, it does not completely get rid of the risk.

Along with staging, other tools can help estimate prognosis and help you and your doctor make decisions about adjuvant therapy. This includes tests that can predict the risk of recurrence by testing your tumor tissue (such as Oncotype Dx™;). Such tests may also help your doctor better understand the risks from the cancer and whether chemotherapy will help reduce those risks.

When surgery to remove the cancer is not possible, it is called inoperable. The doctor will then recommend treating the cancer in other ways. Chemotherapy, targeted therapy, radiation therapy, and/or hormonal therapy may be given to shrink the cancer.

For recurrent cancer, treatment options depend on how the cancer was first treated and the characteristics of the cancer mentioned above, such as ER, PR, and HER2.

Descriptions of the most common treatment options for early-stage and locally advanced breast cancer are listed below. Your care plan should also include treatment for symptoms and side effects, an important part of cancer care. Take time to learn about all of your treatment options and be sure to ask questions about things that are unclear. Talk with your doctor about the goals of each treatment and what you can expect while receiving the treatment. It is also important to check with your health insurance company before any treatment begins to make sure it is covered.
People older than 65 may benefit from having a geriatric assessment before planning treatment.

 

 

Early/Localized/Operable Breast Cancer


Treatment Option Overview for Early/Localized/Operable Breast Cancer
Surgery:
1. Breast-conserving surgery (lumpectomy) and sentinel node biopsy with or without axillary lymph node dissection for positive sentinel lymph nodes (SLNs).
2. Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction and sentinel node biopsy with or without axillary lymph node dissection for positive SLNs.

Postoperative radiation therapy:
1. Axillary node–negative breast cancer (postmastectomy):
• No additional therapy.
• Radiation therapy.
2. Axillary node–positive breast cancer (postmastectomy):
• For one to three nodes, the role of regional radiation therapy to the infra/supraclavicular nodes, internal mammary nodes, axillary nodes, and chest wall is unclear.
• For four or more nodes or extranodal involvement, regional radiation therapy is advised.
3. Axillary node–negative or positive breast cancer (post–breast-conserving therapy):
• Whole-breast radiation therapy.

Postoperative systemic therapy:
1. Therapy depends on many factors including stage, grade, molecular status of the tumor (e.g., estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2/neu], or triple-negative [ER-negative, PR-negative, and HER2/neu–negative] status).
Adjuvant treatment options may include the following:
• Tamoxifen.
• Aromatase inhibitor (AI) therapy.
• Ovarian function suppression.
• Chemotherapy.

Preoperative systemic therapy:
1. Chemotherapy.
2. HER2 targeted therapy.
3. Endocrine therapy.



Surgery

• Locoregional treatment
• Axillary lymph node management
• Breast reconstruction

Stage I, II, IIIA, and operable IIIC breast cancer often require a multimodal approach to treatment. The diagnostic biopsy and surgical procedure that will be used as primary treatment should be performed as two separate procedures:

Biopsy. In many cases, the diagnosis of breast carcinoma is made by core needle biopsy.

Surgical procedure. After the presence of a malignancy is confirmed by biopsy, the following surgical treatment options can be discussed with the patient before a therapeutic procedure is selected:
        •Breast-conserving surgery.
        •Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction.

To guide the selection of adjuvant therapy, many factors including stage, grade, and molecular status of the tumor (e.g., ER, PR, HER2/neu, or triple-negative status) are considered.

Locoregional treatment
Selection of a local therapeutic approach depends on the following:
• Location and size of the lesion.
• Analysis of the mammogram.
• Breast size.
• Patient’s desire to preserve the breast.

Options for surgical management of the primary tumor include the following:
Breast-conserving surgery plus radiation therapy. All histologic types of invasive breast cancer may be treated with breast-conserving surgery plus radiation therapy. However, the presence of inflammatory breast cancer, regardless of histologic subtype, is a contraindication to breast-conserving therapy. The presence of multifocal disease in the breast and a history of collagen vascular disease are relative contraindications to breast-conserving therapy.
Mastectomy with or without breast reconstruction.

Surgical staging of the axilla should also be performed.

Survival is equivalent with any of these options, as documented in the European Organization for Research and Treatment of Cancer's trial (EORTC-10801) and other prospective randomized trials. Also, a retrospective study of 753 patients who were divided into three groups based on hormone receptor status (ER positive or PR positive; ER negative and PR negative but HER2/neu positive; and triple negative) found no differences in disease control within the breast in patients treated with standard breast-conserving surgery; however, there are not yet substantive data to support this finding.

The rate of local recurrence in the breast with conservative treatment is low and varies slightly with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental mastectomy, and others). Whether completely clear microscopic margins are necessary has been debated. However, a multidisciplinary consensus panel recently used margin width and ipsilateral breast tumor recurrence from a meta-analysis of 33 studies (n = 28,162 patients) as the primary evidence base for a new consensus regarding margins in stage I and stage II breast cancer patients treated with breast-conserving surgery plus radiation therapy. Results of the meta-analysis include the following:

• Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) were associated with a twofold increase in the risk of ipsilateral breast tumor recurrence compared with negative margins.
• More widely clear margins were not found to significantly decrease the rate of ipsilateral breast tumor recurrence compared with no ink on tumor. Thus, it was recommended that the use of no ink on tumor be the new standard for an adequate margin in invasive cancer.
• There was no evidence that more widely clear margins reduced ipsilateral breast tumor recurrence for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.

For patients undergoing partial mastectomy, margins may be positive after primary surgery, often leading to re-excision. A clinical trial of 235 patients with stage 0 to III breast cancer who underwent partial mastectomy, with or without resection of selective margins, randomly assigned patients to have additional cavity shave margins resected (shave group) or not (no-shave group). Patients in the shave group had a significantly lower rate of positive margins than those in the no-shave group (19% vs. 34%, P = .01) and a lower rate of second surgery for clearing margins (10% vs. 21%, P = .02).[Level of evidence: 1iiDiv]

Axillary lymph node management
Axillary node status remains the most important predictor of outcome in breast cancer patients. Evidence is insufficient to recommend that lymph node staging can be omitted in most patients with invasive breast cancer. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%. Another series reported the incidence of axillary node relapse in patients with T1a tumors treated without axillary lymph node dissection (ALND) was 2%.[Level of evidence: 3iiiA]

The axillary lymph nodes are staged to aid in determining prognosis and therapy. SLN biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor; therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium Tc 99m-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients. These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete ALND.

On the basis of the following body of evidence, SLN biopsy is the standard initial surgical staging procedure of the axilla for women with invasive breast cancer. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy.

Evidence (SLN biopsy):
1. A randomized trial of 1,031 women compared SLN biopsy followed by ALND when the SLN was positive with ALND in all patients.[Level of evidence: 1iiC]
• Quality of life (QOL) at 1 year (as assessed by the frequency of patients experiencing a clinically significant deterioration in the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Breast scale) was superior in the SLN biopsy group (23% deteriorating in the SLN biopsy group vs. 35% in the ALND group; P = .001). Arm function was also better in the SLN group.

2. The National Surgical Adjuvant Breast and Bowel Project’s (NSABP-B-32 [NCT00003830]) multicenter phase III trial randomly assigned women (N = 5,611) to undergo either SLN plus ALND or SLN resection alone, with ALND only if the SLNs were positive.[Level of evidence: 1iiA]
• The study showed no detectable difference in overall survival (OS), disease-free survival (DFS), and regional control. OS was 91.8% for SLN plus ALND versus 90.3% for SLN resection alone (P = .12).

On the basis of the following trial results, ALND is unnecessary after a positive SLN biopsy in patients with limited SLN-positive breast cancer treated with breast conservation or mastectomy, radiation, and systemic therapy.

Evidence (ALND after a positive SLN biopsy in patients with limited SLN-positive breast cancer):
1. A multicenter, randomized clinical trial sought to determine whether ALND is required after an SLN biopsy reveals an SLN metastasis of breast cancer. This phase III noninferiority trial planned to randomly assign 1,900 women with clinical T1 or T2 invasive breast cancer without palpable adenopathy and with one to two SLNs containing metastases identified by frozen section to undergo ALND or no further axillary treatment. All patients underwent lumpectomy, tangential whole-breast radiation therapy, and appropriate systemic therapy; OS was the primary endpoint. Because of enrollment challenges, a total of 891 women out of a target enrollment of 1,900 women were randomly assigned to one of the two treatment arms.[Level of evidence: 1iiA]
• At a median follow-up of 6.3 years, 5-year OS was 91.8% (95% confidence interval [CI], 89.1%–94.5%) with ALND and 92.5% (95% CI, 90.0–95.1%) with SLN biopsy alone.
• The secondary endpoint of 5-year DFS was 82.2% (95% CI, 78.3%–86.3%) with ALND and 83.9% (95% CI, 80.2%–87.9%) with SLN biopsy alone.
2. In a similarly designed trial, 929 women with breast tumors smaller than 5 cm and SLN involvement smaller than 2 mm were randomly assigned to ALND or no ALND.[Level of evidence: 1iiA]
• Patients without axillary dissection had fewer DFS events (hazard ratio [HR], 0.78; 95% CI, 0.55–1.11).
• No difference in OS was observed.
3. The AMAROS (NCT00014612) trial studied ALND and axillary radiation therapy after identification of a positive sentinel node.[Level of evidence: 1iiA]
• ALND and axillary radiation therapy provided excellent and comparable axillary control for patients with T1 or T2 primary breast cancer and no palpable lymphadenopathy who underwent breast-conserving therapy or mastectomy.

• The use of axillary radiation therapy was also associated with significantly less morbidity.

For patients who require an ALND, the standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., at least 6–10), while reducing morbidity from the procedure.

Breast reconstruction
For patients who opt for a total mastectomy, reconstructive surgery may be performed at the time of the mastectomy (i.e., immediate reconstruction) or at some subsequent time (i.e., delayed reconstruction). Breast contour can be restored by the following:

• Submuscular insertion of an artificial implant (silicone- or saline-filled). If an immediate implant cannot technically be performed, a tissue expander can be inserted beneath the pectoral muscle. Saline is injected into the expander to stretch the tissues for a period of weeks or months until the desired volume is obtained. The tissue expander is then replaced by a permanent implant. (Visit the U. S. Food and Drug Administration's [FDA's website] for more information on breast implants.)
• Rectus muscle or other flap. Muscle flaps require a considerably more complicated and prolonged operative procedure, and blood transfusions may be required.
After breast reconstruction, radiation therapy can be delivered to the chest wall and regional nodes in either the adjuvant or local recurrent disease setting. Radiation therapy after reconstruction with a breast prosthesis may affect cosmesis, and the incidence of capsular fibrosis, pain, or the need for implant removal may be increased.

 



Postoperative Radiation Therapy

• Post–breast-conserving surgery
• Regional nodal irradiation
• Postmastectomy
• Timing of postoperative radiation therapy
• Late toxic effects of radiation

Radiation therapy is regularly employed after breast-conserving surgery. Radiation therapy is also indicated for high-risk postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence.

Post–breast-conserving surgery
For women who are treated with breast-conserving surgery without radiation therapy, the risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node–negative women. Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, a large meta-analysis demonstrated a significant reduction in risk of recurrence and breast cancer death. Thus, evidence supports the use of whole-breast radiation therapy after breast-conserving surgery.

Evidence (breast-conserving surgery followed by radiation therapy):
1. A 2011 meta-analysis of 17 clinical trials performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), which included over 10,000 women with early-stage breast cancer, supported whole-breast radiation therapy after breast-conserving surgery.[Level of evidence: 1iiA]
        • Whole-breast radiation therapy resulted in a significant reduction in the 10-year risk of recurrence compared with breast-conserving surgery alone (19% for whole-breast radiation therapy vs. 35% for breast-conserving surgery alone; relative risk (RR) = 0.52; 95% CI, 0.48–0.56) and a significant reduction in the 15-year risk of breast cancer death (21% for whole-breast radiation therapy vs. 25% for breast-conserving surgery alone; RR, 0.82; 95% CI, 0.75–0.90).

With regard to radiation dosing and schedule, the following has been noted:

Whole-breast radiation dose. Conventional whole-breast radiation therapy is delivered to the whole breast (with or without regional lymph nodes) in 1.8 Gy to 2 Gy daily fractions over about 5 to 6 weeks to a total dose of 45 Gy to 50 Gy.
Radiation boost. A further radiation boost is commonly given to the tumor bed. Two randomized trials conducted in Europe have shown that using boosts of 10 Gy to 16 Gy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years (P = .044),[Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001)[Level of evidence: 1iiDiii] Results were similar after a median follow-up of 17.2 years.[Level of evidence: 1iiDii] If a boost is used, it can be delivered either by external-beam radiation therapy, generally with electrons, or by using an interstitial radioactive implant.
Radiation schedule. Some studies show that a shorter fractionation schedule of 42.5 Gy over 3 to 4 weeks is a reasonable alternative for some breast cancer patients.
        • A noninferiority trial of 1,234 randomly assigned patients with node-negative invasive breast cancer analyzed locoregional recurrence rates with conventional whole-breast radiation therapy versus a shorter fractionation schedule. The 10-year locoregional relapse rate among women who received shorter fractionation was not inferior to conventional whole-breast radiation therapy (6.2% for a shorter fractionation schedule vs. 6.7% for whole-breast radiation therapy with absolute difference, 0.5 percentage points; 95% CI, −2.5 to 3.5).[Level of evidence: 1iiDii
        • Similarly, a combined analysis of the randomized United Kingdom Standardisation of Breast Radiotherapy trials (START), (START-A [ISRCTN59368779]) and START-B [ISRCTN59368779]), which collectively randomly assigned 4,451 women with completely excised invasive (pT1–3a, pN0–1, M0) early-stage breast cancer after breast-conserving surgery to receive conventional whole-breast radiation therapy dosing or shorter fractionation, revealed no difference in a 10-year locoregional relapse rate.[Level of evidence: 1iiDii]
        • A meta-analysis that included the three trials mentioned above plus six others confirmed that differences with respect to local recurrence or cosmesis between shorter and conventional fractionation schedules were neither statistically nor clinically significant.

Additional studies are needed to determine whether shorter fractionation is appropriate for women with higher nodal disease burden.

Regional nodal irradiation
Regional nodal irradiation is routinely given postmastectomy to patients with involved lymph nodes; however, its role in patients who have breast-conserving surgery and whole-breast irradiation has been less clear. A randomized trial (NCT00005957) of 1,832 women showed that administering regional nodal irradiation after breast-conserving surgery and whole-breast irradiation reduces the risk of recurrence (10-year DFS, 82.0% vs. 77.0%; HR, 0.76; 95% CI, 0.61–0.94; P = .01) but does not affect survival (10-year OS, 82.8% vs. 81.8%; HR, 0.91; 95% CI, 0.72–1.13; P = .38).[Level of evidence: 1iiA]

Similar findings were reported from the EORTC trial (NCT00002851). Women with a centrally or medially located primary tumor with or without axillary node involvement, or an externally located tumor with axillary involvement, were randomly assigned to receive whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation or not. Breast-conserving surgery was performed for 76.1% of the study population, and the remaining study population underwent mastectomy. No improvement in OS was seen at 10 years among patients who underwent regional nodal irradiation when compared with patients who did not undergo regional nodal radiation (82.3% vs. 80.7%, P = .06). Distant DFS was improved among patients who underwent regional nodal irradiation when compared with patients who did not undergo regional nodal irradiation (78% vs. 75%, P = .02).[Level of evidence: 1iiA]

A meta-analysis that combined the results of the two trials mentioned above found a marginally statistically significant difference in OS (HR, 0.88; 95% CI, 0.78–0.99; P = .034; absolute difference, 1.6% at 5 years).

Postmastectomy
Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given to selected patients considered at high risk for locoregional failure after mastectomy.
Patients at highest risk for local recurrence have one or more of the following:
• Four or more positive axillary nodes.
• Grossly evident extracapsular nodal extension.
• Large primary tumors.
• Very close or positive deep margins of resection of the primary tumor.


In this high-risk group, radiation therapy can decrease locoregional recurrence, even among those patients who receive adjuvant chemotherapy.
Patients with one to three involved nodes without any of the high-risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting is unclear.


Evidence (postoperative radiation therapy in patients with one to three involved lymph nodes):
1.The 2005 EBCTCG meta-analysis of 42,000 women in 78 randomized treatment comparisons indicated that radiation therapy is beneficial, regardless of the number of lymph nodes involved.[Level of evidence: 1iiA]
        • For women with node-positive disease postmastectomy and axillary clearance (removal of axillary lymph nodes and surrounding fat), radiation therapy reduced the 5-year local recurrence risk from 23% to 6% (absolute gain, 17%; 95% CI, 15.2%–18.8%). This translated into a significant reduction (P = .002) in breast cancer mortality, 54.7% versus 60.1%, with an absolute gain of 5.4% (95% CI, 2.9%–7.9%).
        • In subgroup analyses, the 5-year local recurrence rate was reduced by 12% (95% CI, 8%–16%) for women with one to three involved lymph nodes and by 14% (95% CI, 10%–18%) for women with four or more involved lymph nodes. In an updated meta-analysis of 1,314 women with axillary dissection and one to three positive nodes, radiation therapy reduced locoregional recurrence (2P < .00001), overall recurrence (RR, 0.68; 95% CI, 0.57–0.82; 2P = .00006), and breast cancer mortality (RR, 0.80; 95% CI, 0.67–0.95; 2P = .01).[Level of evidence: 1iiA]
        • In contrast, for women at low-risk of local recurrence with node-negative disease, the absolute reduction in 5-year local recurrence was only 4% (P = .002; 95% CI, 1.8%–6.2%), and there was not a statistically significant reduction in 15-year breast cancer mortality (absolute gain, 1.0%; P > .1; 95% CI, -0.8%–2.8%).

Further, an analysis of NSABP trials showed that even in patients with large (>5 cm) primary tumors and negative axillary lymph nodes, the risk of isolated locoregional recurrence was low enough (7.1%) that routine locoregional radiation therapy was not warranted.

Timing of postoperative radiation therapy
The optimal sequence of adjuvant chemotherapy and radiation therapy after breast-conserving surgery has been studied. Based on the following studies, delaying radiation therapy for several months after breast-conserving surgery until the completion of adjuvant chemotherapy does not appear to have a negative impact on overall outcome. Additionally, initiating chemotherapy soon after breast-conserving surgery may be preferable for patients at high risk of distant dissemination.

Evidence (timing of postoperative radiation therapy):
1. In a randomized trial, patients received one of the following regimens:[Level of evidence: 1iiA]
        a. Chemotherapy first (n = 122), consisting of cyclophosphamide, methotrexate, fluorouracil (5-FU), and prednisone (CMFP) plus doxorubicin repeated every 21 days for four cycles, followed by breast radiation.
        b. Breast radiation first (n = 122), followed by the same chemotherapy.

The following results were observed:
        • With a median follow-up of 5 years, OS was 73% for the radiation-first group and 81% for the chemotherapy-first group (P = .11).
        •The 5-year crude rate of first recurrence by site was 5% in the radiation-first group and 14% in the chemotherapy-first group for local recurrence and 32% in the radiation-first group and 20% in the chemotherapy-first group for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = .07).
        • Further analyses revealed that differences in recurrence patterns persisted for most subgroups with the exception of those who had either negative tumor margins or one to three positive lymph nodes. For these two subgroups, sequence assignment made little difference in local or distant recurrence rates, although the statistical power of these subgroup analyses was low.
        • Potential explanations for the increase in distant recurrence noted in the radiation-first group are that chemotherapy was delayed for a median of 17 weeks after surgery, and that this group received lower chemotherapy dosages because of increased myelosuppression.

2. Two additional randomized trials, though not specifically designed to address the timing of radiation therapy and adjuvant chemotherapy, do add useful information.
        a. In the NSABP-B-15 trial, patients who had undergone breast-conserving surgery received either one course of cyclophosphamide, methotrexate, fluorouracil (5-FU) (CMF) (n = 194) followed by radiation therapy followed by five additional cycles of CMF, or they received four cycles of doxorubicin and cyclophosphamide (AC) (n = 199) followed by radiation therapy.[Level of evidence: 1iiA]
                • No differences in DFS, distant DFS, and OS were observed between these two arms.
        b. The International Breast Cancer Study Group trials VI and VII also varied the timing of radiation therapy with CMF adjuvant chemotherapy and reported results similar to NSABP-B-15.

These studies showed that delaying radiation therapy for 2 to 7 months after surgery had no effect on the rate of local recurrence. These findings have been confirmed in a meta-analysis.[Level of evidence: 1iiA]

In an unplanned analysis of patients treated on a phase III trial evaluating the benefit of adding trastuzumab in HER2/neu–positive breast cancer patients, there was no associated increase in acute adverse events or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab. Therefore, delivering radiation therapy concomitantly with trastuzumab appears to be safe and avoids additional delay in radiation therapy treatment initiation.

Late toxic effects of radiation
Late toxic effects of radiation therapy are uncommon, and can be minimized with current radiation delivery techniques and with careful delineation of the target volume. Late effects of radiation include the following:

Radiation pneumonitis. In a retrospective analysis of 1,624 women treated with conservative surgery and adjuvant breast radiation at a single institution, the overall incidence of symptomatic radiation pneumonitis was 1.0% at a median follow-up of 77 months. The incidence of pneumonitis increased to 3.0% with the use of a supraclavicular radiation field and to 8.8% when concurrent chemotherapy was administered. The incidence was only 1.3% in patients who received sequential chemotherapy.[Level of evidence: 3iii]

Cardiac events. Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, was associated with increased cardiac mortality. In women treated with radiation therapy before 1980, an increased cardiac death rate was noted after 10 to 15 years, compared with women with nonradiated or right-side-only radiated breast cancer. This was probably caused by the radiation received by the left myocardium. Modern radiation therapy techniques introduced in the 1990s minimized deep radiation to the underlying myocardium when left-sided chest wall or left-breast radiation was used. Cardiac mortality decreased accordingly.

An analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER) data from 1973 to 1989 reviewing deaths caused by ischemic heart disease in women who received breast or chest wall radiation showed that since 1980, no increased death rate resulting from ischemic heart disease in women who received left chest wall or breast radiation was found.[Level of evidence: 3iB]

Arm lymphedema. Lymphedema remains a major quality-of-life concern for breast cancer patients. Single-modality treatment of the axilla (surgery or radiation) is associated with a low incidence of arm edema. In patients who receive axillary dissection, adjuvant radiation therapy increases the risk of arm edema. Edema occurs in 2% to 10% of patients who receive axillary dissection alone compared with 13% to 18% of patients who receive axillary dissection and adjuvant radiation therapy. (Refer to the PDQ summary on Lymphedema for more information.)

Brachial plexopathy. Radiation injury to the brachial plexus after adjuvant nodal radiation therapy is a rare clinical entity for breast cancer patients. In a single-institution study using current radiation techniques, 449 breast cancer patients treated with postoperative radiation therapy to the breast and regional lymphatics were monitored for 5.5 years to assess the rate of brachial plexus injury. The diagnosis of such injury was made clinically with computerized tomography (CT) to distinguish radiation injury from tumor recurrence.
When 54 Gy in 30 fractions was delivered to the regional nodes, the incidence of symptomatic brachial plexus injury was 1.0%, compared with 5.9% when increased fraction sizes (45 Gy in 15 fractions) were used.

Contralateral breast cancer. One report suggested an increase in contralateral breast cancer for women younger than 45 years who received chest wall radiation therapy after mastectomy. No increased risk of contralateral breast cancer occurred in women aged 45 years and older who received radiation therapy.
Techniques to minimize the radiation dose to the contralateral breast are used to keep the absolute risk as low as possible.

Risk of second malignancy. The rate of second malignancy after adjuvant radiation therapy is very low. Sarcomas in the treated field are rare, with a long-term risk of 0.2% at 10 years. In nonsmokers, the risk of lung cancer as a result of radiation exposure during treatment is minimal when current dosimetry techniques are used. Smokers, however, may have a small increased risk of lung cancer in the ipsilateral lung.

 



Postoperative Systemic Therapy

Adjuvant therapy

• Chemotherapy
• HER2/neu–negative breast cancer
• HER2/neu–positive breast cancer
• Hormone receptor–positive breast cancer
• Bisphosphonates


Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. For example, hormone receptor (ER and/or PR)–positive patients will receive hormone therapy. HER2 overexpression is an indication for using adjuvant trastuzumab, usually in combination with chemotherapy. When neither HER2 overexpression nor hormone receptors are present (i.e., triple-negative breast cancer), adjuvant therapy relies on chemotherapeutic regimens, which may be combined with investigational targeted approaches.

An international consensus panel proposed a risk classification system and systemic therapy treatment options. This classification, with some modification, is described below:

The selection of therapy is most appropriately based on knowledge of an individual’s risk of tumor recurrence balanced against the short-term and long-term risks of adjuvant treatment. This approach allows clinicians to help individuals determine if the gains anticipated from treatment are reasonable for their particular situation.

The treatment options described below should be modified based on both patient and tumor characteristics.


 

Chemotherapy

Adjuvant Chemotherapy

Adjuvant chemotherapy 1970s to 2000: Anthracycline-based regimens versus cyclophosphamide, methotrexate, and fluorouracil (CMF)

The EBCTCG meta-analysis analyzed 11 trials that began from 1976 to 1989 in which women were randomly assigned to receive regimens containing anthracyclines (e.g., doxorubicin or epirubicin) or CMF (cyclophosphamide, methotrexate, and fluorouracil). The result of the overview analysis comparing CMF and anthracycline-containing regimens suggested a slight advantage for the anthracycline regimens in both premenopausal and postmenopausal women.

Adjuvant chemotherapy 2000s to present: The role of adding taxanes to adjuvant therapy

A number of trials have addressed the benefit of adding a taxane (paclitaxel or docetaxel) to an anthracycline-based adjuvant chemotherapy regimen for women with node-positive breast cancer.

1. A literature-based meta-analysis of 13 studies demonstrated that the inclusion of a taxane improved both DFS and OS (DFS: HR, 0.83; 95% CI, 0.79–0.87; P < .001; OS: HR, 0.85; 95% CI, 0.79–0.91; P < .001).[Level of evidence: 1iiA]

2. A U.S. intergroup study (CLB-9344) randomly assigned women with node-positive tumors to three dose levels of doxorubicin (60, 75, and 90 mg/m2) and a fixed dose of cyclophosphamide (600 mg/m2) every 3 weeks for four cycles. After AC (doxorubicin and cyclophosphamide) chemotherapy, patients were randomly assigned for a second time to receive paclitaxel (175 mg/m2) every 3 weeks for four cycles or no further therapy, and women with hormone receptor–positive tumors also received tamoxifen for 5 years.[Level of evidence: 1iiA]
        • Although the dose-escalation of doxorubicin was not beneficial, the addition of paclitaxel resulted in statistically significant improvements in DFS (5%) and OS (3%).

3, The NSABP-B-28 trial randomly assigned 3,060 women with node-positive breast cancer to receive four cycles of postoperative AC or four cycles of AC followed by four cycles of paclitaxel. Women younger than 50 years with receptor-positive disease and all women older than 50 years received tamoxifen.[Level of evidence: 1iiA]
        • DFS was significantly improved by the addition of paclitaxel (HR, 0.83; 95% CI, 0.72–0.96; P = .006; 5-year DFS, 76% vs. 72%).
        • The difference in OS was small (HR, 0.93), however, and not statistically significant (P = .46).

4. In the Breast Cancer International Research Group's trial (BCIRG-001), the FAC regimen was compared with the docetaxel plus doxorubicin and cyclophosphamide (TAC) regimen in 1,491 women with node-positive disease. Six cycles of either regimen were given as adjuvant postoperative therapy.[Level of evidence: 1iiA]
        • There was a 75% DFS rate at 5 years in the TAC group compared with a 68% DFS rate in the FAC group (P = .001).
        • TAC was associated with a 30% overall lower risk of death (5% absolute difference) than was FAC (HR, 0.70; 98% CI, 0.53–0.91; P < .008).
        • Anemia, neutropenia, febrile neutropenia, and infections were more common in the TAC group. No deaths were associated with infections in either group.

5. An Eastern Cooperative Oncology Group–led intergroup trial (E1199 [NCT00004125]) involving 4,950 patients compared, in a factorial design, two schedules (weekly and every 3 weeks) of the two drugs (docetaxel vs. paclitaxel) after standard-dose AC chemotherapy given every 3 weeks.Level of evidence: 1iiA] Study findings include the following:
        • There was no difference observed in the overall comparison with regard to DFS of docetaxel to paclitaxel (odds ratio [OR], 1.03; 95% CI, 0.91–1.16; P = .61) or between the 1-week and 3-week schedules (OR, 1.06; 95% CI, 0.94–1.20; P = .33).
        • There was a significant association between the drug administered and schedule for both DFS (0.003) and OS (0.01). Thus, compared with paclitaxel given every 3 weeks, paclitaxel given weekly improved both DFS (OR, 1.27; 95% CI, 1.01–1.57; P = .006) and OS (OR, 1.32; 95% CI, 1.02–1.72; P = .01).
        • Docetaxel given every 3 weeks was also superior in DFS to paclitaxel given every 3 weeks (OR, 1.23; 95% CI, 1.00–1.52; P = .02), but the difference was not statistically significant for OS (OR, 1.13; 95% CI, 0.88–1.46; P = .25).
        • Docetaxel given weekly was not superior to paclitaxel given every 3 weeks. There was no stated a priori basis for expecting that varying the schedule of administration would have opposite effects for the two drugs.

Chemotherapy schedule: Dose-density
Historically, adjuvant chemotherapy for breast cancer was given on an every 3-week schedule. Studies sought to determine whether decreasing the duration between chemotherapy cycles could improve clinical outcomes. The overall results of these studies support the use of dose-dense chemotherapy for women with HER2-negative breast cancer.
(See 4 Evidences)

Docetaxel and cyclophosphamide
Docetaxel and cyclophosphamide is an acceptable adjuvant chemotherapy regimen.

Evidence (docetaxel and cyclophosphamide):
1.The regimen of docetaxel and cyclophosphamide (TC) compared with AC (doxorubicin and cyclophosphamide) was studied in 1,016 women with stage I or stage II invasive breast cancer. Patients were randomly assigned to receive four cycles of either TC or AC as adjuvant postoperative therapy.[Level of evidence: 1iiA]
        a. At 7 years, the DFS and OS demonstrated that four cycles of TC were superior to standard AC for both DFS and OS.
                • DFS was significantly superior for TC compared with AC (81% vs. 75%, HR, 0.74; 95% CI, 0.56–0.98; P = .033).
                • OS was significantly superior for TC compared with AC (87% vs. 82%, HR, 0.69; 95% CI, 0.50–0.97; P = .032).
        b. Patients had fewer cardiac-related toxic effects with TC than with AC, but they had more myalgia, arthralgia, edema, and febrile neutropenia.

Timing of postoperative chemotherapy
The optimal time to initiate adjuvant therapy is uncertain. A retrospective, observational study has reported the following:

1. A single-institution study of early-stage breast cancer patients diagnosed between 1997 and 2011 revealed that delays in initiation of adjuvant chemotherapy adversely affected survival outcomes.[Level of evidence: 3iiiA]
        • Initiation of chemotherapy 61 days or more after surgery was associated with adverse outcomes among patients with stage II breast cancer (distant relapse-free survival [DRFS]: HR, 1.20; 95% CI, 1.02–1.43) and stage III breast cancer (OS: HR, 1.76; 95% CI, 1.26–2.46; RFS: HR, 1.34; 95% CI, 1.01–1.76; and DRFS: HR, 1.36; 95% CI, 1.02–1.80).
        • Patients with triple-negative breast cancer (TNBC) tumors and those with HER2-positive tumors treated with trastuzumab who started chemotherapy 61 days or more after surgery had worse survival (TNBC: HR, 1.54; 95% CI, 1.09–2.18; HER2-positive: HR, 3.09; 95% CI, 1.49–6.39) than did those who initiated treatment in the first 30 days after surgery.
        • Because of the weaknesses and limitations of this study design, the optimal time to initiate adjuvant chemotherapy remains uncertain.

Toxic effects of chemotherapy
Adjuvant chemotherapy is associated with several well-characterized toxic effects that vary according to the individual drugs used in each regimen.

 

 

HER2/neu–negative breast cancer

Adjuvant Chemotherapy

For HER2/neu–negative breast cancer, there is no single adjuvant chemotherapy regimen that is considered standard or superior to another. Preferred regimen options vary by institution, geographic region, and clinician.

Some of the most important data on the benefit of adjuvant chemotherapy came from the EBCTCG, which reviews data from global breast cancer trials every 5 years. In the 2011 EBCTCG meta-analysis, adjuvant chemotherapy using an anthracycline-based regimen compared with no treatment revealed significant improvement in the risk of recurrence (RR, 0.73; 95% CI, 0.68–0.79), significant reduction in breast cancer mortality (RR, 0.79; 95% CI, 0.72–0.85), and significant reduction in overall mortality (RR, 0.84; 95% CI, 0.78–0.91), which translated into an absolute survival gain of 5%.

Triple-negative breast cancer (TNBC)
TNBC is defined as the absence of staining for ER, PR, and HER2/neu. TNBC is insensitive to some of the most effective therapies available for breast cancer treatment including HER2-directed therapy such as trastuzumab and endocrine therapies such as tamoxifen or the aromatase inhibitors.

Combination chemotherapy
Combination cytotoxic chemotherapy administered in a dose-dense or metronomic schedule remains the standard therapy for early-stage TNBC.

Evidence (neoadjuvant chemotherapy on a dose-dense or metronomic schedule for TNBC):
1. A prospective analysis studied 1,118 patients who received neoadjuvant chemotherapy at a single institution, of whom 255 (23%) had TNBC.[Level of evidence: 3iiDiv]
        • The study observed that patients with TNBC had higher pathologic complete response (pCR) rates than did non-TNBC patients (22% vs. 11%; P = .034). Improved pCR rates may be important because in some studies, pCR is associated with improved long-term outcomes.

Platinum agents
Platinum agents have emerged as drugs of interest for the treatment of TNBC. However, there is no established role for adding them to the treatment of early-stage TNBC outside of a clinical trial.
One trial that treated 28 women with stage II or stage III TNBC with four cycles of neoadjuvant cisplatin resulted in a 22% pCR rate.[Level of evidence: 3iiiDiv]
A randomized clinical trial, CALGB-40603 (NCT00861705), evaluated the benefit of carboplatin added to paclitaxel and doxorubicin plus cyclophosphamide chemotherapy in the neoadjuvant setting. The Triple Negative Trial (NCT00532727) is evaluating carboplatin versus docetaxel in the metastatic setting. These trials will help to define the role of platinum agents for the treatment of TNBC.

Poly (ADP-ribose) polymerase (PARP) inhibitor agents
The PARP inhibitors are being evaluated in clinical trials for patients with BRCA mutations and in TNBC. PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. Because TNBC shares multiple clinicopathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms, it is possible that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death.

 

 

HER2/neu–positive breast cancer

Adjuvant therapy

Treatment options for HER2-positive early breast cancer:
Standard treatment for HER2-positive early breast cancer is 1 year of adjuvant trastuzumab therapy.

Trastuzumab
Several phase III clinical trials have addressed the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2-overexpressing cancers. Study results confirm the benefit of 12 months of adjuvant trastuzumab therapy.

Evidence (duration of trastuzumab therapy):
1. The Herceptin Adjuvant (HERA) (BIG-01-01 [NCT00045032]) trial examined whether the administration of trastuzumab was effective as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, plus or minus locoregional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[Level of evidence: 1iiA] Patients were randomly assigned to one of three study arms:
        • Observation (n = 1,693).
        • 1 year of trastuzumab (n = 1,694).
        • 2 years of trastuzumab (n = 1,694).

Of the patients in the comparison of 1 year of trastuzumab versus observation group, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor (ER and PR)–negative disease.[Level of evidence: 1iiA]

    a. One year of trastuzumab versus observation:
        • Patients who were treated with 1 year of trastuzumab experienced a 46% lower risk of a first event (HR, 0.54; 95% CI, 0.43–0.67; P < .001), corresponding to an absolute DFS benefit of 8.4% at 2 years (95% CI, 2.1–14.8). The updated results at 23.5 months of follow-up showed an unadjusted HR for the risk of death with trastuzumab compared with observation of 0.66 (95% CI, 0.47–0.91; P = .0115), corresponding to an absolute OS benefit of 2.7%.
        • There were 218 DFS events reported in the trastuzumab group, compared with 321 DFS events reported in the observation group. The unadjusted HR for the risk of an event with trastuzumab was 0.64 (0.54–0.76; P < .001), corresponding to an absolute DFS benefit of 6.3%.
        • The benefit of 1 year of trastuzumab over observation persisted, despite crossover of 52% of the patients on observation (HR, 0.76; 95% CI, 0.65–0.88; P = .0005).
    b. One year versus 2 years of trastuzumab:
        • After a median follow-up of 8 years, the results of the comparison of 1 year versus 2 years of trastuzumab were analyzed. No difference in DFS was found between the groups (HR, 0.99; 95% CI, 0.85–1.14; P = .86).

2. In the combined analysis of the NSABP-B-31 (NCT00004067) and intergroup NCCTG-N9831 (NCT00005970) trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.[Level of evidence: 1iiA]
        • The HERA results were confirmed in a joint analysis of the two studies, with a combined enrollment of 3,676 patients. A highly statistically significant improvement in DFS (HR, 0.48; P < .001; 3-year DFS, 87% vs. 75%) was observed, as was a significant improvement in OS (HR, 0.67; P = .015; 3-year OS, 94.3% in the trastuzumab group vs. 91.7% in the control group; 4-year OS, 91.4% in the trastuzumab group vs. 86.6% in the control group).
        • Patients treated with trastuzumab experienced a longer DFS, with a 52% lower risk of a DFS event (HR, 0.48; 95% CI, 0.39–0.59; P < .001), corresponding to an absolute difference in DFS of 11.8% at 3 years and 18% at 4 years. The risk of distant recurrence in patients treated with trastuzumab was 53% lower (HR, 0.47; 95% CI, 0.37–0.61; P < .001), and the risk of death was 33% lower (HR, 0.67; 95% CI, 0.48–0.93; P = .015).
        • In an updated analysis with a median follow-up of 8.4 years, the addition of trastuzumab to chemotherapy led to a 37% relative improvement in OS (HR, 0.63; 95% CI, 0.54–0.73; P < .001) and an increase in the 10-year OS rate from 75.2% to 84%.

3. In the BCIRG-006 (NCT00021255) trial, 3,222 women with early-stage HER2-overexpressing breast cancer were randomly assigned to receive AC followed by docetaxel (AC-T), AC followed by docetaxel plus trastuzumab (AC-T plus trastuzumab), or docetaxel, carboplatin, plus trastuzumab (TCH, a nonanthracycline-containing regimen).[Level of Evidence: 1iiA]
        • A significant DFS and OS benefit was seen in both groups treated with trastuzumab compared with the control group that did not receive trastuzumab.
        • For patients receiving AC-T plus trastuzumab, the 5-year DFS rate was 84% (HR for the comparison with AC-T, 0.64; P < .001), and the OS rate was 92% (HR, 0.63; P < .001). For patients receiving TCH, the 5-year DFS rate was 81% (HR, 0.75; P = .04), and the OS rate was 91% (HR, 0.77; P = .04). The control group had a 5-year DFS rate of 75% and an OS rate of 87%.
        • The authors stated that there was no significant difference in DFS or OS between the two trastuzumab-containing regimens. However, the study was not powered to detect equivalence between the two trastuzumab-containing regimens.
        • The rates of congestive heart failure (CHF) and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P < .001).
        • These trial findings raise the question of whether anthracyclines are needed for the adjuvant treatment of HER2-overexpressing breast cancer. The group receiving AC-trastuzumab showed a small but not statistically significant benefit over TCH.
        • This trial supports the use of TCH as an alternative adjuvant regimen for women with early-stage HER2-overexpressing breast cancer, particularly in those with concerns about cardiac toxic effects.

4. The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab. In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2-overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC.[Level of evidence: 1iiA]
        • At a 3-year median follow-up, the risk of recurrence and/or death was significantly reduced in patients receiving trastuzumab (HR, 0.41; P = .01; 95% CI, 0.21–0.83; 3-year DFS, 89% vs. 78%).
        • The difference in OS (HR, 0.41) was not statistically significant (P = .07; 95% CI, 0.16–1.08).
5. In contrast, another study failed to demonstrate that 6 months of adjuvant trastuzumab was noninferior to 12 months of treatment.[Level of evidence: 1iiA]
        • A 2-year DFS rate was 93.8% (95% CI, 92.6–94.9) in the 12-month group and 91.1% (89.7–92.4) in the 6-month group (HR, 1.28; 95% CI, 1.05–1.56; noninferiority, P = .29).
        • Similar results were noted in a larger, multicenter, randomized study led by the Hellenic Oncology Research Group.[Level of evidence: 1iiA]
        • Therefore, 12 months should remain the standard duration of trastuzumab adjuvant therapy.

A number of studies have evaluated the use of subcutaneous (SQ) trastuzumab in the neoadjuvant and adjuvant settings.

Cardiac toxic effects with adjuvant trastuzumab
Cardiac events associated with adjuvant trastuzumab have been reported in multiple studies. Key study results include the following:
        • In the HERA (BIG-01-01) trial, severe CHF (New York Heart Association class III–IV) occurred in 0.6% of patients treated with trastuzumab. Symptomatic CHF occurred in 1.7% of patients in the trastuzumab arm and 0.06% of patients in the observation arm.
        • In the NSABP B-31 (NCT00004067) trial, 31 of 850 patients in the trastuzumab arm had confirmed symptomatic cardiac events, compared with 5 of 814 patients in the control arm. The 3-year cumulative incidence of cardiac events for trastuzumab-treated patients was 4.1%, compared with 0.8% of patients in the control arm (95% CI, 1.7%–4.9%).
        • In the NCCTG-N9831 trial, 39 cardiac events were reported in the three arms over a 3-year period. The 3-year cumulative incidence of cardiac events was 0.35% in arm A (no trastuzumab), 3.5% in arm B (trastuzumab after paclitaxel), and 2.5% in arm C, (trastuzumab concomitant with paclitaxel).
        • In the AVENTIS-TAX-GMA-302 (BCIRG 006) (NCT00021255) trial, clinically symptomatic cardiac events were detected in 0.38% of patients in the AC/docetaxel (AC-D) arm, 1.87% of patients in the AC/docetaxel/trastuzumab (AC-DH) arm, and 0.37% of patients in the docetaxel/carboplatin/trastuzumab (DCbH) arm. There was also a statistically significant higher incidence of asymptomatic and persistent decrease in left ventricular ejection fraction (LVEF) in the AC-DH arm than with either the AC-D or DCbH arms.
        • In the FINHER trial, none of the patients who received trastuzumab experienced clinically significant cardiac events. LVEF was preserved in all of the women receiving trastuzumab, but the number of patients receiving adjuvant trastuzumab was very low.

Lapatinib
Lapatinib is a small-molecule tyrosine kinase inhibitor that is capable of dual-receptor inhibition of both epidermal growth factor receptor and HER2. There are no data supporting the use of lapatinib as part of adjuvant treatment of early-stage HER2/neu–positive breast cancer.

Evidence (against the use of lapatinib for HER2-positive early breast cancer):
1. In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (ALTTO [NCT00553358]), the role of lapatinib (in combination with, in sequence to, in comparison with, or as an alternative to trastuzumab) in the adjuvant setting was investigated.[Level of evidence: 1iiA]
        • In the primary analysis, at the median follow-up of 4.5 years (range, 1 day–6.4 years), a 16% reduction in the HR for DFS was observed in the lapatinib-plus-trastuzumab arm, compared with the trastuzumab-alone arm (555 DFS events; HR, 0.84; 97.5% CI, 0.70–1.02; P = .048), which was not statistically significant at the .025 significance level.
        • The HR for DFS for the superiority comparison of trastuzumab to lapatinib versus trastuzumab alone in the intention-to-treat population was 0.96 (97.5% CI, 0.80–1.15; P = .61).
        • The 4-year OS was 95% for the lapatinib-plus-trastuzumab arm, 95% for the trastuzumab-to-lapatinib arm, and 94% for the trastuzumab-alone arm. The HR for OS was 0.80 (95% CI, 0.62–1.03; P = .078) for the comparison of lapatinib plus trastuzumab versus trastuzumab alone and 0.91 (95% CI, 0.71–1.16; P = .433) for the comparison of trastuzumab to lapatinib versus trastuzumab alone.
        • The lapatinib-versus-trastuzumab component of the study was closed because, at interim analysis, the HR for DFS was 1.52 in favor of trastuzumab alone and noninferiority was excluded.
        • Combination therapy with lapatinib and trastuzumab also resulted in worsened grade 3 diarrhea (15% vs. 1%), grade 3 rash (5% vs. 1%), and grade 3 hepatobiliary adverse events (3% vs. 1%) compared with trastuzumab alone.

Pertuzumab
Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Its use, in combination with trastuzumab, has been evaluated in a randomized trial in the postoperative setting.

Evidence (pertuzumab):
1. The Breast Intergroup (BIG) trial enrolled 4,805 women with HER2-positive cancer cells in a blinded comparison study for 12 months of trastuzumab plus placebo versus 12 months of trastuzumab plus pertuzumab, which were given in conjunction with standard chemotherapy and hormone therapy.
        • At the time of the final analysis of the primary endpoint (breast cancer, RFS), there was a significant difference in favor of the combination regimen (HR, 0.81; 95% CI, 0.66–1.00; P = .045; 3-year invasive DFS, 94.1% vs. 93.2%).
        • There was no statistically significant difference in OS at the first interim analysis for this endpoint.
        • Patients receiving pertuzumab had more grade 3 diarrhea (9.8% vs. 3.7%) and were more likely to develop heart failure (0.6% vs. 0.2%).

Neratinib
Neratinib is an irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4, which has been approved by the FDA for the extended adjuvant treatment of patients with early-stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy.

Evidence (Neratinib):
1. In the ExteNET (NCT00878709) trial, the safety and efficacy of 12 months of adjuvant neratinib was investigated in patients with early-stage HER2-positive breast cancer (n = 2,840) who had completed (neo) adjuvant trastuzumab up to 2 years before randomization. Patients received neratinib 240 mg oral daily for 1 year or a placebo.[Level of evidence: 1iiA]
        • The primary endpoint was invasive DFS at 2 years after randomization. Invasive DFS at 2 years was 93.9% (95% CI, 92.4–95.2) in the neratinib group and 91.6% (95% CI, 90.0–93.0) in the placebo group.
        • OS data are not mature.
        • The most common grade 1/2 adverse events included diarrhea (55% with neratinib vs. 34% with placebo), nausea (41% vs. 21%), fatigue (25% vs. 20%), vomiting (23% vs. 8%) and abdominal pain (22% vs. 10%). Prophylactic loperamide is recommended in the FDA label during the first 56 days of therapy, and as needed thereafter to help manage diarrhea.
        • The most common grade 3/4 adverse event was diarrhea (40% with neratinib vs. 2% with placebo). All other grade 3/4 adverse events occurred in 2% or less of patients.

 

 

Hormone receptor–positive breast cancer

Adjuvant therapy

Much of the evidence presented in the following sections on therapy for women with hormone receptor–positive disease has been considered in an American Society of Clinical Oncology guideline that describes several options for the management of these patients.[128]

128. Burstein HJ, Temin S, Anderson H, et al.: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J Clin Oncol 32 (21): 2255-69, 2014. [PUBMED Abstract]

Tamoxifen
Tamoxifen has been shown to be of benefit to women with hormone receptor–positive breast cancer.

Evidence (tamoxifen for hormone receptor–positive early breast cancer):
1. The EBCTCG performed a meta-analysis of systemic treatment of early breast cancer by hormone, cytotoxic, or biologic therapy methods in randomized trials involving 144,939 women with stage I or stage II breast cancer. An analysis published in 2005 included information on 80,273 women in 71 trials of adjuvant tamoxifen.[Level of evidence: 1iiA]
        • In this analysis, the benefit of tamoxifen was found to be restricted to women with hormone receptor–positive or hormone receptor–unknown breast tumors. In these women, the 15-year absolute reduction associated with 5 years of use was 12% for recurrence and 9% for mortality.
        • Allocation to approximately 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31%, largely irrespective of the use of chemotherapy and of age (<50 years, 50–69 years, ≥70 years), PR status, or other tumor characteristics.
        • The meta-analysis also confirmed the benefit of adjuvant tamoxifen in hormone receptor–positive premenopausal women. Women younger than 50 years obtained a degree of benefit from 5 years of tamoxifen similar to that obtained by older women. In addition, the proportional reductions in both recurrence and mortality associated with tamoxifen use were similar in women with either node-negative or node-positive breast cancer, but the absolute improvement in survival at 10 years was greater in the node-positive breast cancer group (5.3% vs. 12.5% with 5 years of use).

2. Similar results were found in the IBCSG-13-93 trial. Of 1,246 women with stage II disease, only the women with hormone receptor–positive disease benefited from tamoxifen.
The optimal duration of tamoxifen use has been addressed by the EBCTCG meta-analysis and by several large randomized trials. Ten years of tamoxifen therapy has been shown to be superior to shorter durations of tamoxifen therapy.

Evidence (duration of tamoxifen therapy):
1. The EBCTCG meta-analysis demonstrated that 5 years of tamoxifen was superior to shorter durations. The following results were reported:
        • A highly significant advantage of 5 years versus 1 to 2 years of tamoxifen with respect to the risk of recurrence (proportionate reduction, 15.2%; P <.001) and a less significant advantage with respect to mortality (proportionate reduction, 7.9%; P = .01) was observed.
2. Long-term follow-up of the Adjuvant Tamoxifen Longer Against Shorter (ATLAS [NCT00003016]) trial demonstrated that 10 years of tamoxifen therapy was superior to 5 years of tamoxifen therapy. Between 1996 and 2005, 12,894 women with early breast cancer were randomly assigned to receive 10 years or 5 years of tamoxifen therapy. The following results were reported:[Level of Evidence: 1iiA]
    a. Study results revealed that 10 years of tamoxifen reduced the risk of breast cancer recurrence (617 recurrences for 10 years of tamoxifen vs. 711 recurrences for 5 years of tamoxifen; P = .002), reduced breast-cancer mortality (331 deaths for 10 years of tamoxifen vs. 397 deaths for 5 years of tamoxifen; P = .01), and reduced overall mortality (639 deaths for 10 years of tamoxifen vs. 722 deaths for 5 years of tamoxifen; P = .01).

    b. Of note, from the time of the original breast cancer diagnosis, the benefits of 10 years of therapy were less extreme before than after year 10. At 15 years from the time of diagnosis, breast cancer mortality was 15% at 10 years and 12.2% at 5 years.
    c. Compared with 5 years, 10 years of tamoxifen therapy increased the risk of the following:
        • Pulmonary embolus RR, 1.87; (95% CI, 1.13–3.07; P = .01).
        • Stroke RR, 1.06; (0.83–1.36).
        • Ischemic heart disease RR, 0.76; (0.6–0.95; P = .02).
        • Endometrial cancer RR,
1.74; (1.30–2.34; P = .0002). Notably, the cumulative risk of endometrial cancer during years 5 to 14 from breast cancer diagnosis was 3.1% for women who received 10 years of tamoxifen versus 1.6% for women who received 5 years of tamoxifen. The mortality for years 5 to 14 was 12.2 versus 15 for an absolute mortality reduction of 2.8%.

The results of the ATLAS trial indicated that for women who remained premenopausal after 5 years of adjuvant tamoxifen, continued tamoxifen for 5 more years was beneficial. Women who have become menopausal after 5 years of tamoxifen may also be treated with AI. (Refer to the Aromatase inhibitors section in the Hormone receptor-positive therapy section of this summary for more information.)

Tamoxifen and chemotherapy
Based on the results of an EBCTCG analysis, the use of tamoxifen in women who received adjuvant chemotherapy does not attenuate the benefit of chemotherapy. However, concurrent use of tamoxifen with chemotherapy is less effective than sequential administration.

Ovarian ablation, tamoxifen, and chemotherapy
Evidence suggests ovarian ablation alone is not an effective substitute for other systemic therapies. Further, the addition of ovarian ablation to chemotherapy and/or tamoxifen has not been found to significantly improve outcomes.

Evidence (tamoxifen plus ovarian suppression):
1.The largest study (SOFT [NCT00066690]) to examine the addition of ovarian ablation to tamoxifen with or without chemotherapy randomly assigned 2,033 premenopausal women (53% of whom had received previous chemotherapy) to receive tamoxifen or tamoxifen plus ovarian suppression with triptorelin or ablation with surgery or radiation therapy.[Level of evidence: 1iiDii]
    a. Overall, there was no significant difference in the primary outcome of DFS (HR, 0.83; 95% CI, 0.66–1.04; P = .10); 5-year DFS was 86% in the tamoxifen plus ovarian suppression group versus 84.7% in the tamoxifen alone group.
    b. The authors also reported results from two secondary analyses.
        • In a multivariable Cox proportional hazards model, the tamoxifen plus ovarian suppression arm was statistically superior to the tamoxifen alone arm with respect to DFS (HR, 0.78; 95% CI, 0.62–0.98; P = .03), but the variables included in this analysis were not stated to be prespecified.
        • In a subgroup analysis addressing a secondary endpoint (OS), patients who had previously received chemotherapy were found to have a significantly better outcome if they received tamoxifen plus ovarian ablation (interaction P = .03).
        • The P values in these two secondary analyses were not corrected for multiple comparisons.

 



Aromatase inhibitors (AI)
Premenopausal women
AI have been compared with tamoxifen in premenopausal women in whom ovarian function was suppressed or ablated. The results of these studies have been conflicting.

Evidence (comparison of an AI with tamoxifen in premenopausal women):
1. In one study (NCT00295646), 1,803 women who received goserelin were randomly assigned to a 2 × 2 factorial design trial that compared anastrozole and tamoxifen, with or without zoledronic acid.
• At a median follow-up of 62 months, there was no difference in DFS (HR, 1.08; 95% CI, 0.81–1.44; P = .59).
• OS was superior with tamoxifen (HR, 1.75; 95% CI, 1.08–2.83; P = .02).

2. In two unblinded studies (TEXT [NCT00066703] and SOFT [NCT00066690]), exemestane was also compared with tamoxifen in 4,690 premenopausal women who underwent ovarian ablation.
    a. The use of exemestane resulted in a significant difference in DFS (HR, 0.72; 95% CI, 0.60–0.85; P < .001; 5-year DFS, 91.1% in the exemestane-ovarian suppression group vs. 87.3% in the tamoxifen-ovarian suppression group).[Level of evidence: 1iDii]
    b. No difference in OS (HR, 1.14 for death in the exemestane-ovarian suppression group; 95% CI, 0.86–1.51; P = .37; 5-year OS, 95.9% in the exemestane-ovarian suppression group vs. 96.9% in the tamoxifen-ovarian suppression group) was reported.[Level of evidence: 1iiA]
    c. A follow-up report on the differences in QOL for the exemestane-ovarian suppression group versus the tamoxifen-ovarian suppression group observed the following (the differences cited below were all significant at P < .001 and occurred in patients who did and did not receive chemotherapy):
        • Patients on tamoxifen plus ovarian function suppression were more affected by hot flushes and sweats over 5 years than were those on exemestane plus ovarian function suppression, although these symptoms improved.
        • Patients on exemestane plus ovarian function suppression reported more vaginal dryness, greater loss of sexual interest, and difficulties becoming aroused than did patients on tamoxifen plus ovarian function suppression; these differences persisted over time.
        • An increase in bone or joint pain was more pronounced, particularly in the short term, in patients on exemestane plus ovarian function suppression than in patients on tamoxifen plus ovarian function suppression.
        • Changes in global QOL indicators from baseline were small and similar between treatments over the 5 years.[Level of evidence: 1iC]

Postmenopausal women
In postmenopausal women, the use of AI in sequence with or as a substitute for tamoxifen has been the subject of multiple studies, the results of which have been summarized in an individual patient-level meta-analysis.

----- Initial therapy

Evidence (AI vs. tamoxifen as initial therapy in postmenopausal women):
1. A large, randomized trial of 9,366 patients compared the use of the AI anastrozole and the combination of anastrozole and tamoxifen with tamoxifen alone as adjuvant therapy for postmenopausal patients with node-negative or node-positive disease. Most (84%) of the patients in the study were hormone–receptor (HR) positive. Slightly more than 20% had received chemotherapy.; [Level of evidence: 1iDii]
        • With a median follow-up of 33.3 months, no benefit in DFS was observed for the combination arm relative to tamoxifen alone.
        • Patients on anastrozole, however, had a significantly longer DFS (HR, 0.83) than those on tamoxifen. In an analysis conducted after a median follow-up of 100 months among HR-positive patients, DFS was significantly (P = .003) longer in patients on anastrozole (HR, 0.85; 95% CI, 0.76–0.94), but OS was not improved (HR, 0.97; 95% CI, 0.86–1.11; P = .7).
        • Patients on tamoxifen more frequently developed endometrial cancer and cerebrovascular accidents, whereas patients on anastrozole had more fracture episodes. The frequency of myocardial infarction was similar in both groups. Except for a continued increased frequency of endometrial cancer in the tamoxifen group, these differences did not persist in the posttreatment period.

2. A large, double-blinded, randomized trial of 8,010 postmenopausal women with HR-positive breast cancer compared the use of letrozole with tamoxifen given continuously for 5 years or with crossover to the alternate drug at 2 years. An updated analysis from the International Breast Cancer Study Group (IBCSG-1-98 [NCT00004205]) reported results on the 4,922 women who received tamoxifen or letrozole for 5 years at a median follow-up of 51 months.[151][Level of evidence: 1iDii]         • DFS was significantly superior in patients treated with letrozole (HR, 0.82; 95% CI, 0.71–0.95; P = .007; 5-year DFS, 84.0% vs. 81.1%).         • OS was not significantly different in patients treated with letrozole (HR, 0.91; 95% CI, 0.75–1.11; P = .35).

3. In the meta-analysis, which included 9,885 women from multiple trials, the 10-year recurrence risk was 19.1% in the AI group versus 22.7% in the tamoxifen group (RR, 0.80; 95% CI, 0.73–0.88; P < .001). The overall 10-year mortality rate was also reduced from 24.0% to 21.3%. (RR, 0.89; 95% CI, 0.8–0.97; P = .01).[Level of evidence: 1A]

----- Sequential tamoxifen and AI versus 5 years of tamoxifen
Several trials and meta-analyses have examined the effect of switching to anastrozole or exemestane to complete a total of 5 years of therapy after 2 to 3 years of tamoxifen. The evidence, as described below, indicates that sequential tamoxifen and AI is superior to remaining on tamoxifen for 5 years.

Evidence (sequential tamoxifen and AI vs. 5 years of tamoxifen):
1. Two trials carried out in sequence by the same group enrolled a total of 828 patients and were reported together; one trial used aminoglutethimide as the AI, and the other trial used anastrozole. After a median follow-up of 78 months, an improvement in all-cause mortality (HR, 0.61; 95% CI, 0.42–0.88; P = .007) was observed in the AI groups.[Level of evidence: 1iiA]
2. Two other trials were reported together.[153] A total of 3,224 patients were randomly assigned after 2 years of tamoxifen to continue tamoxifen for a total of 5 years or to take anastrozole for 3 years. There was a significant difference in event-free survival (EFS) (HR, 0.80; 95% CI, P = .0009), but not in OS (5-year OS, 97% for the switched arm vs. 96% for the tamoxifen-alone arm; P = .16).[Level of evidence: 1iDii]
3. A large, double-blinded, randomized trial (EORTC-10967 [ICCG-96OEXE031-C1396-BIG9702]) (NCT00003418) of 4,742 patients compared continuing tamoxifen with switching to exemestane for a total of 5 years of therapy in women who had received 2 to 3 years of tamoxifen.[Level of evidence: 1iDii]
        • After the second planned interim analysis, when median follow-up for patients on the study was 30.6 months, the results were released because of a highly significant (P < .005) difference in DFS (HR, 0.68) favoring the exemestane arm.
        • After a median follow-up of 55.7 months, the HR for DFS was 0.76 (95% CI, 0.66–0.88; P = .001) in favor of exemestane.[Level of evidence: 1iA]
        • At 2.5 years after random assignment, 3.3% fewer patients on exemestane had developed a DFS event (95% CI, 1.6–4.9). The HR for OS was 0.85 (95% CI, 0.7–1.02; P = .08).

In the meta-analysis, which included 11,798 patients from six trials, the 10-year recurrence rate was reduced from 19% to 17% in the AI-containing groups (RR, 0.82; 95% CI, 0.75–0.91; P = .0001). The overall 10-year mortality was 17.5% in the tamoxifen group and 14.6% in the AI-containing group (RR, 0.82; 95% CI, 0.73–0.91; P = .0002).[Level of evidence: 1A]

----- Sequential tamoxifen and AI for 5 years versus 5 years of an AI
The evidence indicates that there is no benefit to the sequential use of tamoxifen and an AI for 5 years over 5 years of an AI.

Evidence (sequential use of tamoxifen and an AI vs. 5 years of an AI):
1. A large, randomized trial of 9,779 patients compared DFS of postmenopausal women with hormone receptor–positive breast cancer between initial treatment with sequential tamoxifen for 2.5 to 3 years followed by exemestane for a total of 5 years versus exemestane alone for 5 years. The primary endpoints were DFS at 2.75 years and 5.0 years.[Level of evidence: 1iDii]
        • Five-year DFS was 85% in the sequential group and 86% in the exemestane-alone group (HR, 0.97; 95% CI, 0.88–1.08; P = .60).

2. Similarly in the IBCSG 1-98 (NCT00004205) trial, two sequential arms were compared with 5 years of letrozole.[Level of evidence: 1iDii]
        • There was no difference in DFS when the two sequential arms were compared with 5 years of letrozole (letrozole to tamoxifen HR, 1.06; 95% CI, 0.91–1.23; P = .45 and tamoxifen to letrozole HR, 1.07; 95% CI, 0.92–1.25; P = .36).

In the meta-analysis, which included 12,779 patients from the trials, the 7-year recurrence rate was slightly reduced from 14.5% to 13.8% in the groups that received 5 years of an AI (RR, 0.90; 95% CI, 0.81–0.99; P = .045). Overall mortality at 7 years was 9.3% in the tamoxifen-followed-by-AI groups and 8.2% in the AI-alone groups (RR, 0.89; 95% CI, 0.78–1.03; P = .11).[Level of evidence: 1A]

----- One AI versus another for 5 years
1. The mild androgen activity of exemestane prompted a randomized trial that evaluated whether exemestane might be preferable to anastrozole, in terms of its efficacy (i.e., EFS) and toxicity, as upfront therapy for postmenopausal women diagnosed with HR-positive breast cancer.[Level of evidence: 1iiA] The MA27 (NCT00066573) trial randomly assigned 7,576 postmenopausal women to receive 5 years of anastrozole or exemestane.
        • At a median follow-up of 4.1 years, no difference in efficacy was seen (HR, 1.02; 95% CI, 0.87–1.18; P = .86).[Level of evidence: 1iiD]
        • The two therapies also were not significantly different in terms of impact on bone mineral density or fracture rates.[Level of evidence: 1iiD]

2. In the Femara Versus Anastrozole Clinical Evaluation (FACE [NCT00248170]) study, 4,136 patients with HR-positive disease were randomly assigned to receive either letrozole or anastrozole.
        • There was no significant difference in DFS (HR, 0.93; 95% CI, 0.80–1.07; P = .3150) at the time of a final analysis that was conducted when there were 709 of the planned 959 events.
        • There were no substantial differences in adverse events between the arms.

----- Switching to an AI after 5 years of tamoxifen
The evidence, as described below, indicates that switching to an AI after 5 years of tamoxifen is superior to stopping tamoxifen at that time.

1. A large, double-blinded, randomized trial (CAN-NCIC-MA17 [NCT00003140]) of 5,187 patients compared the use of letrozole versus placebo in receptor-positive postmenopausal women who received tamoxifen for approximately 5 (4.5–6.0) years.[Level of evidence: 1iDii]
        • After the first planned interim analysis, when median follow-up for patients on study was 2.4 years, the results were unblinded because of a highly significant (P < .008) difference in DFS (HR, 0.57), favoring the letrozole arm.
        • After 3 years of follow-up, 4.8% of the women on the letrozole arm had developed recurrent disease or new primaries versus 9.8% on the placebo arm (95% CI for the difference, 2.7%–7.3%). Because of the early unblinding of the study, longer-term comparative data on the risks and benefits of letrozole in this setting will not be available.
        • An updated analysis including all events before unblinding confirmed the results of the interim analysis. In addition, a statistically significant improvement in distant DFS was found for patients on letrozole (HR, 0.60; 95% CI, 0.43–0.84; P = .002). Although no statistically significant difference was found in the total study population, the node-positive patients on letrozole also experienced a statistically significant improvement in OS (HR, 0.61; 95% CI, 0.38–0.98; P = .04), although the P value was not corrected for multiple comparisons.

2. The NSABP B-33 (NCT00016432) trial that was designed to compare 5 years of exemestane with placebo after 5 years of tamoxifen was stopped prematurely when the results of CAN-NCIC-MA17 became available. At the time of analysis, 560 of the 783 patients who were randomly assigned to receive exemestane remained on that drug and 344 of the 779 patients who were randomly assigned to receive placebo had crossed over to exemestane.[Level of evidence: 1iDii]
        • An intent-to-treat analysis of the primary study endpoint, DFS, demonstrated a nonsignificant benefit of exemestane (HR, 0.68; P = .07).

----- Duration of AI therapy
Evidence (additional 5 years of letrozole vs. placebo):
1.A double-blind, randomized, trial assessed the effect of an additional 5 years of letrozole versus placebo in 1,918 women who had received 5 years of an AI.[167] Patients who received previous tamoxifen therapy were included. The majority of women on the study (70.6%) had received 4.5 to 6 years of adjuvant tamoxifen, but a significant proportion of them (20.7%) had been treated initially with an AI.
    a. At a median follow-up of 6.3 years, DFS, the primary study endpoint, was significantly improved in patients randomly assigned to receive letrozole (HR, 0.66; 95% CI, 0.48–0.91; P = .01), and 5-year DFS was improved from 91% to 95%.[Level of evidence: 1iDii]
    b. OS rates showed no difference (HR, 0.97; 95% CI, 0.73–1.28; P = .83). Some patients on letrozole had fractures (14%) compared with the patients on placebo with fractures (9%) (P = .001).
    c. QOL was assessed with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and Menopause-Specific QOL (MENQOL) instruments. More than 85% of participants completed yearly assessments over a 5-year period.
        • No between-group differences were found on the four MENQOL subscales or on the SF-36 summary score.
        • SF-36 role-emotional and bodily pain scores were statistically significantly worse (P = .03) among patients receiving letrozole, but the differences observed were fewer than the minimum clinically important differences for the SF-36 instrument.

 

 

Bisphosphonates

The role of bisphosphonates as part of adjuvant therapy for early-stage breast cancer is unclear.
Evidence (bisphosphonates in the treatment of early breast cancer):
1. A meta-analysis has been conducted that included the individual patient data of 18,766 patients from 26 adjuvant trials of bisphosphonates of any type. Overall, reductions associated with bisphosphonate use in recurrence (RR, 0.94; 95% CI, 0.87–1.01; 2P = .08), distant recurrence (RR, 0.92; 95% CI, 0.85–0.99; 2P = .03), and breast cancer mortality (RR, 0.91; 95% CI, 0.83–0.99; 2P = .04) were of only borderline significance, but the reduction in bone recurrence was more definite (RR, 0.83; 95% CI, 0.73–0.94; 2P = .004).

        • In a prespecified subgroup analysis, among premenopausal women, treatment had no apparent effect on any outcome, but among 11,767 postmenopausal women, it produced highly significant reductions in recurrence (RR, 0.86; 95% CI, 0.78–0.94; 2P = .002), distant recurrence (RR, 0.82; 95% CI, 0.74–0.92; 2P = .0003), bone recurrence (RR, 0.72; 95% CI, 0.60–0.86; 2P = .0002), and breast cancer mortality (RR, 0.82; 95% CI, 0.73–0.93; 2P = .002).


An ongoing phase III trial (NCT01077154) is examining the activity of the bone-modifying agent, denosumab, in stage II and stage III breast cancer.

 

 



Preoperative Systemic Therapy

Neoadjuvant therapy

• Preoperative Systemic Therapy • Patient selection, staging, treatment, and follow-up
• HER2/neu–negative breast cancer
• HER2/neu-positive breast cancer
• Cardiac toxic effects with pertuzumab and lapatinib
• Preoperative endocrine therapy
• Postoperative therapy


Preoperative chemotherapy, also known as primary or neoadjuvant chemotherapy, has traditionally been administered in patients with locally advanced breast cancer in an attempt to reduce tumor volume and allow for definitive surgery. In addition, preoperative chemotherapy is being used for patients with primary operable stage II or stage III breast cancer.
A meta-analysis of multiple, randomized clinical trials has demonstrated that preoperative chemotherapy is associated with identical DFS and OS compared with the administration of the same therapy in the adjuvant setting.[Level of evidence: 1iiA] Current consensus opinion for use of preoperative chemotherapy recommends anthracycline- and taxane-based therapy, and prospective trials suggest that preoperative anthracycline- and taxane-based therapy is associated with higher response rates than alternative regimens (e.g., anthracycline alone).[Level of evidence: 1iiDiv]

A potential advantage of preoperative systemic therapy is the increased likelihood of success with definitive local therapy in those presenting with locally-advanced, unresectable disease. It may also offer benefit to carefully selected patients with primary operable disease by enhancing the likelihood of breast conservation and providing prognostic information where pCR is obtained. In these cases, a patient can be informed that there is a very low risk of recurrence compared with a situation in which a large amount of residual disease remains.

pCR has been utilized as a surrogate endpoint for long-term outcomes, such as DFS, EFS, and OS, in preoperative clinical trials in breast cancer.
A pooled analysis (CTNeoBC) of 11 preoperative randomized trials (n = 11,955) determined that pCR, defined as no residual invasive cancer in the breast and axillary nodes with presence or absence of in situ cancer (ypT0/is ypN0 or ypT0 ypN0), provided a better association with improved outcomes compared with eradication of invasive tumor from the breast alone (ypT0/is). pCR could not be validated in this study as a surrogate endpoint for improved EFS and OS.[Level of evidence: 3iiiD]
A patient-level meta-analysis, which included 36 studies (n = 5,768) of preoperative therapy in stages I–III breast cancer, indicated an improvement in EFS for those obtaining a pCR versus no pCR (HR, 0.37; 95% CI, 0.32–0.43).[Level of evidence: 3iiiD]
On the basis of a strong association of pCR with substantially improved outcomes in individual patients with more aggressive subtypes of breast cancer, the FDA has supported use of pCR as an endpoint in preoperative clinical trials for patients with high-risk, early-stage breast cancer.

Postoperative radiation therapy may also be omitted in a patient with histologically negative axillary nodes after preoperative therapy, irrespective of lymph node status before preoperative therapy, allowing for tailoring of treatment to the individual.


Potential disadvantages with this approach include the inability to determine an accurate pathological stage after preoperative chemotherapy. However, the knowledge of the presence of residual disease may provide more personalized prognostic information, as noted above.

Patient selection, staging, treatment, and follow-up
Multidisciplinary management of patients undergoing preoperative therapy by an experienced team is essential to optimize the following:

• Patient selection.
• Choice of systemic therapy.
• Management of the axilla and surgical approach.
• Decision to administer adjuvant radiation therapy.

The tumor histology, grade, and receptor status are carefully evaluated before preoperative therapy is initiated.
Patients whose tumors have a pure lobular histology, low grade, or high HR expression and HER2-negative status are less likely to respond to chemotherapy and should be considered for primary surgery, especially when the nodes are clinically negative. Even if adjuvant chemotherapy is administered after surgery in these cases, a third-generation regimen (anthracycline/taxane based) may be avoided.

Before beginning preoperative therapy, the extent of the disease within the breast and regional lymph nodes should be assessed. Staging of systemic disease may include the following:

• CT scan of the chest and abdomen and a bone scan.
• Positron-emission tomography.

Baseline breast imaging is performed when breast-conserving therapy is desired to identify the tumor location and exclude multicentric disease. Suspicious abnormalities are usually biopsied before beginning treatment and a marker placed at the center of the breast tumor(s). When possible, suspicious axillary nodes may be biopsied before initiation of systemic treatment.

The optimal timing of sentinel lymph node (SLN) biopsy has not been established in patients receiving preoperative therapy. The following points should be considered:
If suspicious nodes are positive for malignancy at baseline, an SLN biopsy may be performed after preoperative therapy but is associated with a high false-negative rate. If the procedure is performed with both radiocolloid and blue dye and at least two nodes are sampled (provides 10.8% false-negative rate) and are negative, then axillary lymph node dissection (ALND) may be omitted.[Level of evidence: 2Div]; [Level of evidence: 3iiD]; [Level of evidence: 3iiDiv] Alternatively, it is acceptable in this circumstance to perform ALND, based on the possibility of undetected positive nodes.

In patients with clinically negative nodes, SLN biopsy may be performed before preoperative therapy because of the false-negative rates observed when performed after preoperative therapy. If the SLN biopsy is negative, ALND can be omitted.

• If SLN biopsy is performed after preoperative chemotherapy, the baseline clinical and postchemotherapy pathological nodal status should be taken into consideration when deciding whether ALND is necessary. ALND is usually performed in the setting of node-positivity.


When considering preoperative therapy, treatment options include the following:
• For HER2-negative breast tumors, an anthracycline-taxane based chemotherapy regimen.
• For HER2-positive disease, chemotherapy and HER2-targeted therapy.
• Ideally, the entire treatment regimen is administered before surgery.
• For postmenopausal women with hormone receptor–positive breast cancer, chemotherapy is an option. For those who cannot be given chemotherapy, preoperative endocrine therapy may be an option.
• For premenopausal women with hormone–responsive cancer, the use of preoperative endocrine therapy is under investigation.


Regular clinical assessment of response to therapy is necessary after beginning preoperative therapy. Repeat radiographic assessment is also required if breast conservation is the surgical goal. Patients with progressive disease during preoperative therapy may either transition to a non–cross-resistant regimen or proceed to surgery, if feasible. Although switching to a non–cross-resistant regimen results in a higher pCR rate than continuing the same therapy, there is no clear evidence that other breast cancer outcomes are improved with this approach.

 



HER2/neu–negative breast cancer

Neoadjuvant therapy

Early trials examined whether anthracycline-based regimens used in the adjuvant setting would prolong DFS and OS when used in the preoperative setting. The evidence supports higher rates of breast-conserving therapy with the use of a preoperative anthracycline chemotherapy regimen than with postoperative use, but no improvement in survival was noted with the preoperative strategy.

Evidence (preoperative anthracycline-based regimen):
1. A randomized clinical trial (NSABP-B-18) was designed to determine whether the preoperative combination of four cycles of AC would more effectively prolong DFS and OS than the same chemotherapy given in the adjuvant setting.[Level of evidence: 1iiA]
        • After preoperative therapy, 36% of the patients had a complete clinical response.
        • More patients treated with preoperative chemotherapy were able to have breast-conserving procedures as compared with those patients in the postoperative chemotherapy group (68% vs. 60%; P = .001).
        • No statistically significant difference existed, however, in DFS, distant DFS, or OS in the patients who received preoperative chemotherapy as compared with those who received postoperative chemotherapy.

2. An EORTC randomized trial (EORTC-10902) likewise demonstrated no improvement in DFS or OS but showed an increased frequency of conservative surgery with the use of preoperative versus postoperative FEC chemotherapy.[Level of evidence: 1iiA]

In an effort to improve the results observed with AC alone, a taxane was added to the chemotherapy regimen. The following study results support the addition of a taxane to an anthracycline-based chemotherapy regimen for HER2-negative breast tumors.

Evidence (anthracycline/taxane-based chemotherapy regimen):
1. In an effort to improve on the results observed with AC alone, the National Surgical Adjuvant Breast and Bowel Project (NSABP B-27 [NCT00002707]) trial was conducted.[Level of evidence: 1iiD]
        • The administration of preoperative AC followed by docetaxel was associated with a higher clinical complete response rate compared with the administration of AC alone (63.6% for AC followed by docetaxel and 40.1% for AC alone; P < .001); a higher pCR rate was also observed (26.1% for AC followed by docetaxel and 13.7% for AC alone; P < .001).

2. Data from NSABP B-27 and the Aberdeen Breast Group Trial support the use of anthracycline- and taxane-based regimens in women with initial response or with relative resistance to anthracyclines.

3. Alternative anthracycline/taxane schedules have also been evaluated (concurrent TAC) and appear similar in efficacy to the sequential approach described above.[Level of evidence: 1iiDiv]


4. The phase III GeparSepto trial (NCT01583426) investigated an alternative taxane (nab-paclitaxel) in patients with untreated primary breast cancer. Patients (n = 1,229) were randomly assigned to receive 12 weeks of nab-paclitaxel or paclitaxel followed by epirubicin and cyclophosphamide (EC) for four cycles. The pCR rate was higher in the nab-paclitaxel arm (233 patients, 38%; 95% CI, 35%–42%) when compared with the paclitaxel arm (174 patients, 29%; 95% CI, 25%–33%).[Level of evidence: 1iiDiv]

5.The incorporation of many additional cytotoxic agents to anthracycline- and taxane-based regimens has not offered a significant additional benefit to breast conservation or pCR rate in unselected breast cancer populations.[Level of evidence: 1iiDiv]

Promising results have been observed, however, with the addition of carboplatin to anthracycline-taxane combination chemotherapy regimens in patients with triple-negative breast cancer (TNBC). Future definitive studies evaluating survival endpoints and the identification of biomarkers of response or resistance are necessary before the addition of carboplatin to standard preoperative chemotherapy can be considered a new standard of care.

Evidence (adding carboplatin to an anthracycline/taxane-based chemotherapy regimen in patients with TNBC):
1. In the GeparSixto (NCT01426880) trial, carboplatin was added to an anthracycline/taxane-based backbone.[Level of evidence: 1iiDiv]
        • Higher pCR rates were observed with the addition of carboplatin to an anthracycline/taxane-based backbone compared with anthracycline/taxane alone (36.9% vs. 53.2%; P = .005) in patients with TNBC.
        • The more intensive regimen was also associated with increased toxicity and treatment discontinuations (39% vs. 48%).

2. The CALGB 40603 (NCT00861705) trial compared an anthracycline/taxane backbone alone with an anthracycline/taxane backbone plus carboplatin in patients with stage II and stage III TNBC.[Level of evidence: 1iiDiv]
        • The pCR rate for the breast and axilla was 54% for the anthracycline/taxane backbone plus carboplatin group versus 41% for the anthracycline/taxane backbone alone group (P = .0029)

Importantly, results of studies in the adjuvant and metastatic settings have not demonstrated an OS benefit with the addition of bevacizumab to chemotherapy versus chemotherapy alone. However, the addition of bevacizumab to preoperative chemotherapy has been associated with an increased pCR rate alongside increased toxicity such as hypertension, cardiac toxicity, hand-foot syndrome, and mucositis (e.g., NSABP B-40 [NCT00408408] and GeparQuinto [NCT00567554]).[Level of evidence: 1iiDiv] However, it is not clear that the modest benefit observed will translate into a longer term survival advantage.

 

 



HER2/neu–positive breast cancer

Neoadjuvant therapy

After the success in the adjuvant setting, initial reports from phase II studies indicated improved pCR rates when trastuzumab, a monoclonal antibody that binds the extracellular domain of HER2, was added to preoperative anthracycline- and taxane-based regimens.[Level of evidence: 1iiDiv] This has been confirmed in phase III studies.

Trastuzumab
Evidence (trastuzumab):
1. A phase III (NOAH) study randomly assigned patients with HER2-positive locally advanced or inflammatory breast cancers to undergo preoperative chemotherapy with or without 1 year of trastuzumab therapy.[Level of evidence:1iiA]
        • Study results confirmed that the addition of trastuzumab to preoperative chemotherapy resulted not only in improved clinical responses (87% vs. 74%) and pathologic responses (breast and axilla, 38% vs. 19%) but also in EFS, the primary outcome.[Level of evidence:1iiA]
        • After a median follow-up of 5.4 years, the EFS benefit was 58% with the addition of trastuzumab to chemotherapy (95% CI, 48–66) and 43% (95% CI, 34–52) in patients in the chemotherapy group. The unadjusted HR for EFS between the two randomized HER2-positive treatment groups was 0.64 (95% CI, 0.44–0.93; two-sided log-rank P = .016). EFS was strongly associated with pCR in patients who received trastuzumab.
        • Symptomatic cardiac failure occurred in two patients who received concurrent doxorubicin and trastuzumab for two cycles. Close cardiac monitoring of LVEF and the total dose of doxorubicin not exceeding 180 mg/m2 accounted for the relatively low number of declines in LVEF and only two cardiac events. (Refer to the Cardiac toxic effects with adjuvant trastuzumab section in this summary for more information.)[Level of evidence: 1iiD]

2. A phase III trial (Z1041 [NCT00513292]) randomly assigned patients with operable HER2-positive breast cancer to receive trastuzumab sequential to or concurrent with the anthracycline component (fluorouracil, epirubicin, cyclophosphamide) of the preoperative chemotherapy regimen.[Level of evidence: 1iiDiv]
        • There was no significant difference in pCR rate in the breast between the arms (56.5% sequential, 54.2% concurrent; difference, 2.3% with 95% CI, -9.3–13.9).
        • In addition, asymptomatic declines in LVEF during preoperative chemotherapy were identified in similar proportions of patients in each arm.
        • The conclusion was that concurrent administration of trastuzumab with anthracyclines is not warranted based on these findings.

A phase III (HannaH [NCT00950300]) trial also demonstrated that the pharmacokinetics and efficacy of preoperative SQ trastuzumab is noninferior to the IV formulation. This international, open-label trial (n = 596) randomly assigned women with operable, locally advanced, or inflammatory HER2-positive breast cancer to undergo preoperative chemotherapy (anthracycline/taxane-based), with either SQ-administered or IV-administered trastuzumab every 3 weeks before surgery. Patients received adjuvant trastuzumab to complete 1 year of therapy.[Level of evidence: 1iiD] The pCR rates between the arms differed by 4.7% (95% CI, 4.0–13.4); 40.7% in the IV-administered group versus 45.4% in the SQ-administered group, demonstrating noninferiority for the SQ formulation. Data regarding the DFS and OS differences between the arms are not yet available.

An ongoing trial, SafeHer (NCT01566721), is evaluating the safety of self-administered versus clinician-administered SQ trastuzumab. SQ trastuzumab is approved for use in Europe in early- and late-stage breast cancer.

Newer HER2-targeted therapies (lapatinib, pertuzumab) have also been investigated. It appears that dual targeting of the HER2 receptor results in an increase in pCR rate; however, no survival advantage has been demonstrated to date with this approach.

Pertuzumab
Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Pertuzumab, in combination with trastuzumab with or without chemotherapy, has been evaluated in two preoperative clinical trials in an attempt to improve on the pCR rates observed with trastuzumab and chemotherapy.

Evidence (pertuzumab):
1.In the open-label, randomized, phase II NeoSPHERE (NCT00545688) trial, 417 women with tumors that were larger than 2 cm or node-positive, and who had HER2-positive breast cancer, were randomly assigned to one of four preoperative regimens:[Level of evidence: 1iiDiv]
a. Docetaxel plus trastuzumab.
b. Docetaxel plus trastuzumab and pertuzumab.
c. Pertuzumab plus trastuzumab.
d. Docetaxel plus pertuzumab.

The following results were observed:
• The pCR rates were 29%, 46%, 17%, and 24%, respectively. Therefore, the highest pCR rate was seen in the preoperative treatment arm with dual HER2 blockade plus chemotherapy.
• The addition of pertuzumab to the docetaxel plus trastuzumab combination did not appear to increase toxic effects, including the risk of cardiac adverse events.

2. The open-label, randomized, phase II TRYPHAENA (NCT00976989) trial sought to evaluate the tolerability and activity associated with trastuzumab and pertuzumab.[Level of evidence: 1iiDiv] All 225 women with tumors that were larger than 2 cm or node positive, and who had operable, locally advanced, or inflammatory HER2-positive breast cancer, were randomly assigned to one of three preoperative regimens:
a. Concurrent FEC plus trastuzumab plus pertuzumab (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab.
b. FEC alone (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab (×3).
c. Concurrent docetaxel and carboplatin plus trastuzumab plus pertuzumab (×6).

The following results were observed:
• The pCR rate was equivalent across all three treatment arms (62%, 57%, and 66%, respectively).
• All three arms were associated with a low incidence of cardiac adverse events of 5% or less.

On the basis of these studies, the FDA-granted accelerated approval for the use of pertuzumab as part of preoperative treatment for women with early-stage, HER2-positive breast cancer whose tumors are larger than 2 cm or node-positive. The FDA approved no more than three to six cycles of pertuzumab. Thus, a pertuzumab-based regimen as outlined above is a new treatment option for patients with HER2-positive breast cancer who are candidates for preoperative therapy. There is insufficient evidence to recommend concomitant anthracycline/pertuzumab or sequential use of doxorubicin with pertuzumab.
The APHINITY (NCT01358877) trial, a randomized, phase III, adjuvant study for women with HER2-positive breast cancer, is the confirmatory trial for this accelerated approval.

Lapatinib
Lapatinib is a small-molecule kinase inhibitor that is capable of dual receptor inhibition of both epidermal growth factor receptor and HER2. Study results do not support the use of lapatinib in the preoperative setting.

Evidence (lapatinib):
1. The role of lapatinib in the preoperative setting was examined in the GeparQuinto [NCT00567554] trial. This phase III trial randomly assigned women with HER2-positive early-stage breast cancer to receive chemotherapy with trastuzumab or chemotherapy with lapatinib, with pCR as the primary endpoint.[Level of evidence: 1iiDiv]
        • pCR in the chemotherapy and lapatinib arm was significantly lower than it was with chemotherapy and trastuzumab (22.7% vs. 30.3%; P = .04).
        • Other endpoints of DFS, RFS, and OS have not been reported.

2. CALGB 40601 (NCT00770809) was a phase III trial that randomly assigned patients with stage II and III HER2-positive breast cancer to receive either paclitaxel plus trastuzumab or paclitaxel plus trastuzumab plus lapatinib. The primary endpoint of the study was pCR in the breast. [Level of evidence: 1iiDiv]
        • pCR in patients who received paclitaxel plus trastuzumab was 46% (95% CI, 37%–55%), and pCR in the patients who received paclitaxel plus trastuzumab plus lapatinib was 56% (95% CI, 47%–65%; P = .13), indicating no benefit with the addition of lapatinib.

3. The NeoALTTO [NCT00553358] phase III trial randomly assigned 455 women with HER2-positive early-stage breast cancer (tumor size >2 cm) to receive preoperative lapatinib, or preoperative trastuzumab, or preoperative lapatinib plus trastuzumab. This anti-HER2 therapy was given alone for 6 weeks and then weekly paclitaxel was added to the regimen for an additional 12 weeks. The primary endpoint of this study was pCR.
        • pCR was significantly higher in the lapatinib-plus-trastuzumab combination arm (51.3%; 95% CI, 43.1–59.5) than in the trastuzumab-alone arm (29.5%; 95% CI, 22.4–37.5).
        • No significant difference in pCR was seen between the lapatinib (24.7%, 95% CI, 18.1–32.3) and trastuzumab groups (difference, -4.8%, -17.6–8.2; P = .34).
        • An updated analysis for the prespecified secondary endpoints of event-free survival and OS indicate no difference between the groups.

More definitive efficacy data were provided by the phase III ALLTO (NCT00490139) trial that randomly assigned women to receive trastuzumab or trastuzumab plus lapatinib in the adjuvant setting. The trial did not meet its primary endpoint of DFS. The doubling in pCR rate observed with the addition of lapatinib to trastuzumab in the NeoALTTO trial did not translate into improved survival outcomes in the ALTTO trial at 4.5 years of median follow-up. This indicates that there is currently no role for the use of lapatinib in the preoperative or adjuvant settings.

Cardiac toxic effects with pertuzumab and lapatinib
A pooled analysis of cardiac safety in 598 cancer patients treated with pertuzumab was performed using data supplied by Roche and Genentech.[Level of evidence: 3iiiD]
• Asymptomatic left ventricular systolic dysfunction was observed in 6.9% of patients receiving pertuzumab alone (n = 331; 95% CI, 4.5–10.2), 3.4% of patients receiving pertuzumab in combination with a nonanthracycline-containing chemotherapy (n = 175; 95% CI, 1.3–7.3), and 6.5% of patients receiving pertuzumab in combination with trastuzumab (n = 93; 95% CI, 2.4–13.5).
• Symptomatic heart failure was observed in 1 (0.3%), 2 (1.1%), and 1 (1.1%) patients, respectively.

A meta-analysis of randomized trials (n = 6) that evaluated the administration of anti-HER2 monotherapy (trastuzumab or lapatinib or pertuzumab) versus dual anti-HER2 therapy (trastuzumab plus lapatinib or trastuzumab plus pertuzumab) was performed.[Level of evidence: 3iiiD]

• LVEF decline was observed in 3.1% of the patients who received monotherapy (95% CI, 2.2%–4.4%) and 2.9% of the patients who received dual therapy (95% CI, 2.1%–4.1%).
• Symptomatic heart failure was observed in 0.88% of the patients who received monotherapy (95% CI, 0.47%–1.64%) and 1.49% of the patients who received dual therapy (95% CI, 0.98%–2.23%).

Preoperative endocrine therapy
Preoperative endocrine therapy may be an option for postmenopausal women with HR-positive breast cancer when chemotherapy is not a suitable option because of comorbidities or performance status. Although the toxicity profile of preoperative hormonal therapy over the course of 3 to 6 months is favorable, the pCR rates obtained (1%–8%) are far lower than have been reported with chemotherapy in unselected populations.[Level of Evidence: 1iDiv]

Longer duration of preoperative therapy may be required in this patient population. Preoperative tamoxifen was associated with an overall response rate of 33%, with maximum response occurring up to 12 months after therapy in some patients. A randomized study of 4, 8, or 12 months of preoperative letrozole in elderly patients who were not fit for chemotherapy indicated that the longer duration of therapy resulted in the highest pCR rate (17.5% vs. 5% vs. 2.5%, P-value for trend < .04).[Level of Evidence: 1iiDiv]

The AI have also been compared with tamoxifen in the preoperative setting. Overall objective response and breast-conserving therapy rates with 3 to 4 months preoperative therapy were either statistically significantly improved in the AI-treated women or comparable to tamoxifen-associated outcomes. An American College of Surgeons Oncology Group trial is currently comparing the efficacy of anastrozole, letrozole, or exemestane in the preoperative setting.

The use of preoperative endocrine therapy in premenopausal women with hormone-responsive breast cancer remains investigational.

Postoperative therapy
Capecitabine
One clinical trial suggested that there is a benefit to using capecitabine as adjuvant therapy in patients who did not obtain a pCR after preoperative chemotherapy.

Evidence (capecitabine):
1. In a study conducted in Japan and Korea, 910 women with HER2/neu–negative breast cancers, who had residual disease after preoperative chemotherapy with anthracyclines, taxanes, or both, were randomly assigned in a nonblinded fashion to receive 6 to 8 four-weekly cycles of capecitabine or no further chemotherapy. The study was terminated because of the results of a planned interim analysis, and a final analysis was done.
        • In the final analysis, which included 887 eligible patients, DFS, the primary endpoint, was statistically significantly prolonged (HR, 0.70; 95% CI, 0.53–0.92; P = .01; 5-year DFS, 74.1% vs. 67.6%).
        • OS, a secondary endpoint, was also longer in the capecitabine group (HR, 0.59; 95% CI, 0.39–0.90; P = .01; 5-year OS, 89.2% vs. 83.6%).
        • In the capecitabine group, 73.4% of the patients experienced hand-foot syndrome of varying degrees of severity.

This approach and participation in clinical trials of novel therapies should be considered for patients with residual disease after preoperative therapy. EA1131 (NCT02445391) is a randomized phase III clinical trial that randomly assigned patients with residual basal-like TNBC after preoperative therapy to receive platinum-based chemotherapy or capecitabine. S1418/BR006 (NCT02954874) is a phase III trial evaluating the efficacy of pembrolizumab as adjuvant therapy for patients with residual TNBC (≥1 cm invasive cancer or residual nodes) after preoperative therapy.

Radiation therapy is administered after breast conservation in most women who have received preoperative therapy to reduce the risk of locoregional recurrence. Baseline clinical and subsequent pathologic staging should be considered in deciding whether to administer postmastectomy radiation.

Other adjuvant systemic treatments may be administered either postoperatively, during, or after completion of adjuvant radiation, including adjuvant hormonal therapy for patients with HR-positive disease and adjuvant trastuzumab for those with HER2-positive disease. (Refer to the Hormone receptor–positive breast cancer subsection in the Early/Localized/Operable Breast Cancer section of this summary for more information.)

 

 



Posttherapy Surveillance

The frequency of follow-up and the appropriateness of screening tests after the completion of primary treatment for stage I, stage II, or stage III breast cancer remain controversial.

Evidence from randomized trials indicates that periodic follow-up with bone scans, liver sonography, chest x-rays, and blood tests of liver function does not improve survival or quality of life when compared with routine physical examinations. Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.[209] On the basis of these data, acceptable follow-up can be limited to the following for asymptomatic patients who complete treatment for stages I to III breast cancer:

        • Physical examination.
        • Annual mammography.

 

 

 

Locally Advanced or Inflammatory Breast Cancer


Treatment Option Overview for Locally Advanced or Inflammatory Breast Cancer
Based on available evidence, multimodality therapy delivered with curative intent is the standard of care for patients with locally advanced or inflammatory breast cancer.

The standard treatment options for locally advanced or inflammatory breast cancer may include the following:

1. Breast-conserving surgery or total mastectomy with axillary lymph node dissection.
2. Chemotherapy.
3. Radiation therapy.
4. Hormone therapy.

Initial surgery is generally limited to biopsy to permit the determination of histology, estrogen receptor (ER) and progesterone receptor levels, and human epidermal growth factor receptor 2 (HER2/neu) overexpression.

The standard chemotherapy regimen for initial treatment is the same as that used in the adjuvant setting (refer to the Postoperative Systemic Therapy section of this summary for more information), although trials done solely in patients with locally advanced disease have not shown a statistically significant advantage to dose-dense chemotherapy.

For patients who respond to preoperative chemotherapy, local therapy may consist of total mastectomy with axillary lymph node dissection followed by postoperative radiation therapy to the chest wall and regional lymphatics. Breast-conserving therapy can be considered for patients with a good partial or complete response to preoperative chemotherapy. Subsequent systemic therapy may consist of further chemotherapy. Hormone therapy is administered to patients with ER-positive or ER-unknown tumors.

Although the evidence described below has not been replicated, it suggests patients with locally advanced or inflammatory breast cancer should be treated with curative intent.

Evidence (multimodality therapy):
1. In a retrospective series, 70 patients with locally advanced breast cancer and supraclavicular metastases received preoperative chemotherapy. Patients then received local therapy that consisted of either total mastectomy and axillary lymph node dissection or breast-conserving surgery and axillary lymph node dissection before or after radiation therapy. Patients who did not respond to preoperative chemotherapy were treated with surgery and/or radiation therapy. After completion of local therapy, chemotherapy was continued for 4 to 15 cycles, followed by radiation therapy.
        • Approximately 32% of patients with ipsilateral supraclavicular node involvement and no evidence of distant metastases (pN3c) had prolonged disease-free survival (DFS) at 10 years with combined-modality therapy.
        • These results have been confirmed in a separate series of patients treated in British Columbia.

2. A series of 178 patients with inflammatory breast cancer were treated with a combined-modality approach. Patients were treated with induction chemotherapy, then local therapy (radiation therapy or mastectomy), followed by chemotherapy, and, if mastectomy was performed, radiation therapy.[Level of evidence: 3iiiDii]

Subsequent trials have confirmed that patients with locally advanced and inflammatory breast cancer can experience long-term DFS when treated with initial chemotherapy.

All patients are considered candidates for clinical trials to evaluate the most appropriate manner in which to administer the various components of new multimodality regimens.

 

 

Locoregional Recurrent Breast Cancer


Treatment Option Overview for Locoregional Recurrent Breast Cancer
Recurrent breast cancer is often responsive to therapy, although treatment is rarely curative at this stage of disease. Patients with locoregional breast cancer recurrence may become long-term survivors with appropriate therapy.

The rates of locoregional recurrence have been reduced over time, and a meta-analysis suggests a recurrence rate of less than 3% in patients treated with breast-conserving surgery and radiation therapy. The rates are somewhat higher (up to 10%) for those treated with mastectomy. Nine percent to 25% of patients with locoregional recurrence will have distant metastases or locally extensive disease at the time of recurrence.

Before treatment for recurrent breast cancer, restaging to evaluate the extent of disease is indicated. Cytologic or histologic documentation of recurrent disease is obtained whenever possible. When therapy is selected, the estrogen-receptor (ER) status, progesterone-receptor (PR) status, and human epidermal growth factor receptor 2 (HER2/neu) status at the time of recurrence and previous treatment are considered, if known.

ER status may change at the time of recurrence. In a single small study by the Cancer and Leukemia Group B (MDA-MBDT-8081), 36% of hormone receptor–positive tumors were found to be receptor negative in biopsy specimens isolated at the time of recurrence. Patients in this study had no interval treatment. If ER and PR statuses are unknown, then the site(s) of recurrence, disease-free interval, response to previous treatment, and menopausal status are useful in the selection of chemotherapy or hormone therapy.

Treatment options for locoregional recurrent breast cancer include the following:

1. Chemotherapy.
2. Hormone therapy.
3. Radiation therapy.
4. Surgery.
5. Targeted therapy (e.g., trastuzumab).

Patients with locoregional recurrence should be considered for further local treatment (e.g., mastectomy). In one series, the 5-year actuarial rate of relapse for patients treated for invasive recurrence after initial breast conservation and radiation therapy was 52%.

Treatment options also depend on the site of recurrence, as follows:

• Cutaneous: A phase III randomized study showed that local control of cutaneous metastases could be achieved with the application of topical miltefosine; however, the drug is not currently available in the United States.[Level of evidence: 1iiDiii]
• Chest wall: Local chest wall recurrence after mastectomy is usually the harbinger of widespread disease, but, in a subset of patients, it may be the only site of recurrence. For patients in this subset, surgery and/or radiation therapy may be curative. Patients with chest wall recurrences of less than 3 cm, axillary and internal mammary node recurrence (not supraclavicular, which has a poorer survival), and a greater-than-2-year disease-free interval before recurrence have the best chance for prolonged survival. The 5-year disease-free survival (DFS) rate in one series of such patients was 25%, with a 10-year rate of 15%. The locoregional control rate was 57% at 10 years. Systemic therapy should be considered in patients with locoregional recurrence.
• Breast: In the Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer (CALOR [NCT00074152]) trial, patients with a history of breast-conserving surgery or mastectomy with clear margins and complete excision of an isolated local recurrence of their breast cancer were randomly assigned to receive either chemotherapy of the physician's choice or no chemotherapy. The study was closed early because of poor accrual. The original sample size for a hazard ratio (HR) of 0.74 was 977 patients (347 DFS events) and was revised subsequently to 265 patients (HR 0.6; 124 DFS events), with only 162 enrolled at the time of study closure.[Level of evidence: 1iiDii]
• Five-year DFS was 69% in the chemotherapy arm versus 57% in the no-chemotherapy arm (HR, 0.59; 95% confidence interval, 0.35–0.99; P = .046), with most benefit seen in the subgroup with hormone receptor–negative disease.
• This trial supports consideration of adjuvant chemotherapy after complete resection of isolated locoregional recurrence of breast cancer.

(Refer to the Metastatic (systemic) disease section of this summary for information about treatment for recurrent metastatic breast cancer.) All patients with recurrent breast cancer are considered candidates for ongoing clinical trials.

 

 

Metastatic Breast Cancer


Treatment Option Overview forMetastatic Breast Cancer
• Hormone Receptor (HR)-Positive or HR-Unknown Breast Cancer
        • Tamoxifen and aromatase inhibitor (AI) therapy
        • Mammalian target of rapamycin (mTOR) inhibitor therapy
• HR-Negative Breast Cancer
• HER2/neu–Positive Breast Cancer
        • Monoclonal antibody therapy
        • Tyrosine kinase inhibitor therapy
• Germline BRCA Mutation
• Chemotherapy
        • Cardiac toxic effects with anthracyclines
• Surgery
• Radiation Therapy
• Bone Modifier Therapy
• Bevacizumab
• Current Clinical Trials


Treatment of metastatic disease is palliative in intent. Goals of treatment include prolonging life and improving quality of life. Although median survival has been reported to be 18 to 24 months, some patients experience long-term survival. Among patients treated with systemic chemotherapy at a single institution between 1973 and 1982, 263 patients (16.6%) achieved complete responses. Of those, 49 patients (3.1% of the total group) remained in complete remission for more than 5 years, and 26 patients (1.5%) were still in complete remission at 16 years.[Level of evidence: 3iiDiii]

Treatment options for metastatic breast cancer include the following:
1.Hormone therapy (tamoxifen, aromatase inhibitors).
2.Targeted therapy (e.g., trastuzumab, lapatinib, pertuzumab, mammalian target of rapamycin [mTOR] inhibitors, and CDK4/6 inhibitors).
3.Chemotherapy.
4.Surgery, for patients with limited symptomatic metastases.
5.Radiation therapy, for patients with limited symptomatic metastases.
6.Bone modifier therapy, for patients with bone metastases.

Cytologic or histologic documentation of metastatic disease is obtained whenever possible.

Treatment of metastatic breast cancer will usually involve hormone therapy and/or chemotherapy with or without trastuzumab. All patients with metastatic breast cancer are considered candidates for ongoing clinical trials.


Hormone Receptor (HR)-Positive or HR-Unknown Breast Cancer (Metastatic)


Tamoxifen and aromatase inhibitor (AI) therapy

Initial hormone therapy
Initial hormone therapy depends, in part, on the patient's menopausal status.
For postmenopausal patients with newly diagnosed metastatic disease and estrogen receptor (ER)–positive tumors, progesterone receptor (PR)–positive tumors, or ER/PR–unknown tumors, hormone therapy is generally used as initial treatment. Hormone therapy is especially indicated if the patient’s disease involves only bone and soft tissue and the patient either has not received adjuvant antiestrogen therapy or has been off such therapy for more than 1 year.

While tamoxifen has been used for many years in treating postmenopausal women with newly metastatic disease that is ER positive, PR positive, or ER/PR unknown, several randomized trials suggest equivalent or superior response rates and progression-free survival (PFS) for the AI compared with tamoxifen.[Level of evidence: 1iiDiii]


Evidence (initial hormone therapy in postmenopausal women):
1. A meta-analysis evaluated patients with metastatic disease who were randomly assigned to receive either an AI as their first or second hormone therapy, or standard therapy (tamoxifen or a progestational agent).[Level of evidence: 1iA]
        • Patients who received an AI as either their first or second hormone therapy for metastatic disease and were randomly assigned to receive a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (hazard ratio [HRdeath], 0.87; 95% confidence interval [CI], 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).

2. Conflicting results were found in two trials that compared the combination of the antiestrogen fulvestrant (refer to the discussion of second-line hormone therapy for more information about this drug) and anastrozole with anastrozole alone in the first-line treatment of HR-positive postmenopausal patients with recurrent or metastatic disease. In both studies, fulvestrant was administered as a 500-mg loading dose on day 1; 250 mg was administered on days 15 and 29, and monthly thereafter; plus, 1 mg of anastrozole was administered daily. The Southwest Oncology Group (SWOG) trial included more patients who presented with metastatic disease; the Fulvestrant and Anastrozole Combination Therapy (FACT [NCT00256698]) study enrolled more patients who had previously received tamoxifen.
        • The SWOG trial (SWOG-0226 [NCT00075764]), which enrolled 707 patients, demonstrated a statistically significant difference in PFS (HR, 0.80; 95% CI, 0.68–0.94; P = .007) and overall survival (OS) (HR, 0.81; 95% CI, 0.65–1.00; P = .05).[Level of evidence: 1iA]
        • In contrast, the FACT trial , which enrolled 514 patients, found no difference in either disease-free survival (DFS) (HR, 0.99; 95% CI, 0.81–1.20; P = .91) or OS (HR, 1.0; 95% CI, 0.76–1.32; P = 1.00).[Level of evidence: 1iA]

Another initial treatment option for postmenopausal women is AI therapy combined with cyclin-dependent kinase inhibitor therapy (refer to the Cyclin-dependent kinase inhibitor therapy section of this summary for more information).

In premenopausal women, several randomized but underpowered trials have tried to determine whether combined hormone therapy (luteinizing hormone–releasing hormone [LH-RH] agonists plus tamoxifen) is superior to either approach alone. Results have been inconsistent.

Evidence (initial hormone therapy in premenopausal women):
1. The best study design compared buserelin (an LH-RH agonist) versus tamoxifen versus the combination in 161 premenopausal women with hormone receptor–positive tumors.[Level of evidence: 1iiA]
        • Patients who received buserelin and tamoxifen had a significantly improved median survival of 3.7 years compared with those who received tamoxifen alone (median survival, 2.9 years) or buserelin alone (median survival, 2.5 years) (P = .01).[Level of evidence: 1iiA]
        • Very few women in this trial received adjuvant tamoxifen, which makes it difficult to assess whether these results are applicable to women who relapse after adjuvant tamoxifen.

Second-line hormone therapy
Women whose tumors are ER positive or ER unknown, with bone or soft tissue metastases only, and who have been treated with tamoxifen, may be offered second-line hormone therapy. Examples of second-line hormone therapy in postmenopausal women include selective AI, such as anastrozole, letrozole, or exemestane; megestrol acetate; estrogens; androgens; and fulvestrant, an ER down-regulator.

Evidence (second-line hormone therapy):
1. Compared with megestrol acetate, all three currently available AI have demonstrated, in prospective randomized trials, at least equal efficacy and better tolerability.
2. In a meta-analysis that included randomized trials of patients who received an AI as either their first or second hormone therapy for metastatic disease, those who were randomly assigned to receive a third-generation drug (e.g., anastrozole, letrozole, exemestane, or vorozole) lived longer (HRdeath 0.87; 95% CI, 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[Level of evidence: 1iA]
3. Two randomized trials that enrolled 400 and 451 patients whose disease had progressed after they received tamoxifen demonstrated that fulvestrant yielded results similar to those of anastrozole in terms of its impact on PFS. The proper sequence of these therapies is currently not known.
4. No benefit has been found in combining anastrozole and fulvestrant in patients who had previously been treated with an AI.

Mammalian target of rapamycin (mTOR) inhibitor therapy
Endocrine therapy is recommended for patients with metastatic hormone receptor–positive disease. However, patients inevitably develop resistance to endocrine therapy. Preclinical models and clinical studies suggest that mTOR inhibitors might enhance the efficacy of endocrine therapies.

Evidence (mTOR inhibitor therapy):
1. The Breast Cancer Trial of Oral Everolimus (BOLERO-2 [NCT00863655]) was a randomized, phase III, placebo-controlled trial in which patients with hormone receptor–positive metastatic breast cancer that is resistant to nonsteroidal aromatase inhibition were randomly assigned to receive either the mTOR inhibitor everolimus plus exemestane, or placebo plus exemestane.[Level of evidence: 1iDiii]
        • At the interim analysis, median PFS was 6.9 months for everolimus plus exemestane and 2.8 months for placebo plus exemestane (HR, 0.43; 95% CI, 0.35–0.54; P < .001).
• The addition of everolimus to exemestane was more toxic than was placebo plus exemestane, with the most-common grade 3 or 4 adverse events being stomatitis (8% vs. 1%), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%).
        • The results of this study reported a benefit in PFS with the addition of an mTOR inhibitor to endocrine therapy, but there were more side effects.
        • There was no OS benefit to the combination after further follow-up.

2. Evidence of mTOR inhibitor activity in human epidermal growth factor receptor 2 (HER2)–positive breast cancer was shown in the double-blind, placebo-controlled, phase III BOLERO-3 (NCT01007942) trial.[Level of evidence: 1iDiii] In the BOLERO-3 trial, 569 patients with HER2-positive, trastuzumab-resistant, breast cancer, who had received previous taxane therapy, were randomly assigned to receive either everolimus plus trastuzumab plus vinorelbine, or placebo plus trastuzumab plus vinorelbine.
        • At median follow-up of 20.2 months, median PFS was 7.0 months in the everolimus group versus 5.78 months in the placebo group (HR, 0.78; 95% CI, 0.65–0.95; P = .0067).
        • Serious adverse events were reported in 117 patients (42%) in the everolimus group and 55 patients (20%) in the placebo group.
        • Final OS outcomes for this trial have not yet been reported.

Cyclin-dependent kinase inhibitor therapy
Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) have been implicated in the continued proliferation of HR-positive breast cancer resistant to endocrine therapy. CDK inhibitors have been approved by the U.S. Food and Drug Administration (FDA) in the first-line setting. Palbociclib is an orally available CDK4/6 inhibitor that has been shown in two trials to enhance the efficacy of endocrine therapy.

Evidence (cyclin-dependent kinase inhibitor therapy):
1. PALOMA-2 (NCT01740427) confirmed the results of the PALOMA-1 trial. This phase III, double-blind trial compared placebo plus letrozole with palbociclib plus letrozole as initial therapy for ER-positive postmenopausal patients with advanced disease (n = 666). Based on the high rates of neutropenia seen in the study it is unlikely that blinding was maintained in many cases.
        • The primary endpoint (investigator-assessed PFS) was met with a median PFS of 24.8 months in the palbociclib-plus-letrozole group compared with 14.5 months in the placebo-plus-letrozole group (HR, 0.58; 95% CI, 0.46–0.72; P < .001).[Level of evidence: 1iDiii]
        • No OS data are available.
        • Patients who received palbociclib experienced more frequent cytopenias (66.4% grade 3/4 in palbociclib-treated patients vs. 1.4% in placebo-treated patients). Other common adverse events included nausea, arthralgia, fatigue, and alopecia. The most common grade 3/4 adverse events other than neutropenia included leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%).
        • The FDA-granted accelerated approval to palbociclib on the basis of these results.

2. PALOMA-3 (NCT01942135) is a double-blind, phase III trial of 521 patients with hormone receptor–positive, HER2/neu–negative, advanced breast cancer who had relapsed from or progressed on previous endocrine therapy who were randomly assigned to receive either fulvestrant or fulvestrant plus palbociclib. Premenopausal and postmenopausal patients were eligible. Premenopausal patients received goserelin. The preplanned stopping boundary was crossed at the time of the first interim analysis of investigator-assessed PFS.[Level of Evidence: 1iC]
        • The final analysis showed a median PFS of 9.5 months on the palbociclib-fulvestrant arm versus 4.6 months on the placebo-fulvestrant arm (HR, 0.46; 95% CI, 0.36–0.59; P < .0001).[Level of Evidence: 1iC]
        • Cytopenias, particularly neutropenia, were much more frequent on the palbociclib-containing arm, but febrile neutropenia was very uncommon (1%) in both groups. Patients receiving palbociclib had more-frequent fatigue, nausea, and headache.
        • Tumor PIK3CA mutational status did not significantly affect the magnitude of benefit associated with fulvestrant plus palbociclib (two-sided Pinteraction = 0.83).
        • Global quality of life as assessed by the European Organisation for Research and Treatment of Cancer questionnaire, QLQ-C30, was better maintained on the palbociclib-fulvestrant arm (mean change, -0.9 points vs. -4.0 points; P = 0.03).
        • Patients continue to receive blinded therapy; OS results are not yet available.

3. Ribociclib, another CDK4/6 inhibitor, has also been tested in the first-line setting for postmenopausal patients with HR positive and HER2 negative recurrent or metastatic breast cancer. A phase III, placebo-controlled trial (NCT01958021) randomly assigned 668 patients to receive ribociclib plus letrozole or placebo plus letrozole.[36] Based on the high rates of neutropenia seen in the study, it is unlikely that blinding was maintained in many cases.
    a. The primary endpoint (investigator-assessed PFS) was met. A preplanned interim analysis was performed after 243 patients had disease progression or died, and median duration of follow-up was 15.3 months. After 18 months, the PFS rate was 63.0% (95% CI, 54.6–70.3) in the ribociclib group and 42.2% (95% CI, 34.8–49.5) in the placebo group.[Level of evidence: 1iDiii]
    b. No OS data are available.
    c. Adverse events in patients included neutropenia in the ribociclib group (74.3%) and in the placebo group (5.2%), nausea (51.5% and 28.5%), infection (50.3% and 42.4%), fatigue (36.5% and 30.0%), and diarrhea (35.0% and 22.1%).         • These events were mostly grade 1/2 with the exception of cytopenia.
        • Grade 3/4 neutropenia occurred in 59.3% of patients in the ribociclib group and 0.9% of patients in the placebo group.
        • The rate of febrile neutropenia was 1.5% in the ribociclib group and 0% in the placebo group.
        • An increase in QTcF (QT interval corrected for heart rate according to Fridericia’s formula) interval of more than 60 ms from baseline was observed in nine patients (2.7%) in the ribociclib arm compared with zero patients in the placebo arm.

4. The MONARCH 2 (NCT02107703) study tested abemaciclib (CDK4/6 inhibitor) in a phase III, placebo-controlled trial that randomly assigned 669 patients with HR-positive and HER2-negative advanced breast cancer (with previous progression on endocrine therapy) to receive abemaciclib plus fulvestrant or placebo plus fulvestrant.
    a. The primary endpoint (investigator-assessed PFS) was met, with median duration of follow-up of 19.5 months. The median PFS was 16.4 months for the abemaciclib-fulvestrant arm versus 9.3 months for the placebo-fulvestrant arm (HR, 0.55; 95% CI, 0.45–0.68; P < .001).[Level of evidence: 1iDiii]
    b. No OS data are available.
    c. Adverse events included diarrhea in the abemaciclib group (86.4%) and in the placebo group (24.7%), neutropenia (46% and 4%), nausea (45.1% and 22.9%), fatigue (39.9% and 26.9%), and abdominal pain (35.4% and 15.7%).
        • These events were mostly grade 1/2. Grade 1/2 diarrhea occurred in 73% of the patients in the abemaciclib group and in 24.2% of the placebo group. Anti-diarrheal medicine effectively managed this symptom in most cases, according to the study report.
        • Grade 3 diarrhea occurred in 13.4% of patients in the abemaciclib group and 0.4% of patients in the placebo group. No grade 4 diarrhea was reported.
        • Grade 3/4 neutropenia occurred in 25.5% of patients in the abemaciclib group and 1.7% of patients in the placebo group. Febrile neutropenia was reported in six patients in the abemaciclib arm.

 

 

HR-Negative Breast Cancer (Metastatic)


The treatment for HR-negative breast cancer is chemotherapy. (Refer to the Chemotherapy section of this summary for more information.)


 

HER2/neu–Positive Breast Cancer (Metastatic)


A number of HER2-targeted agents (e.g., trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib) have been approved for treatment of this disease.


SUMMARY:
Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer is single-agent chemotherapy plus trastuzumab.
No difference in OS, time to disease progression, or response rate was shown in the Breast Cancer International Research Group’s phase III trial (BCIRG-007 [NCT00047255]) that compared carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer.
Lapatinib plus capecitabine has shown activity in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab.


Monoclonal antibody therapy

Antibody therapy targeting the HER2 pathway has been used since the 1990s and has revolutionized the treatment of HER2-positive metastatic breast cancer.

Trastuzumab
Approximately 20% to 25% of patients with breast cancer have tumors that overexpress HER2/neu. Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor. In patients previously treated with cytotoxic chemotherapy whose tumors overexpress HER2/neu, administration of trastuzumab as a single agent resulted in a response rate of 21%.[Level of evidence: 3iiiDiv]

Evidence (trastuzumab):
1. In a phase III trial, patients with metastatic disease were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel) or the same chemotherapy plus trastuzumab.[Level of evidence: 1iiA]
        • Patients treated with chemotherapy plus trastuzumab had an OS advantage over those who received chemotherapy alone (25.1 months vs. 20.3 months, P = .05).[Level of evidence: 1iiA]

Notably, when combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.

Clinical trials comparing multiagent chemotherapy plus trastuzumab with single-agent chemotherapy have yielded conflicting results.
        • In one randomized study of patients with metastatic breast cancer treated with trastuzumab, paclitaxel, and carboplatin, patients tolerated the combination well and had a longer time to disease progression, compared with those treated with trastuzumab and paclitaxel alone.[Level of evidence: 1iDiii]
        • However, no difference in OS, time to disease progression, or response rate was shown in the Breast Cancer International Research Group’s phase III trial (BCIRG-007 [NCT00047255]) that compared carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for metastatic HER2-overexpressing breast cancer.[Level of evidence: 1iiA]

Outside of a clinical trial, standard first-line treatment for metastatic HER2-overexpressing breast cancer is single-agent chemotherapy plus trastuzumab.

Pertuzumab
Pertuzumab is a humanized monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than does trastuzumab. The binding of pertuzumab to HER2 prevents dimerization with other ligand-activated HER receptors, most notably HER3.

Evidence (pertuzumab):
1. The phase III CLEOPATRA (NCT00567190) trial assessed the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel, in the first-line HER2-positive metastatic setting.[Level of evidence: 1iA]
        • With a median follow-up of 50 months, the median OS was 40.8 months in the control group versus 56.5 months in the pertuzumab group (HR favoring pertuzumab group, 0.68; 95% CI, 0.56–0.84; P < .001). Median PFS per investigator assessment was improved by 6.3 months by the addition of pertuzumab (HR, 0.68; 95% CI, 0.58–0.80).
        • Median OS was 56.5 months in the pertuzumab group compared with 40.8 months in the placebo group (HR, 0.68; 95% CI, 0.57–0.84; P < .001).
        • The toxicity profile was similar in both treatment groups, with no increase in cardiac toxic effects seen in the pertuzumab combination arm.

Ado-trastuzumab emtansine
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. T-DM1 allows specific intracellular drug delivery to HER2-overexpressing cells, potentially improving the therapeutic index and minimizing exposure of normal tissue.

Evidence (T-DM1):
1. The phase III EMILIA or TDM4370g (NCT00829166) study was a randomized open-label trial that enrolled 991 patients with HER2-overexpressing, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane.[Level of evidence: 1iiA] Patients were randomly assigned to receive either T-DM1 or lapatinib plus capecitabine.
        • Median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (HR, 0.65; 95% CI, 0.55–0.77; P < .001).
        • Median OS was longer with trastuzumab emtansine versus lapatinib plus capecitabine (29.9 months vs. 25.9 months; HR, 0.75 [95% CI, 0.64–0.88].
        • The incidences of thrombocytopenia and increased serum aminotransferase levels were higher in patients who received T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar syndrome were higher in patients who received lapatinib plus capecitabine.

2. Further evidence of T-DM1’s activity in metastatic HER2-overexpressed breast cancer was shown in a randomized phase II study of T-DM1 versus trastuzumab plus docetaxel.[Level of evidence: 1iiDiii] This trial randomly assigned 137 women with HER2-overexpressed breast cancer in the first-line metastatic setting.
        • At median follow-up of 14 months, median PFS was 9.2 months with trastuzumab plus docetaxel and 14.2 months with T-DM1 (HR, 0.59; 95% CI, 0.36–0.97).
        • Preliminary OS results were similar between treatment arms.
        • T-DM1 had a favorable safety profile compared with trastuzumab plus docetaxel, with fewer grade 3 adverse events (46.4% vs. 90.9%), adverse events leading to treatment discontinuations (7.2% vs. 40.9%), and serious adverse events (20.3% vs. 25.8%).

3. Evidence of activity of T-DM1 in heavily pretreated patients with metastatic, HER2-overexpressed breast cancer who had received previous trastuzumab and lapatinib was shown in the randomized phase III TH3RESA (NCT01419197) study of T-DM1 versus physician’s choice of treatment.[Level of evidence: 1iiA] This trial randomly assigned 602 patients in a 2:1 ratio (404 patients assigned to T-DM1 and 198 patients assigned to physician’s choice) and allowed crossover to T-DM1.
        • At a median follow-up of 7.2 months in the T-DM1 group and 6.5 months in the physician’s choice group, median PFS was 6.2 months in the T-DM1 group and 3.3 months in the physician’s choice group (HR, 0.528; 95% CI, 0.422–0.661; P < .0001).
        • Overall survival was significantly longer with trastuzumab emtansine versus the treatment of physician’s choice (median OS, 22.7 months vs. 15.8 months; HR, 0.68; 95% CI, 0.54–0.85; P = .0007).

4. The role of T-DM1 as first-line treatment of metastatic HER2-overexpressed breast cancer was evaluated in the phase III MARIANNE (NCT01120184) trial.[Level of evidence: 1iDiii] This study randomly assigned 1,095 patients to receive either trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab.
        • The median PFS for these treatment groups was 13.7 months for the trastuzumab-plus-taxane group, 14.1 months for the T-DM1-plus-placebo group, and 15.2 months for the T-DM1-plus-pertuzumab group.
        • There was no significant difference in PFS with T-DM1 plus placebo compared with trastuzumab plus taxane (HR, 0.91; 97.5% CI, 0.73–1.13), or with T-DM1 plus pertuzumab compared with trastuzumab plus taxane (HR, 0.87; 97.5% CI, 0.69–1.08).
        • Therefore, neither T-DM1 plus placebo nor T-DM1 plus pertuzumab showed PFS superiority over trastuzumab plus taxane.

 



Tyrosine kinase inhibitor therapy


Lapatinib
Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor.
Lapatinib plus capecitabine has shown activity in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab.

Evidence (lapatinib):
1. A nonblinded randomized trial (GSK-EGF100151) compared the combination of capecitabine and lapatinib with capecitabine alone in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab.[Level of evidence: 1iiA]
        • Median time to disease progression in the lapatinib-plus-capecitabine arm was 8.4 months compared with 4.4 months in the capecitabine-alone arm (HR, 0.49; 95% CI, 0.34–0.71; P < .001).
        • There was no difference in OS (HR, 0.92; 95% CI, 0.58–1.46; P = .72).[Level of evidence: 1iiA]
        • Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. (Refer to the PDQ summary on Gastrointestinal Complications for more information about diarrhea.)
        • No data are available on quality of life or treatment after disease progression.

 

 

Germline BRCA Mutation


For patients with metastatic breast cancer who carry a germline BRCA mutation, the oral inhibitor of poly(adenosine diphosphate-ribose) polymerase (PARP) has shown activity. BRCA1 and BRCA2 are tumor-suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. PARP plays a critical role in DNA repair and has been studied as therapy for patients with breast cancer who harbor a germline BRCA mutation.

The OlympiAD (NCT02000622) trial was a randomized, open-label, phase III trial that randomly assigned 302 patients, in a 2:1 ratio, to receive olaparib (300 mg bid) or standard therapy (either single-agent capecitabine, eribulin, or vinorelbine). All patients had received anthracycline and taxane previously in either the adjuvant or metastatic setting, and those with HR-positive disease had also received endocrine therapy previously.

Median PFS was significantly longer in the olaparib group than in the standard therapy group (7.0 mo vs. 4.2. mo; HR for disease progression or death, 0.58; 95% CI, 0.43–0.80; P < .001).[Level of evidence: 1iiA] OS did not differ between the two treatment groups with median time to death (HRdeath, 0.90; 95% CI, 0.63–1.29; P = .57). Olaparib was less toxic than standard therapy, with a rate of grade 3 or higher adverse events of 36.6% in the olaparib group and 50.5% in the standard therapy group, with anemia, nausea, vomiting, fatigue, headache, and cough occurring more frequently with olaparib; neutropenia, palmar-plantar erythrodysesthesia, and liver-function test abnormalities occurred more commonly with chemotherapy. Of note, subset analysis suggested that PFS improvement with olaparib appeared greater in the TNBC subgroup (HR, 0.43; 95% CI, 0.29–0.63) than in the HR-positive subgroup (HR, 0.82; 95% CI, 0.55–1.26).

(Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)

 

Chemotherapy (For Metastatic Breast Cancer)


Patients on hormone therapy whose tumors have progressed are candidates for cytotoxic chemotherapy. There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. Patients with HR-negative tumors and those with visceral metastases or symptomatic disease are also candidates for cytotoxic agents.


Single agents that have shown activity in metastatic breast cancer include the following:
•Anthracyclines: •Doxorubicin. •Epirubicin. •Liposomal doxorubicin. •Mitoxantrone.
•Taxanes: •Paclitaxel. •Docetaxel. •Albumin-bound nanoparticle paclitaxel (ABI-007 or Abraxane).
•Alkylating agents.
•Cyclophosphamide.
•Fluoropyrimidines: •Capecitabine. •5-Fluorouracil (5-FU).
•Antimetabolites: •Methotrexate.
•Vinca alkaloids: •Vinorelbine. •Vinblastine. •Vincristine.
•Platinum: •Carboplatin. •Cisplatin.
•Other: •Gemcitabine. •Mitomycin C. •Eribulin mesylate. •Ixabepilone.

Combination regimens that have shown activity in metastatic breast cancer include the following:
•AC: Doxorubicin and cyclophosphamide.
•EC: Epirubicin and cyclophosphamide.
•Docetaxel and doxorubicin.
•CAF: Cyclophosphamide, doxorubicin, and 5-FU.
•CMF: Cyclophosphamide, methotrexate, and 5-FU.
•Doxorubicin and paclitaxel.
•Docetaxel and capecitabine.
•Vinorelbine and epirubicin.
•Capecitabine and ixabepilone.
•Carboplatin and gemcitabine.
•Gemcitabine and paclitaxel.

There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. An Eastern Cooperative Oncology intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin, given both as a combination and sequentially. Although response rate and time to disease progression were both better for the combination, survival was the same in both groups.[Level of evidence: 1iiA];

The selection of therapy in individual patients is influenced by the following:
• Rate of disease progression.
• Presence or absence of comorbid medical conditions.
• Physician/patient preference.

At this time, no data support the superiority of any particular regimen. Sequential use of single agents or combinations can be used for patients who relapse with metastatic disease. Combination chemotherapy is often given if there is evidence of rapidly progressive disease or visceral crisis. Combinations of chemotherapy and hormone therapy have not shown an OS advantage over the sequential use of these agents. A systematic review of 17 randomized trials found that the addition of one or more chemotherapy drugs to a chemotherapy regimen in the attempt to intensify the treatment improved tumor response but had no effect on OS.[Level of evidence: 1iiA]

Decisions regarding the duration of chemotherapy may take into account the following:
•Patient preference and goals of treatment.
•Presence of toxicities from previous therapies.
•Availability of alternative treatment options.
The optimal time for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, two randomized trials have shown a prolonged DFS after immediate treatment with a different chemotherapy regimen compared with observation and treatment upon relapse.[Level of evidence: 1iiA] Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment; in one of these studies, survival was actually worse in the group that was treated immediately. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomly assigned to receive either a different chemotherapy versus observation or a different chemotherapy regimen given at higher versus lower doses.[Level of evidence: 1iiA] However, 324 patients who achieved disease control were randomly assigned to maintenance chemotherapy or observation. Patients who received maintenance chemotherapy (paclitaxel and gemcitabine) had improved PFS at 6 months and improved OS. This was associated with an increased rate of adverse events.[Level of evidence: 1iiA] Because there is no standard approach for treating metastatic disease, patients requiring second-line regimens are good candidates for clinical trials.

Cardiac toxic effects with anthracyclines
The potential for anthracycline-induced cardiac toxic effects should be considered in the selection of chemotherapeutic regimens for selected patients. Recognized risk factors for cardiac toxicity include the following:
• Advanced age.
• Previous chest-wall radiation therapy.
• Previous anthracycline exposure.
• Hypertension and known underlying heart disease.
• Diabetes.

The cardioprotective drug dexrazoxane has been shown to decrease the risk of doxorubicin-induced cardiac toxicity in patients in controlled studies. The use of this agent has permitted patients to receive higher cumulative doses of doxorubicin and has allowed patients with cardiac risk factors to receive doxorubicin.[93-96] The risk of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion.[97] The American Society of Clinical Oncology guidelines suggest the use of dexrazoxane in patients with metastatic cancer who have received a cumulative dose of doxorubicin of 300 mg/m2 or more when further treatment with an anthracycline is likely to be of benefit. Dexrazoxane has a similar protective effect in patients receiving epirubicin.

 

 

Surgery (in Metastatic Breast Cancer)


Surgery may be indicated for select patients. For example, patients may need surgery if the following issues occur:

• Fungating/painful breast lesions (mastectomy).
• Parenchymal brain or vertebral metastases with spinal cord compression.
• Isolated lung metastases.
• Pathologic (or impending) fractures.
• Pleural or pericardial effusions.

(Refer to the PDQ summary on Cancer Pain for more information;
refer to the PDQ summary on Cardiopulmonary Syndromes for information about pleural and pericardial effusions.)


 

Radiation Therapy (in Metastatic Breast Cancer)


Radiation therapy has a major role in the palliation of localized symptomatic metastases.
Indications for external-beam radiation therapy include the following:
• Painful bony metastases.
• Unresectable central nervous system metastases (i.e., brain, meninges, and spinal cord).
• Bronchial obstruction.
• Fungating/painful breast or chest wall lesions.
• After surgery for decompression of intracranial or spinal cord metastases.
• After fixation of pathologic fractures.
Strontium chloride Sr 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases.


 

Bone Modifier Therapy (in Metastatic Breast Cancer)


The use of bone modifier therapy to reduce skeletal morbidity in patients with bone metastases should be considered. Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate.

The optimal dosing schedule for zoledronate was studied in CALGB-70604 [Alliance; NCT00869206], which randomly assigned 1,822 patients, 855 of whom had metastatic breast cancer, to receive zoledronic acid every 4 weeks or every 12 weeks. Skeletal-related events were similar in both groups, with 260 patients (29.5%) in the zoledronate every-4-week dosing group and 253 patients (28.6%) in the zoledronate every-12-week dosing group experiencing at least one skeletal-related event (risk difference of -0.3% [1-sided 95% CI, -4% to infinity]; P < .001 for noninferiority).[Level of evidence: 1iiD] This study suggests that the longer dosing interval of zoledronate every 12 weeks is a reasonable treatment option.

The monoclonal antibody denosumab inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL). A meta-analysis of three phase III trials (NCT00321464, NCT00321620, and NCT00330759) comparing zoledronate versus denosumab for management of bone metastases suggests that denosumab is similar to zoledronate in reducing the risk of a first skeletal-related event.

(Refer to the PDQ summary on Cancer Pain for more information on bisphosphonates.)


 

Bevacizumab (in Metastatic Breast Cancer)


Bevacizumab is a humanized monoclonal antibody directed against all isoforms of vascular endothelial growth factor–A. Its role in the treatment of metastatic breast cancer remains controversial.

Evidence (bevacizumab for metastatic breast cancer):
1. The efficacy and safety of bevacizumab as a second- and third-line treatment for patients with metastatic breast cancer were studied in a single, open-label, randomized trial. The study enrolled 462 patients who had received previous anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab.[Level of evidence: 1iiA]
        • The study failed to demonstrate a statistically significant effect on PFS (4.9 mo with combination therapy vs. 4.2 mo with capecitabine alone; HR, 0.98) or OS (15.1 mo vs. 14.5 mo).[Level of Evidence: 1iiA]

2. ECOG-2100 (NCT00028990), an open-label, randomized, phase III trial, compared paclitaxel alone with paclitaxel and bevacizumab.[Level of evidence: 1iiA]
        • The trial demonstrated that the addition of bevacizumab to paclitaxel significantly prolonged median PFS compared with paclitaxel alone as the initial treatment for patients with metastatic breast cancer (11.8 mo vs. 5.9 mo; HR, 0.60; P < .001).[Level of Evidence: 1iiA]
        • The addition of bevacizumab did not improve OS (26.7 mo vs. 25.2 mo; P = .16).
        • Notably, patients treated on the bevacizumab-containing arm had significantly higher rates of severe
proteinuria, cerebrovascular ischemia, and infection.

3. The AVADO (NCT00333775) trial randomly assigned 736 patients to receive docetaxel plus either placebo or bevacizumab at 7.5 mg/kg or 15 mg/kg every 3 weeks as the initial treatment for patients with metastatic breast cancer.[Level of evidence: 1iiA]
        • The combination of docetaxel plus bevacizumab at 15 mg/kg, but not 7.5 mg/kg, modestly improved median PFS compared with placebo (10.1 mo vs. 8.1 mo) but did not improve OS (30.2 mo vs. 31.9 mo; P = .85).[Level of Evidence: 1iiA]
        • More toxicity was seen in patients in the bevacizumab-containing arms, with significantly higher rates of bleeding and hypertension compared with patients in the placebo arms.

4. The RIBBON 1 (NCT00262067) trial randomly assigned 1,237 patients in a 2:1 fashion to receive either standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.[Level of evidence: 1iiA]
        • Median PFS was longer for each bevacizumab-containing combination (capecitabine cohort: increased from 5.7 mo to 8.6 mo; HR, 0.69; 95% CI, 0.56–0.84; log-rank, P < .001; and taxane/anthracycline cohort: increased from 8.0 mo to 9.2 mo; HR, 0.64; 95% CI, 0.52–0.80; log-rank, P < .001).[Level of Evidence: 1iiA]
        • No statistically significant differences in OS between the placebo- and bevacizumab-containing arms were observed.
        • Toxicities associated with bevacizumab were similar to those seen in previous bevacizumab clinical trials.
5. The RIBBON 2 (NCT00281697) trial studied the efficacy of bevacizumab as a second-line treatment for metastatic breast cancer. This trial randomly assigned 684 patients in a 2:1 fashion to receive either standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo.[Level of evidence: 1iA]
        • Median PFS increased from 5.1 to 7.2 months for the bevacizumab-containing treatment arm (stratified HR for PFS, 0.78; 95% CI, 0.64–0.93; P = .0072).
        • However, no statistically significant difference in OS was seen (16.4 mo for chemotherapy plus placebo vs. 18.0 mo for chemotherapy plus bevacizumab, P = .3741).[Level of evidence: 1iA]
        • Toxicities associated with bevacizumab were similar to those seen in previous clinical trials.

In November 2011, on the basis of the consistent finding that bevacizumab improved PFS only modestly but did not improve OS, and given bevacizumab’s considerable toxicity profile, the FDA revoked approval of bevacizumab for the treatment of metastatic breast cancer.


 

 

Ductal Carcinoma In Situ


Introduction
Ductal carcinoma in situ (DCIS) is a noninvasive condition. DCIS can progress to invasive cancer, but estimates of the probability of this vary widely. Some reports include DCIS in breast cancer statistics. In 2015, DCIS is expected to account for about 16% of all newly diagnosed invasive plus noninvasive breast tumors in the United States. For invasive and noninvasive tumors detected by screening, DCIS accounts for approximately 25% of all cases.

The frequency of a DCIS diagnosis has increased markedly in the United States since the use of screening mammography became widespread. Very few cases of DCIS present as a palpable mass, with more than 90% being diagnosed by mammography alone.

DCIS comprises a heterogeneous group of histopathologic lesions that have been classified into the following subtypes primarily on the basis of architectural pattern:
• Micropapillary.
• Papillary.
• Solid.
• Cribriform.
• Comedo.

Comedo-type DCIS consists of cells that appear cytologically malignant, with the presence of high-grade nuclei, pleomorphism, and abundant central luminal necrosis. Comedo-type DCIS appears to be more aggressive, with a higher probability of associated invasive ductal carcinoma.


Treatment Options for Patients With DCIS

Treatment options for DCIS include the following:
1. Breast-conserving surgery or mastectomy plus radiation therapy with or without tamoxifen.
2. Total mastectomy with or without tamoxifen.


In the past, the customary treatment for DCIS was mastectomy. The rationale for mastectomy included a 30% incidence of multicentric disease, a 40% prevalence of residual tumor at mastectomy after wide excision alone, and a 25% to 50% incidence of in-breast recurrence after limited surgery for palpable tumor, with 50% of those recurrences being invasive carcinoma. The combined local and distant recurrence rate after mastectomy is 1% to 2%. No randomized comparisons of mastectomy versus breast-conserving surgery plus breast radiation therapy are available.

Because breast-conserving surgery combined with breast radiation therapy is successful for invasive carcinoma, this conservative approach was extended to DCIS. To determine whether breast-conserving surgery plus radiation therapy was a reasonable approach to the management of DCIS, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) have each completed prospective randomized trials in which women with localized DCIS and negative surgical margins after excisional biopsy were randomly assigned to receive either breast radiation therapy (50 Gy) or no further therapy.

Evidence (breast-conserving surgery plus radiation therapy to the breast):
1. Of the 818 women enrolled in the NSABP-B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or smaller. Results were reported at the 12-year actuarial follow-up interval.; [Level of evidence: 1iiDii]
        • The overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005).
        • Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001).
        •Nine pathologic features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.

2. Similarly, of the 1,010 patients enrolled in the EORTC-10853 trial, mammography detected lesions in 71% of the women. Results were reported at a median follow-up of 10.5 years.[Level of evidence: 1iiDii]
        • The overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P < .001), with a similarly effective reduction of invasive recurrence rates (13% to 8%, P = .065) and noninvasive recurrence rates (14% to 7%, P = .001).
        • In this analysis, parameters associated with an increased risk of in-breast recurrence included age 40 years or younger, palpable disease, intermediate or poorly differentiated DCIS, cribriform or solid growth pattern, and indeterminate margins. Elsewhere, margins of less than 1 mm have been associated with an unacceptable local recurrence rate, even with radiation therapy.

In both of these studies, the effect of radiation therapy was consistent across all assessed risk factors.

3. The benefit of administering radiation therapy has been confirmed in a systematic review of four randomized trials (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.41–0.58; P < .00001). In this study, the number needed to treat with radiation therapy was nine women to prevent one ipsilateral breast recurrence.

4. A large national clinical trial by the Radiation Therapy Oncology Group (RTOG-9804 [NCT00003857]) comparing breast-conserving surgery and tamoxifen with or without radiation therapy was closed because of poor accrual (636 of planned 1,790 patients accrued). Patients with good-risk DCIS (defined as mammographically detected low- or intermediate-grade DCIS, measuring less than 2.5 cm with margins of 3 mm or more) were enrolled.
        • With a median follow-up of 7 years, the ipsilateral local failure rate was low with observation (6.7%; 95% CI, 3.2%–9.6%) but was decreased significantly with the addition of radiation therapy (0.9%; 95% CI, 0.0%–2.2%).

The results of the NSABP-B-17 and EORTC-10853 trials plus two others were included in a meta-analysis that demonstrated reductions in all ipsilateral breast events (HR, 0.49; 95% CI, 0.41–0.58; P < .00001), ipsilateral invasive recurrence (HR, 0.50; 95% CI, 0.32–0.76; P = .001), and ipsilateral DCIS recurrence (HR, 0.61; 95% CI, 0.39–0.95; P = .03).[Level of evidence: 1iiD] After 10 years of follow-up, there was, however, no significant effect on breast cancer mortality, mortality from causes other than breast cancer, or all-cause mortality.

To identify a favorable group of patients for whom postoperative radiation therapy could be omitted, several pathologic staging systems have been developed and tested retrospectively, but consensus recommendations have not been achieved.

The Van Nuys Prognostic Index is one pathologic staging system that combines three predictors of local recurrence (i.e., tumor size, margin width, and pathologic classification). It was used to retrospectively analyze 333 patients treated with either excision alone or excision and radiation therapy. Using this prognostic index, patients with favorable lesions who received surgical excision alone had a low recurrence rate (i.e., 2%, with a median follow-up of 79 mo). A subsequent analysis of these data was performed to determine the influence of margin width on local control. Patients whose excised lesions had margin widths of 10 mm or more in every direction had an extremely low probability of local recurrence with surgery alone (4%, with a mean follow-up of 8 y).

Both reviews are retrospective, noncontrolled, and subject to substantial selection bias. In contrast, the prospective NSABP trial did not identify any subset of patients who did not benefit from the addition of radiation therapy to breast-conserving surgery in the management of DCIS.

To determine whether tamoxifen adds to the efficacy of local therapy in the management of DCIS, the NSABP performed a double-blind prospective trial (NSABP-B-24).

Evidence (adjuvant endocrine therapy):
1. In NSABP-B-24, 1,804 women were randomly assigned to receive breast-conserving surgery, radiation therapy (50 Gy), and placebo or breast-conserving surgery, radiation therapy, and tamoxifen (20 mg qd for 5 y). Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured 1 cm or less, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases.
        • Women in the tamoxifen group had fewer breast cancer events at 5 years than did those treated with a placebo (8.2% vs. 13.4%; P = .009).[Level of evidence: 1iDii]
        • With tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5 years (P = .03).
        • Tamoxifen also decreased the incidence of contralateral breast neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year (P = .01).
        • The benefit of tamoxifen extended to patients with positive or uncertain margins. (Refer to the PDQ summary on Breast Cancer Prevention for more information.)
        • No survival advantage was demonstrated for the use of tamoxifen.
2. In NSABP-B-24, 1,804 women were randomly assigned to receive breast-conserving surgery, radiation therapy (50 Gy), and placebo or breast-conserving surgery, radiation therapy, and tamoxifen (20 mg qd for 5 y). Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured 1 cm or less, and more than 80% were detected mammographically. Breast cancer events were defined as the presence of new ipsilateral disease, contralateral disease, or metastases.
        • No survival advantage was demonstrated for the use of tamoxifen.

3. In the NSABP-B35 double-blind study, 3,104 postmenopausal women with DCIS who were treated with breast-conserving surgery were randomly assigned to receive either adjuvant tamoxifen or anastrozole, in addition to adjuvant radiation therapy.
        • The use of anastrozole was associated with significantly fewer breast cancer events (HR, 0.73; P = .023) but no improvement in survival.[Level of evidence: 1iDi]
4. The Second International Breast Cancer Intervention Study (IBIS II DCIS [NCT00078832]) trial enrolled 2,980 postmenopausal women in a double-blind comparison of tamoxifen with anastrozole as adjuvant therapy. All of the women had breast conserving surgery, and 71% of them had radiation therapy.
        • No difference in the rate of breast cancer recurrence in favor of anastrozole was found (HR, 0.89; 95% CI, 0.64–1.23; P = .49), and there was no difference in survival.

The decision to prescribe endocrine therapy after a diagnosis of DCIS often involves a discussion with the patient about the potential benefits and side effects of each agent.

 

 

Systemic therap for Breast Cancer

There are 3 general categories of systemic therapy used for early-stage and locally-advanced breast cancer: chemotherapy, hormonal therapy, and targeted therapy. Treatment options are based on information about the cancer and patients' overall health and treatment preferences.


Hormonal therapy

Hormonal therapy, also called endocrine therapy, is an effective treatment for most tumors that test positive for either estrogen or progesterone receptors (called ER-positive or PR-positive. This type of tumor uses hormones to fuel its growth. Blocking the hormones can help prevent a cancer recurrence and death from breast cancer when used either by itself or after adjuvant or neoadjuvant chemotherapy.

Hormonal therapy may be given before surgery to shrink a tumor and make surgery easier. This approach is called neoadjuvant hormonal therapy. It may also be given after surgery to reduce the risk of recurrence. This is called adjuvant hormonal therapy.

• Tamoxifen. Tamoxifen is a drug that blocks estrogen from binding to breast cancer cells. It is effective for lowering the risk of recurrence in the breast that had cancer, the risk of developing cancer in the other breast, and the risk of distant recurrence. It is also approved by the FDA to reduce the risk of breast cancer in women at high risk for developing breast cancer and for lowering the risk of a local recurrence for women with DCIS who have had a lumpectomy. Tamoxifen works well in women who have been through menopause and those who have not.

Tamoxifen is a pill that is taken daily by mouth. It is important to discuss any other medications or supplements you take with your doctor, as there are some that can interfere with tamoxifen. Common side effects of tamoxifen include hot flashes as well as vaginal dryness, discharge or bleeding. Very rare risks include a cancer of the lining of the uterus; cataracts; and blood clots. However, tamoxifen may improve bone health and cholesterol levels.

• Aromatase inhibitors (AIs). AIs decrease the amount of estrogen made in tissues other than the ovaries in postmenopausal women by blocking the aromatase enzyme. This enzyme changes weak male hormones called androgens into estrogen when the ovaries have stopped making estrogen during menopause. These drugs include anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara). All of the AIs are pills taken daily by mouth. Only women who have been through menopause can take AIs. Treatment with AIs, either alone or following tamoxifen, can be as effective as taking tamoxifen alone at reducing the risk of recurrence in post-menopausal women.

The side effects of AIs may include muscle and joint pain, hot flashes, vaginal dryness, an increased risk of osteoporosis and broken bones, and increased cholesterol levels. Research shows that all 3 AI drugs work equally well and have similar side effects. However, women who have undesirable side effects while taking 1 AI may have fewer side effects with another AI for unclear reasons.

Women who have not gone through menopause should not take AIs, as they do not block the effects of estrogen made by the ovaries. Often, doctors will monitor blood estrogen levels in women whose periods have recently stopped, or those whose periods stop with chemotherapy to be sure that the ovaries are no longer producing estrogen.

Women who have gone through menopause and are prescribed hormonal therapy have several options:
• Start therapy with an AI for up to 5 years
• Begin treatment with tamoxifen for 2 to 3 years and then switch to an AI for 2 to 3 years
• Take tamoxifen for 5 years then switch to an AI for up to 5 years, in what is called extended hormonal therapy
Research shows that taking tamoxifen for up to 10 years can further reduce the risk of recurrence following a diagnosis of early-stage and locally advanced breast cancer. However, side effects are also increased with longer duration of therapy. Learn more about ASCO's recommendations for hormonal therapy for hormone receptor-positive breast cancer.

Hormonal therapy for premenopausal women
As noted above, premenopausal women should not take AIs, as they will not work. Options for adjuvant hormonal therapy for premenopausal women include the following:
• 5 or more years of tamoxifen, possibly switching to an AI after menopause begins
• Either tamoxifen or an AI combined with suppression of ovarian function. One of the oldest hormone treatments for hormone receptor-positive breast cancer is to stop the ovaries from making estrogen, called ovarian suppression. Medications called gonadotropin or luteinizing releasing hormone (GnRH or LHRH) analogues stop the ovaries from making estrogen, causing temporary menopause. Goserelin (Zoladex) and leuprolide (Lupron) are drugs given by injection that can stop the ovaries from making estrogen for 1 to 3 months. These drugs are given with tamoxifen or AIs as part of adjuvant therapy for breast cancer. Surgical removal of the ovaries, which is a permanent way to stop the ovaries from working, may also be considered in certain situations.

Targeted therapyy

Targeted therapy is a treatment that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. These treatments are very focused and work differently than chemotherapy. This type of treatment blocks the growth and spread of cancer cells while limiting damage to healthy cells.

Recent studies show that not all tumors have the same targets. To find the most effective treatment, your doctor may run tests to identify the genes, proteins, and other factors in your tumor. In addition, many research studies are taking place now to find out more about specific molecular targets and new treatments directed at them.

The first approved targeted therapies for breast cancer were hormonal therapies. Then, HER2-targeted therapies were approved to treat HER2-positive breast cancer.

HER2-targeted therapy
• Trastuzumab. This drug is approved as a therapy for non-metastatic HER2-positive breast cancer. Currently, patients with stage I to stage III breast cancer (see Stages) should receive a trastuzumab-based regimen often including a combination of trastuzumab with chemotherapy, followed by completion of 1 year of adjuvant trastuzumab. Patients receiving trastuzumab have a small (2% to 5%) risk of heart problems. This risk is increased if a patient has other risk factors for heart disease or receives chemotherapy that also increases the risk of heart problems at the same time. These heart problems may go away and can be treatable with medication.

• Pertuzumab (Perjeta). This drug is approved as part of neoadjuvant treatment for breast cancer in combination with trastuzumab and chemotherapy.

• Ado-trastuzumab emtansine or T-DM1 (Kadcyla). T-DM1 is a combination of trastuzumab linked to a type of chemotherapy. This allows the drug to deliver chemotherapy into the cancer cell while reducing the chemotherapy received by healthy cells. T-DM1 is approved to treat metastatic breast cancer, and studies are now testing T-DM1 as a treatment for early-stage breast cancer.

• Neratinib (Nerlynx). This oral drug is approved as a treatment for higher-risk HER2-positive, early-stage breast cancer. It is taken for a year, starting after patients have finished 1 year of trastuzumab.

 



Chemotherapy

Chemotherapy is the use of drugs to destroy cancer cells, usually by ending the cancer cells’ ability to grow and divide.

Chemotherapy may be given before surgery to shrink a large tumor and make surgery easier, called neoadjuvant chemotherapy. It may also be given after surgery to reduce the risk of recurrence, called adjuvant chemotherapy.

A chemotherapy regimen, or schedule, usually consists of a specific number of cycles given over a set period of time. Chemotherapy may be given on many different schedules depending on what worked best in clinical trials for that specific type of regimen. It may be given once a week, once every 2 weeks (also called dose-dense), once every 3 weeks, or even once every 4 weeks. There are many types of chemotherapy used to treat breast cancer. Common drugs include:

•Capecitabine (Xeloda) •Carboplatin (Paraplatin) •Cisplatin (Platinol) •Cyclophosphamide (Neosar) •Docetaxel (Docefrez, Taxotere) •Doxorubicin (Adriamycin) •Pegylated liposomal doxorubicin (Doxil) •Epirubicin (Ellence) •Fluorouracil (5-FU, Adrucil) •Gemcitabine (Gemzar) •Methotrexate (multiple brand names) •Paclitaxel (Taxol) •Protein-bound paclitaxel (Abraxane) •Vinorelbine (Navelbine) •Eribulin (Halaven) •Ixabepilone (Ixempra)

A patient may receive 1 drug at a time or combinations of different drugs given at the same time. Research has shown that combinations of certain drugs are sometimes more effective than single drugs for adjuvant treatment. The following drugs or combinations of drugs may be used as adjuvant therapy for early-stage and locally advanced breast cancer:

• AC (doxorubicin and cyclophosphamide)
• AC or EC (epirubicin and cyclophosphamide) followed by T (doxorubicin and cyclophosphamide, followed by paclitaxel or docetaxel, or the reverse)
• CAF (cyclophosphamide, doxorubicin, and 5-FU)
• CEF (cyclophosphamide, epirubicin, and 5-FU)
• CMF (cyclophosphamide, methotrexate, and 5-FU)
• EC (epirubicin, cyclophosphamide)
• TAC (docetaxel, doxorubicin, and cyclophosphamide)
• TC (docetaxel and cyclophosphamide)

Therapies that target the HER2 receptor may be given with chemotherapy for HER2-positive breast cancer (see Targeted therapy, above). An example is the antibody trastuzumab. Combination regimens for HER2-positive breast cancer may include:
• ACTH (doxorubicin, cyclophosphamide, paclitaxel, trastuzumab)
• TCH (docetaxel, carboplatin, trastuzumab)
• TH (paclitaxel, trastuzumab)
• THP (paclitaxel or docetaxel, trastuzumab, pertuzumab)
• TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab)

The side effects of chemotherapy depend on the individual, the drug(s) used, and the schedule and dose used. These side effects can include fatigue, risk of infection, nausea and vomiting, hair loss, loss of appetite, and diarrhea. These side effects can often be very successfully prevented or managed during treatment with supportive medications, and they usually go away after treatment is finished. Rarely, long-term side effects may occur, such as heart damage, nerve damage, or secondary cancers. Many patients feel well during chemotherapy treatment and are active taking care of their families, working, and exercising during treatment, although each person’s experience can be different. Talk with your health care team about the possible side effects of your specific chemotherapy plan.

Learn more about the basics of chemotherapy and preparing for treatment. The medications used to treat cancer are continually being evaluated. Talking with your doctor, oncology nurse, or pharmacist is often the best way to learn about the medications prescribed for you, their purpose, and their potential side effects or interactions with other medications. Learn more about your prescriptions by using searchable drug databases.