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Breast Cancer Treatment (PDQ®)

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General Information About Breast Cancer
Histopathologic Classification of Breast Cancer
Stage Information for Breast Cancer
Early/Localized/Operable Breast Cancer
Locally Advanced or Inflammatory Breast Cancer
Locoregional Recurrent Breast Cancer
Metastatic Breast Cancer
Ductal Carcinoma In Situ
Changes to This Summary (10/13/2017)
About This PDQ Summary

General Information About 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. Refer to the following PDQ summaries for more information on these cancer types:

Breast cancer also affects men and children and may occur during pregnancy, although it is rare in these populations. Refer to the following PDQ summaries for more information:

Incidence and Mortality

Estimated new cases and deaths from breast cancer (women only) in the United States in 2017: [1]

Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 61,000 cases of in situ disease and 246,660 cases of invasive disease in 2016. [2] Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 71,280 American women will die of lung cancer in 2017. [1] Men account for 1% of breast cancer cases and breast cancer deaths (refer to the Special Populations section in the PDQ summary on Breast Cancer Screening for more information).

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 [3] and the United Kingdom [4] 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. [5]

Anatomy

Drawing of female breast anatomy showing  the lymph nodes, nipple, areola, chest wall, ribs, muscle, fatty tissue, lobe, ducts, and lobules.Anatomy of the female breast. The nipple and areola are shown on the outside of the breast. The lymph nodes, lobes, lobules, ducts, and other parts of the inside of the breast are also shown.

Risk Factors

Increasing age is the most important risk factor for most cancers. Other risk factors for breast cancer include the following:

Age-specific risk estimates are available to help counsel and design screening strategies for women with a family history of breast cancer. [23] [24]

Of all women with breast cancer, 5% to 10% may have a germline mutation of the genes BRCA1 and BRCA2. [25] Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry. [26] 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. [27] Male BRCA2 mutation carriers also have an increased risk of breast cancer. [28]

Mutations in either the BRCA1 or the BRCA2 gene also confer an increased risk of ovarian cancer [28] [29] or other primary cancers. [28] [29] Once a BRCA1 or BRCA2 mutation has been identified, other family members can be referred for genetic counseling and testing. [30] [31] [32] [33] (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.)

Protective Factors

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

(Refer to the PDQ summary on Breast Cancer Prevention for more information about factors that decrease 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:

The following tests and procedures are used to diagnose breast cancer:

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. [52] [53] [54] The development of a contralateral breast cancer is associated with an increased risk of distant recurrence. [55] 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. [56] [57]

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. [58] [59] [60]

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): [61]

The use of molecular profiling in breast cancer includes the following: [65]

On the basis of ER, PR, and HER2/neu results, breast cancer is classified as one of the following types:

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. [66] [67]

Gene profile tests include the following:

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.
  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-20 trial. [73] 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). [76]
  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). [78] 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.
  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. [79] Primary endpoint results from this study are awaited.

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:

Related Summaries

Other PDQ summaries containing information related to breast cancer include the following:

References:

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  45. Goss PE, Ingle JN, Alés-Martínez JE, et al.: Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 364 (25): 2381-91, 2011.
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  48. Rebbeck TR, Levin AM, Eisen A, et al.: Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91 (17): 1475-9, 1999.
  49. Kauff ND, Satagopan JM, Robson ME, et al.: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346 (21): 1609-15, 2002.
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  51. Kauff ND, Domchek SM, Friebel TM, et al.: Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol 26 (8): 1331-7, 2008.
  52. Rosen PP, Groshen S, Kinne DW, et al.: Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up. J Clin Oncol 11 (11): 2090-100, 1993.
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Histopathologic Classification of Breast Cancer

Table 1 describes the histologic classification of breast cancer based on tumor location. [1] Infiltrating or invasive ductal cancer is the most common breast cancer histologic type and comprises 70% to 80% of all cases.

Table 1. Tumor Location and Related Histologic Subtype

Tumor Location Histologic Subtype
Carcinoma, NOS 
DuctalIntraductal (in situ)
Invasive with predominant component  
Invasive, NOS  
Comedo 
Inflammatory  
Medullary with lymphocytic infiltrate  
Mucinous (colloid)  
Papillary  
Scirrhous  
Tubular  
Other  
LobularInvasive with predominant in situ component
Invasive [2]  
NipplePaget 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:

References:

  1. Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
  2. Yeatman TJ, Cantor AB, Smith TJ, et al.: Tumor biology of infiltrating lobular carcinoma. Implications for management. Ann Surg 222 (4): 549-59; discussion 559-61, 1995.
  3. Chaney AW, Pollack A, McNeese MD, et al.: Primary treatment of cystosarcoma phyllodes of the breast. Cancer 89 (7): 1502-11, 2000.
  4. Carter BA, Page DL: Phyllodes tumor of the breast: local recurrence versus metastatic capacity. Hum Pathol 35 (9): 1051-2, 2004.

Stage Information for Breast Cancer

The American Joint Committee on Cancer (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:

Definitions of TNM and AJCC Stage Groupings

The AJCC has designated staging by tumor, node, and metastasis (TNM) classification to define breast cancer. [1] When this system was modified in 2002, some nodal categories that were previously considered stage II were reclassified as stage III. [2] 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. [3]

Table 2. Primary Tumor (T)a,b

TXPrimary tumor cannot be assessed.
T0No evidence of primary tumor.
TisCarcinoma in situ.
Tis (DCIS)DCIS.
Tis (LCIS)LCIS.*
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.
T1Tumor ≤20 mm in greatest dimension.
T1miTumor ≤1 mm in greatest dimension.
T1aTumor >1 mm but ≤5 mm in greatest dimension.
T1bTumor >5 mm but ≤10 mm in greatest dimension.
T1cTumor >10 mm but ≤20 mm in greatest dimension.
T2Tumor >20 mm but ≤50 mm in greatest dimension.
T3Tumor >50 mm in greatest dimension.
T4Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules).c
T4aExtension to the chest wall, not including only pectoralis muscle adherence/invasion.
T4bUlceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the skin, which do not meet the criteria for inflammatory carcinoma.
T4cBoth T4a and T4b.
T4dInflammatory carcinoma.
DCIS = ductal carcinoma in situ; LCIS = lobular carcinoma in situ.
*Information about LCIS is not included in this summary.
aReprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
bThe 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.
cInvasion of the dermis alone does not qualify as T4.

Table 3. Regional Lymph Nodes (N)a

Clinical
NXRegional lymph nodes cannot be assessed (e.g., previously removed).
N0No regional lymph node metastases.
N1Metastases to movable ipsilateral level I, II axillary lymph node(s).
N2Metastases 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. 
N2aMetastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures.
N2bMetastases only in clinically detectedb ipsilateral internal mammary nodes and in the absence of clinically evident level I, II axillary lymph node metastases.
N3Metastases 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. 
N3aMetastases in ipsilateral infraclavicular lymph node(s).
N3b Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s).
N3cMetastases in ipsilateral supraclavicular lymph node(s).
aReprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
bClinically 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.

Table 4. Pathologic (pN)a,b

pNXRegional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study).
pN0No 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.
pN1Micrometastases.
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.c 
pN1miMicrometastases (>0.2 mm and/or >200 cells but none >2.0 mm).
pN1aMetastases in 1–3 axillary lymph nodes, at least one metastasis >2.0 mm.
pN1bMetastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.c
pN1cMetastases 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.
pN2Metastases in 4–9 axillary lymph nodes.
OR 
Metastases in clinically detectedd internal mammary lymph nodes in the absence of axillary lymph node metastases. 
pN2aMetastases in 4–9 axillary lymph nodes (at least 1 tumor deposit >2 mm).
pN2bMetastases in clinically detectedd internal mammary lymph nodes in the absence of axillary lymph node metastases.
pN3Metastases 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.c  
OR 
Metastases in ipsilateral supraclavicular lymph nodes. 
pN3aMetastases in ≥10 axillary lymph nodes (at least 1 tumor deposit >2.0 mm).
OR 
Metastases to the infraclavicular (level III axillary lymph) nodes. 
pN3bMetastases 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.c 
pN3cMetastases 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.
aReprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
bClassification 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).
cNot clinically detected is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination.
dClinically 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.

Table 5. Distant Metastases (M)a

M0No 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.
M1Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven >0.2 mm.
aReprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.

Table 6. Anatomic Stage/Prognostic Groupsa,b

StageTNMIllustration
0TisN0M0 
IAT1bN0M0

Stage I breast cancer. Drawing shows stage IA on the left; the tumor is 2 cm or smaller and has not spread outside the breast. Drawings in the middle and on the right show stage IB. In the drawing in the middle, no tumor is found in the breast, but small clusters of cancer cells are found in the lymph nodes. In the drawing on the right, the tumor is 2 cm or smaller and small clusters of cancer cells are found in the lymph nodes.

IBT0N1miM0 
 T1bN1miM0 
IIAT0N1cM0

Stage IIA breast cancer. Drawing on the left shows no tumor in the breast, but cancer is found in 3 axillary lymph nodes. Drawing in the middle shows the tumor size is 2 cm or smaller and cancer is found in 3 axillary lymph nodes. Drawing on the right shows the tumor is larger than 2 cm but not larger than 5 cm and has not spread to the lymph nodes.

 T1bN1cM0 
 T2N0M0 
IIBT2N1M0

Stage IIB breast cancer. The drawing on the left shows the tumor is larger than 2 cm but not larger than 5 cm and small clusters of cancer cells are in the lymph nodes. The drawing in the middle shows the tumor is larger than 2 cm but not larger than 5 cm and cancer is in 3 axillary lymph nodes. The drawing on the right shows the tumor is larger than 5 cm but has not spread to the lymph nodes.

 T3N0M0 
IIIAT0N2M0

Stage IIIA breast cancer. The drawing on the left shows no tumor in the breast; cancer is found in 8 axillary lymph nodes. The drawing in the middle shows the tumor is larger than 5 cm and small clusters of cancer cells are in the lymph nodes. The drawing on the right shows the tumor is larger than 5 cm and cancer is in 3 axillary lymph nodes.

 T1bN2M0 
 T2N2M0 
 T3N1M0 
 T3N2M0 
IIIBT4N0M0

Stage IIIB breast cancer. The drawing on the left is a cross section of the breast showing  that cancer has spread to the chest wall. The ribs, muscle, and fatty tissue are also shown. The drawing on the right shows the tumor has spread to the skin of the breast. An inset shows inflammatory breast cancer.

 T4N1M0 
 T4N2M0 
IIICAny TN3M0

Stage IIIC breast cancer. The drawing on the left shows cancer in lymph nodes in the axilla. The drawing in the middle shows cancer in lymph nodes above the collarbone. The drawing on the right shows cancer in lymph nodes in the axilla and in lymph nodes near the breastbone.

IVAny TAny NM1

Stage IV breast cancer; drawing shows other parts of the body where breast cancer may spread, including the brain, lung, liver, and bone. An inset shows cancer cells spreading from the breast, through the blood and lymph system, to another part of the body where metastatic cancer has formed.

aReprinted with permission from AJCC: Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
bT1 includes T1mi.
cT0 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.

References:

  1. Breast. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 347-76.
  2. Singletary SE, Allred C, Ashley P, et al.: Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20 (17): 3628-36, 2002.
  3. Woodward WA, Strom EA, Tucker SL, et al.: Changes in the 2003 American Joint Committee on Cancer staging for breast cancer dramatically affect stage-specific survival. J Clin Oncol 21 (17): 3244-8, 2003.

Early/Localized/Operable Breast Cancer

Treatment Option Overview for Early/Localized/Operable Breast Cancer

Standard treatment options for early, localized, or operable breast cancer may include the following:

    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):
  2. Axillary node–positive breast cancer (postmastectomy):
  3. Axillary node–negative or positive breast cancer (post–breast-conserving 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:
    Preoperative systemic therapy:
  1. Chemotherapy.
  2. HER2 targeted therapy.
  3. Endocrine therapy.

Surgery

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:

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. [1] [2] [3] [4] [5]

Locoregional treatment

Selection of a local therapeutic approach depends on the following: [6]

Options for surgical management of the primary tumor include the following:

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) [8] and other prospective randomized trials. [9] [10] [11] [12] [13] [14] [15] 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. [16]

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. [17] [18] [19] 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: [20]

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). [21] 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). [21][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%. [22] [23] Another series reported the incidence of axillary node relapse in patients with T1a tumors treated without axillary lymph node dissection (ALND) was 2%. [24][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. [25] [26] These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete ALND. [27] [28] [29] [30]

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. [31][Level of evidence: 1iiC]
  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. [32][Level of evidence: 1iiA]

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. [33][Level of evidence: 1iiA]
  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. [34][Level of evidence: 1iiA]
  3. The AMAROS (NCT00014612) trial studied ALND and axillary radiation therapy after identification of a positive sentinel node. [35][Level of evidence: 1iiA]

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). [36] [37] [38] [39] Breast contour can be restored by the following:

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. [40]

Postoperative Radiation Therapy

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. [41]

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. [42] 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. [43] 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. [43][Level of evidence: 1iiA]

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

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). [51][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). [52][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). [53]

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: [54] [55] [56]

In this high-risk group, radiation therapy can decrease locoregional recurrence, even among those patients who receive adjuvant chemotherapy. [57]

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. [41][Level of evidence: 1iiA]

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. [59]

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: [60][Level of evidence: 1iiA]
    1. 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.
    2. Breast radiation first (n = 122), followed by the same chemotherapy.

    The following results were observed:

  2. Two additional randomized trials, though not specifically designed to address the timing of radiation therapy and adjuvant chemotherapy, do add useful information.
    1. 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. [61][Level of evidence: 1iiA]
      • No differences in DFS, distant DFS, and OS were observed between these two arms.
    2. 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. [62]

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. [63][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. [64] 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:

Postoperative Systemic Therapy

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. [82] This classification, with some modification, is described below:

Table 7. Systemic Treatment for Early Breast Cancer by Subtypea

Subtype Treatment Options Comments
Luminal A–like
– Hormone receptor–positiveEndocrine therapy alone in most casesConsider chemotherapy if:
– HER2-negative– High tumor burden (≥4 LNs, T3 or higher) 
– PR >20%  
– Ki67 low– Grade 3 
Luminal B–like
– Hormone receptor–positiveEndocrine therapy plus chemotherapy in most cases 
– HER2-negative  
– Either Ki67 high or PR low  
HER2-positive Chemotherapy plus anti-HER2 therapyUse endocrine therapy, if also hormone receptor–positive
May consider omitting chemotherapy plus anti-HER2, for small node-negative tumors  
Triple-negativeChemotherapyMay consider omitting CT, for small node-negative tumors
CT = chemotherapy; ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; LN = lymph node; PR = progesterone receptor.
aModified from Senkus et al. [82]

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.

Table 8. Adjuvant Systemic Treatment Options for Women With Stages I, II, IIIA, and Operable IIIC Breast Cancer

Patient Group Treatment Options
Premenopausal, hormone receptor–positive (ER or PR)No additional therapy
Tamoxifen 
Tamoxifen plus chemotherapy 
Ovarian function suppression plus tamoxifen 
Ovarian function suppression plus aromatase inhibitor 
Premenopausal, hormone receptor–negative (ER or PR)No additional therapy
Chemotherapy 
Postmenopausal, hormone receptor–positive (ER or PR)No additional therapy
Upfront aromatase inhibitor therapy or tamoxifen followed by aromatase inhibitor with or without chemotherapy 
Postmenopausal, hormone receptor–negative (ER or PR)No additional therapy
Chemotherapy 
ER = estrogen receptor; PR = progesterone receptor.

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. [83]

Evidence (anthracycline-based regimens):

  1. The EBCTCG overview analysis directly compared anthracycline-containing regimens (mostly 6 months of fluorouracil, epirubicin, and cyclophosphamide [FEC] or fluorouracil, doxorubicin, and cyclophosphamide [FAC]) with CMF (either PO or intravenous [IV]) in approximately 14,000 women, 64% of whom were younger than 50 years. [83]

Study results suggest that particular tumor characteristics (i.e., node-positive breast cancer with HER2/neu overexpression) may predict anthracycline-responsiveness.

Evidence (anthracycline-based regimen in women with HER2/neu amplification):

  1. Data from retrospective analyses of randomized clinical trials suggest that, in patients with node-positive breast cancer, the benefit from standard-dose versus lower-dose adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF), [2] or the addition of doxorubicin to the adjuvant regimen, [3] is restricted to those patients whose tumors overexpress HER2/neu.[Level of evidence: 1iiA]
  2. A retrospective analysis of the HER2/neu status of 710 premenopausal, node-positive women was undertaken to see the effects of adjuvant chemotherapy with CMF or cyclophosphamide, epirubicin, and fluorouracil (CEF). [85][Level of evidence: 2A] HER2/neu was measured using fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemical methods.
  3. Similar results were seen in a meta-analysis that included 5,354 patients in whom HER2 status was known from eight randomized trials (including the one just described) comparing anthracycline-containing regimens with nonanthracycline-containing regimens. [86]

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.

Evidence (adding a taxane to an anthracycline-based regimen):

  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). [87][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. [88][Level of evidence: 1iiA]
  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. [89][Level of evidence: 1iiA]
  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. [90] [91][Level of evidence: 1iiA]

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. [92][Level of evidence: 1iiA] Study findings include the following:

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.

Evidence (administration of dose-dense chemotherapy in women with HER2-negative breast cancer):

  1. A U.S. intergroup trial (CLB-9741 [NCT00003088]) of 2,005 node-positive patients compared, in a 2 × 2 factorial design, the use of concurrent AC followed by paclitaxel with sequential doxorubicin, paclitaxel, and cyclophosphamide given every 2 weeks with filgrastim or every 3 weeks. [93][Level of evidence: 1iiA]
  2. An Italian trial (NCT00433420) compared two versus three weekly doses of epirubicin plus cyclophosphamide (with or without fluorouracil) in a factorial design, with a result similar to a U.S. intergroup trial; however, this trial also demonstrated a difference in OS. [96]
  3. A meta-analysis of dose-dense versus standard dosing included data from eight trials including 17,188 patients. [97]
  4. A randomized, phase III, double-blind study (NCT01519700.) demonstrated noninferiority for the duration of severe neutropenia of a biosimilar filgrastim, EP2006, compared with the U.S.-licensed product. [98][Level of evidence: 1iDiv]

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. [99] [100][Level of evidence: 1iiA]
    1. At 7 years, the DFS and OS demonstrated that four cycles of TC were superior to standard AC for both DFS and OS. [100]
      • 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).
    2. Patients had fewer cardiac-related toxic effects with TC than with AC, but they had more myalgia, arthralgia, edema, and febrile neutropenia. [99]

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. [101][Level of evidence: 3iiiA]

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. Common toxic effects include the following:

Less common, but serious, toxic effects include the following:

(Refer to the PDQ summary on Treatment-Related Nausea and Vomiting; for information on mucositis, refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation; for information on symptoms associated with premature menopause, refer to the PDQ summary on Hot Flashes and Night Sweats.)

The use of anthracycline-containing regimens, however—particularly those containing an increased dose of cyclophosphamide—has been associated with a cumulative risk of developing acute leukemia of 0.2% to 1.7% at 5 years. [104] [105] This risk increases to more than 4% in patients receiving high cumulative doses of both epirubicin (>720 mg/m2) and cyclophosphamide (>6,300 mg/m2). [106]

Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens. [107] However, data on this topic from prospective, randomized studies are lacking.

The EBCTCG meta-analysis revealed that women who received adjuvant combination chemotherapy did have a 20% (standard deviation = 10) reduction in the annual odds of developing contralateral breast cancer. [84] This small proportional reduction translated into an absolute benefit that was marginally statistically significant, but indicated that chemotherapy did not increase the risk of contralateral disease. In addition, the analysis showed no statistically significant increase in deaths attributed to other cancers or to vascular causes among all women randomly assigned to receive chemotherapy.

HER2/neu–negative breast cancer

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%. [108]

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. [109]

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. [110][Level of evidence: 3iiDiv]

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. [111][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. [112] 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

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. [113][Level of evidence: 1iiA] Patients were randomly assigned to one of three study arms:

    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. [114] [115][Level of evidence: 1iiA]

    1. 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%. [114]
      • 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%. [114]
      • 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). [115]
    2. 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. [115] No difference in DFS was found between the groups (HR, 0.99; 95% CI, 0.85–1.14; P = .86). [115]
  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. [116] [117][Level of evidence: 1iiA]
  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). [119][Level of Evidence: 1iiA]
  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. [120][Level of evidence: 1iiA]
  5. In contrast, another study failed to demonstrate that 6 months of adjuvant trastuzumab was noninferior to 12 months of treatment. [121][Level of evidence: 1iiA]

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:

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. [125][Level of evidence: 1iiA]

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. [126]

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. [127][Level of evidence: 1iiA]

Hormone receptor–positive breast cancer

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]

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. [83][Level of evidence: 1iiA]
  2. Similar results were found in the IBCSG-13-93 trial. [129] 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. [83] [130] [131] [132] [133] 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: [83]
  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: [133][Level of Evidence: 1iiA]
    1. 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).
    2. 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.
    3. 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. [133] 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. [83] However, concurrent use of tamoxifen with chemotherapy is less effective than sequential administration. [134]

Ovarian ablation, tamoxifen, and chemotherapy

Evidence suggests ovarian ablation alone is not an effective substitute for other systemic therapies. [135] [136] [137] [138] [139] Further, the addition of ovarian ablation to chemotherapy and/or tamoxifen has not been found to significantly improve outcomes. [137] [139] [140] [141] [142]

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. [143][Level of evidence: 1iiDii]
    1. 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.
    2. 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. [144]
  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. [145]
    1. 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). [145][Level of evidence: 1iDii]
    2. 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. [145][Level of evidence: 1iiA]
    3. 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): [146]
      • 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. [146][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. [147]

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. [148]; [149][Level of evidence: 1iDii]
  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. [150] 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]
  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). [147][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. [152] [153] [154] 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. [154][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). [154][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. [155][Level of evidence: 1iDii]

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). [147][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. [157][Level of evidence: 1iDii]
  2. Similarly in the IBCSG 1-98 (NCT00004205) trial, two sequential arms were compared with 5 years of letrozole. [158][Level of evidence: 1iDii]

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). [147][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. [159][Level of evidence: 1iiA] The MA27 (NCT00066573) trial randomly assigned 7,576 postmenopausal women to receive 5 years of anastrozole or exemestane.
  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. [161]

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. [162][Level of evidence: 1iDii]
  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. [166][Level of evidence: 1iDii]

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.
    1. 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%. [167][Level of evidence: 1iDii]
    2. 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).
    3. 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. [168] 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).

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

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. [169][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). [170] [171][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). [172] pCR could not be validated in this study as a surrogate endpoint for improved EFS and OS. [172][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). [173][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:

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: [174]

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:

When considering preoperative therapy, treatment options include the following:

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. [179] [180] 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

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. [181] [182] [183][Level of evidence: 1iiA]
  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. [184][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. [170][Level of evidence: 1iiD]
  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. [179]
  3. Alternative anthracycline/taxane schedules have also been evaluated (concurrent TAC) and appear similar in efficacy to the sequential approach described above. [185][Level of evidence: 1iiDiv]
  4. The phase III GeparSepto trial (NCT01583426) investigated an alternative taxane (nab-paclitaxel) in patients with untreated primary breast cancer. [186] 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%). [186][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. [187][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. [188][Level of evidence: 1iiDiv]
  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. [189][Level of evidence: 1iiDiv]

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]). [190] [191][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

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. [192][Level of evidence: 1iiDiv] This has been confirmed in phase III studies. [193] [194]

Trastuzumab

Evidence (trastuzumab):

  1. A phase III study (NOAH) randomly assigned patients with HER2-positive locally advanced or inflammatory breast cancers to undergo preoperative chemotherapy with or without 1 year of trastuzumab therapy. [194][Level of evidence:1iiA]
  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. [196][Level of evidence: 1iiDiv]

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. [197][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. [198] [199]

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, [198] 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: [198][Level of evidence: 1iiDiv]
    1. Docetaxel plus trastuzumab.
    2. Docetaxel plus trastuzumab and pertuzumab.
    3. Pertuzumab plus trastuzumab.
    4. Docetaxel plus pertuzumab.

    The following results were observed:

  2. The open-label, randomized, phase II TRYPHAENA (NCT00976989) trial sought to evaluate the tolerability and activity associated with trastuzumab and pertuzumab. [200][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:
    1. Concurrent FEC plus trastuzumab plus pertuzumab (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab.
    2. FEC alone (×3) followed by concurrent docetaxel plus trastuzumab plus pertuzumab (×3).
    3. Concurrent docetaxel and carboplatin plus trastuzumab plus pertuzumab (×6).

    The following results were observed:

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. [191] 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. [191][Level of evidence: 1iiDiv]
  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. [201] [Level of evidence: 1iiDiv]
  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.

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. [125] 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. [203][Level of evidence: 3iiiD]

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. [204][Level of evidence: 3iiiD]

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. [205][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. [206] 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). [171][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 [205] or comparable to tamoxifen-associated outcomes. [171] 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. [207] The study was terminated because of the results of a planned interim analysis, and a final analysis was done.

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. [208] [209] [210] 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:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  183. Rastogi P, Anderson SJ, Bear HD, et al.: Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26 (5): 778-85, 2008.
  184. van der Hage JA, van de Velde CJ, Julien JP, et al.: Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 19 (22): 4224-37, 2001.
  185. Vriens BE, Aarts MJ, de Vries B, et al.: Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer. Eur J Cancer 49 (15): 3102-10, 2013.
  186. Untch M, Jackisch C, Schneeweiss A, et al.: Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol 17 (3): 345-56, 2016.
  187. von Minckwitz G, Rezai M, Loibl S, et al.: Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol 28 (12): 2015-23, 2010.
  188. von Minckwitz G, Schneeweiss A, Loibl S, et al.: Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 15 (7): 747-56, 2014.
  189. Sikov WM, Berry DA, Perou CM, et al.: Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33 (1): 13-21, 2015.
  190. Rastogi P, Buyse ME, Swain SM, et al.: Concurrent bevacizumab with a sequential regimen of doxorubicin and cyclophosphamide followed by docetaxel and capecitabine as neoadjuvant therapy for HER2- locally advanced breast cancer: a phase II trial of the NSABP Foundation Research Group. Clin Breast Cancer 11 (4): 228-34, 2011.
  191. Untch M, Loibl S, Bischoff J, et al.: Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 13 (2): 135-44, 2012.
  192. Buzdar AU, Ibrahim NK, Francis D, et al.: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23 (16): 3676-85, 2005.
  193. Untch M, Rezai M, Loibl S, et al.: Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol 28 (12): 2024-31, 2010.
  194. Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375 (9712): 377-84, 2010.
  195. Gianni L, Eiermann W, Semiglazov V, et al.: Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 15 (6): 640-7, 2014.
  196. Buzdar AU, Suman VJ, Meric-Bernstam F, et al.: Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol 14 (13): 1317-25, 2013.
  197. Ismael G, Hegg R, Muehlbauer S, et al.: Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 13 (9): 869-78, 2012.
  198. Gianni L, Pienkowski T, Im YH, et al.: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13 (1): 25-32, 2012.
  199. Baselga J, Bradbury I, Eidtmann H, et al.: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 379 (9816): 633-40, 2012.
  200. Schneeweiss A, Chia S, Hickish T, et al.: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24 (9): 2278-84, 2013.
  201. Carey LA, Berry DA, Cirrincione CT, et al.: Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. J Clin Oncol 34 (6): 542-9, 2016.
  202. de Azambuja E, Holmes AP, Piccart-Gebhart M, et al.: Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 15 (10): 1137-46, 2014.
  203. Lenihan D, Suter T, Brammer M, et al.: Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol 23 (3): 791-800, 2012.
  204. Valachis A, Nearchou A, Polyzos NP, et al.: Cardiac toxicity in breast cancer patients treated with dual HER2 blockade. Int J Cancer 133 (9): 2245-52, 2013.
  205. Eiermann W, Paepke S, Appfelstaedt J, et al.: Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 12 (11): 1527-32, 2001.
  206. Preece PE, Wood RA, Mackie CR, et al.: Tamoxifen as initial sole treatment of localised breast cancer in elderly women: a pilot study. Br Med J (Clin Res Ed) 284 (6319): 869-70, 1982.
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  210. Khatcheressian JL, Wolff AC, Smith TJ, et al.: American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol 24 (31): 5091-7, 2006.

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. [1]

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. [2] 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. [3]
  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. [5][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. [1]

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.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

  1. Petrelli F, Coinu A, Lonati V, et al.: Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies. Anticancer Drugs 27 (7): 702-8, 2016.
  2. Berg CD, Swain SM: Results of Concomitantly Administered Chemoradiation for Locally Advanced Noninflammatory Breast Cancer. Semin Radiat Oncol 4 (4): 226-235, 1994.
  3. Brito RA, Valero V, Buzdar AU, et al.: Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 19 (3): 628-33, 2001.
  4. Olivotto IA, Chua B, Allan SJ, et al.: Long-term survival of patients with supraclavicular metastases at diagnosis of breast cancer. J Clin Oncol 21 (5): 851-4, 2003.
  5. Ueno NT, Buzdar AU, Singletary SE, et al.: Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemother Pharmacol 40 (4): 321-9, 1997.

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. [1] The rates are somewhat higher (up to 10%) for those treated with mastectomy. [2] Nine percent to 25% of patients with locoregional recurrence will have distant metastases or locally extensive disease at the time of recurrence. [3] [4] [5]

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. [6] 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. [7]

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%. [4]

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

(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.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

  1. Darby S, McGale P, Correa C, et al.: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378 (9804): 1707-16, 2011.
  2. Buchanan CL, Dorn PL, Fey J, et al.: Locoregional recurrence after mastectomy: incidence and outcomes. J Am Coll Surg 203 (4): 469-74, 2006.
  3. Aberizk WJ, Silver B, Henderson IC, et al.: The use of radiotherapy for treatment of isolated locoregional recurrence of breast carcinoma after mastectomy. Cancer 58 (6): 1214-8, 1986.
  4. Abner AL, Recht A, Eberlein T, et al.: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 11 (1): 44-8, 1993.
  5. Haffty BG, Fischer D, Beinfield M, et al.: Prognosis following local recurrence in the conservatively treated breast cancer patient. Int J Radiat Oncol Biol Phys 21 (2): 293-8, 1991.
  6. Kuukasjärvi T, Kononen J, Helin H, et al.: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 14 (9): 2584-9, 1996.
  7. Perry MC, Kardinal CG, Korzun AH, et al.: Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. J Clin Oncol 5 (10): 1534-45, 1987.
  8. Leonard R, Hardy J, van Tienhoven G, et al.: Randomized, double-blind, placebo-controlled, multicenter trial of 6% miltefosine solution, a topical chemotherapy in cutaneous metastases from breast cancer. J Clin Oncol 19 (21): 4150-9, 2001.
  9. Schwaibold F, Fowble BL, Solin LJ, et al.: The results of radiation therapy for isolated local regional recurrence after mastectomy. Int J Radiat Oncol Biol Phys 21 (2): 299-310, 1991.
  10. Halverson KJ, Perez CA, Kuske RR, et al.: Survival following locoregional recurrence of breast cancer: univariate and multivariate analysis. Int J Radiat Oncol Biol Phys 23 (2): 285-91, 1992.
  11. Halverson KJ, Perez CA, Kuske RR, et al.: Isolated local-regional recurrence of breast cancer following mastectomy: radiotherapeutic management. Int J Radiat Oncol Biol Phys 19 (4): 851-8, 1990.
  12. Aebi S, Gelber S, Anderson SJ, et al.: Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial. Lancet Oncol 15 (2): 156-63, 2014.

Metastatic Breast Cancer

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, [1] 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. [2][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

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. [3] [4] [5][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). [6][Level of evidence: 1iA]
  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. [7] [8] 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. [7] [8]

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. [9] [10] [11]

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. [12][Level of evidence: 1iiA]

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; [13] [14] [15] [16] [17] [18] [19] [20] [21] and fulvestrant, an ER down-regulator. [22] [23]

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. [13] [14] [15] [16] [17] [18] [19] [24]
  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). [6][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. [25] [26] The proper sequence of these therapies is currently not known. [24] [27]
  4. No benefit has been found in combining anastrozole and fulvestrant in patients who had previously been treated with an AI. [28]

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. [29][Level of evidence: 1iDiii]
  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. [31][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.

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. [32] 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). [33] Based on the high rates of neutropenia seen in the study it is unlikely that blinding was maintained in many cases.
  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. [34][Level of Evidence: 1iC]
  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.
    1. 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. [36][Level of evidence: 1iDiii]
    2. No OS data are available.
    3. 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. [37]
    1. 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). [37][Level of evidence: 1iDiii]
    2. No OS data are available.
    3. 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

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

Antibody therapy targeting the HER2 pathway has been used since the 1990s and has revolutionized the treatment of HER2-positive metastatic breast cancer. A number of HER2-targeted agents (e.g., trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib) have been approved for treatment of this disease.

Monoclonal antibody therapy

Trastuzumab

Approximately 20% to 25% of patients with breast cancer have tumors that overexpress HER2/neu. [38] Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor. [38] 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%. [39][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. [40][Level of evidence: 1iiA]

Notably, when combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity. [41]

Clinical trials comparing multiagent chemotherapy plus trastuzumab with single-agent chemotherapy have yielded conflicting results.

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. [44] [45][Level of evidence: 1iA]

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. [46][Level of evidence: 1iiA] Patients were randomly assigned to receive either T-DM1 or 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. [48][Level of evidence: 1iiDiii] This trial randomly assigned 137 women with HER2-overexpressed breast cancer in the first-line metastatic setting.
  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. [49][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.
  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. [51][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.

Tyrosine kinase inhibitor therapy

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. [52][Level of evidence: 1iiA]

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). [53] 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). [53][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

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. [54]

Single agents that have shown activity in metastatic breast cancer include the following:

Combination regimens that have shown activity in metastatic breast cancer include the following:

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. [83] Although response rate and time to disease progression were both better for the combination, survival was the same in both groups. [83][Level of evidence: 1iiA]; [84] [85]

The selection of therapy in individual patients is influenced by the following:

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. [1] [86] 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. [87][Level of evidence: 1iiA]

Decisions regarding the duration of chemotherapy may take into account the following:

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. [88] [89][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, [89] 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 [90] or a different chemotherapy regimen given at higher versus lower doses. [91][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. [92][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:

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] [94] [95] [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. [98] Dexrazoxane has a similar protective effect in patients receiving epirubicin. [99]

Surgery

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

(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

Radiation therapy has a major role in the palliation of localized symptomatic metastases. [100] Indications for external-beam radiation therapy include the following:

Strontium chloride Sr 89, a systemically administered radionuclide, can be administered for palliation of diffuse bony metastases. [101] [102]

Bone Modifier Therapy

The use of bone modifier therapy to reduce skeletal morbidity in patients with bone metastases should be considered. [103] Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity. [104] [105] [106][Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate. [107]

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. [108] 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). [108][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. [109]

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

Bevacizumab

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. [110] The study enrolled 462 patients who had received previous anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab. [110][Level of evidence: 1iiA]
  2. ECOG-2100 (NCT00028990), an open-label, randomized, phase III trial, compared paclitaxel alone with paclitaxel and bevacizumab. [111][Level of evidence: 1iiA]
  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. [112][Level of evidence: 1iiA]
  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. [113][Level of evidence: 1iiA]
  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. [114][Level of evidence: 1iA]

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.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  78. O'Shaughnessy J, Miles D, Vukelja S, et al.: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 20 (12): 2812-23, 2002.
  79. Serin D, Verrill M, Jones A, et al.: Vinorelbine alternating oral and intravenous plus epirubicin in first-line therapy of metastatic breast cancer: results of a multicentre phase II study. Br J Cancer 92 (11): 1989-96, 2005.
  80. Thomas ES, Gomez HL, Li RK, et al.: Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 25 (33): 5210-7, 2007.
  81. O'Shaughnessy J, Schwartzberg L, Danso MA, et al.: Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol 32 (34): 3840-7, 2014.
  82. Albain KS, Nag SM, Calderillo-Ruiz G, et al.: Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 26 (24): 3950-7, 2008.
  83. Sledge GW, Neuberg D, Bernardo P, et al.: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 21 (4): 588-92, 2003.
  84. Seidman AD: Sequential single-agent chemotherapy for metastatic breast cancer: therapeutic nihilism or realism? J Clin Oncol 21 (4): 577-9, 2003.
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  86. Perez EA: Current management of metastatic breast cancer. Semin Oncol 26 (4 Suppl 12): 1-10, 1999.
  87. Jones D, Ghersi D, Wilcken N: Addition of drug/s to a chemotherapy regimen for metastatic breast cancer. Cochrane Database Syst Rev 3: CD003368, 2006.
  88. Falkson G, Gelman RS, Pandya KJ, et al.: Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol 16 (5): 1669-76, 1998.
  89. Peters WP, Jones RB, Vrendenburgh J, et al.: A large, prospective, randomized trial of high-dose combination alkylating agents (CPB) with autologous cellular support (ABMS) as consolidation for patients with metastatic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy (AFM). [Abstract] Proceedings of the American Society of Clinical Oncology 15: A-149, 121, 1996.
  90. Muss HB, Case LD, Richards F 2nd, et al.: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. The Piedmont Oncology Association. N Engl J Med 325 (19): 1342-8, 1991.
  91. Falkson G, Gelman RS, Glick J, et al.: Metastatic breast cancer: higher versus low dose maintenance treatment when only a partial response or a no change status is obtained following doxorubicin induction treatment. An Eastern Cooperative Oncology Group study. Ann Oncol 3 (9): 768-70, 1992.
  92. Park YH, Jung KH, Im SA, et al.: Phase III, multicenter, randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as first-line chemotherapy: KCSG-BR07-02. J Clin Oncol 31 (14): 1732-9, 2013.
  93. Swain SM, Whaley FS, Gerber MC, et al.: Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 15 (4): 1333-40, 1997.
  94. Swain SM, Whaley FS, Gerber MC, et al.: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15 (4): 1318-32, 1997.
  95. Hensley ML, Schuchter LM, Lindley C, et al.: American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17 (10): 3333-55, 1999.
  96. Marty M, Espié M, Llombart A, et al.: Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 17 (4): 614-22, 2006.
  97. Hortobagyi GN, Frye D, Buzdar AU, et al.: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63 (1): 37-45, 1989.
  98. Hensley ML, Hagerty KL, Kewalramani T, et al.: American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 27 (1): 127-45, 2009.
  99. Venturini M, Michelotti A, Del Mastro L, et al.: Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14 (12): 3112-20, 1996.
  100. Hartsell WF, Scott CB, Bruner DW, et al.: Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97 (11): 798-804, 2005.
  101. Porter AT, McEwan AJ, Powe JE, et al.: Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25 (5): 805-13, 1993.
  102. Quilty PM, Kirk D, Bolger JJ, et al.: A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol 31 (1): 33-40, 1994.
  103. Hillner BE, Ingle JN, Chlebowski RT, et al.: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21 (21): 4042-57, 2003.
  104. Paterson AH, Powles TJ, Kanis JA, et al.: Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 11 (1): 59-65, 1993.
  105. Hortobagyi GN, Theriault RL, Lipton A, et al.: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16 (6): 2038-44, 1998.
  106. Powles T, Paterson A, McCloskey E, et al.: Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res 8 (2): R13, 2006.
  107. Rosen LS, Gordon D, Kaminski M, et al.: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98 (8): 1735-44, 2003.
  108. Himelstein AL, Foster JC, Khatcheressian JL, et al.: Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA 317 (1): 48-58, 2017.
  109. Lipton A, Fizazi K, Stopeck AT, et al.: Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48 (16): 3082-92, 2012.
  110. Miller KD, Chap LI, Holmes FA, et al.: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23 (4): 792-9, 2005.
  111. Miller K, Wang M, Gralow J, et al.: Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357 (26): 2666-76, 2007.
  112. Miles DW, Chan A, Dirix LY, et al.: Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28 (20): 3239-47, 2010.
  113. Robert NJ, Diéras V, Glaspy J, et al.: RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 29 (10): 1252-60, 2011.
  114. Brufsky AM, Hurvitz S, Perez E, et al.: RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 29 (32): 4286-93, 2011.

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. [1] 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. [2]

DCIS comprises a heterogeneous group of histopathologic lesions that have been classified into the following subtypes primarily on the basis of architectural pattern:

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. [3]

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. [4] 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. [4] [5] 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. [6] [7] [8] [9]

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. [7]; [9][Level of evidence: 1iiDii]
  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. [9][Level of evidence: 1iiDii]

    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. [11]
  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. [12]

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). [13][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. [11]

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. [14] [15] [16] [17]

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. [17] 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. [18] 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. [3] [6] [13] [19]

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). [20] 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.
  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). [20] 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.
  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.
  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. [23]

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.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

  1. American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. Available online. Last accessed July 13, 2017.
  2. Siegel R, Ward E, Brawley O, et al.: Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61 (4): 212-36, 2011 Jul-Aug.
  3. Fisher ER, Dignam J, Tan-Chiu E, et al.: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 86 (3): 429-38, 1999.
  4. Fonseca R, Hartmann LC, Petersen IA, et al.: Ductal carcinoma in situ of the breast. Ann Intern Med 127 (11): 1013-22, 1997.
  5. Lagios MD, Westdahl PR, Margolin FR, et al.: Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer 50 (7): 1309-14, 1982.
  6. Fisher B, Dignam J, Wolmark N, et al.: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 16 (2): 441-52, 1998.
  7. Fisher B, Land S, Mamounas E, et al.: Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience. Semin Oncol 28 (4): 400-18, 2001.
  8. Julien JP, Bijker N, Fentiman IS, et al.: Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 355 (9203): 528-33, 2000.
  9. Bijker N, Meijnen P, Peterse JL, et al.: Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853--a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 24 (21): 3381-7, 2006.
  10. Chan KC, Knox WF, Sinha G, et al.: Extent of excision margin width required in breast conserving surgery for ductal carcinoma in situ. Cancer 91 (1): 9-16, 2001.
  11. Correa C, McGale P, Taylor C, et al.: Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr 2010 (41): 162-77, 2010.
  12. McCormick B, Winter K, Hudis C, et al.: RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol 33 (7): 709-15, 2015.
  13. Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast. Cochrane Database Syst Rev 11: CD000563, 2013.
  14. Page DL, Lagios MD: Pathologic analysis of the National Surgical Adjuvant Breast Project (NSABP) B-17 Trial. Unanswered questions remaining unanswered considering current concepts of ductal carcinoma in situ. Cancer 75 (6): 1219-22; discussion 1223-7, 1995.
  15. Fisher ER, Costantino J, Fisher B, et al.: Response - blunting the counterpoint. Cancer 75 (6): 1223-1227, 1995.
  16. Holland R, Peterse JL, Millis RR, et al.: Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 11 (3): 167-80, 1994.
  17. Silverstein MJ, Lagios MD, Craig PH, et al.: A prognostic index for ductal carcinoma in situ of the breast. Cancer 77 (11): 2267-74, 1996.
  18. Silverstein MJ, Lagios MD, Groshen S, et al.: The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 340 (19): 1455-61, 1999.
  19. Goodwin A, Parker S, Ghersi D, et al.: Post-operative radiotherapy for ductal carcinoma in situ of the breast--a systematic review of the randomised trials. Breast 18 (3): 143-9, 2009.
  20. Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353 (9169): 1993-2000, 1999.
  21. Houghton J, George WD, Cuzick J, et al.: Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 362 (9378): 95-102, 2003.
  22. Margolese RG, Cecchini RS, Julian TB, et al.: Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial. Lancet 387 (10021): 849-56, 2016.
  23. Forbes JF, Sestak I, Howell A, et al.: Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial. Lancet 387 (10021): 866-73, 2016.

Changes to This Summary (10/13/2017)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Early/Localized/Operable Breast Cancer

Added Pertuzumab as a new subsection.

Added Neratinib as a new subsection.

Added text about the Femara Versus Anastrozole Clinical Evaluation study, in which 4,136 patients with hormone receptor (HR)–positive disease were randomly assigned to receive either letrozole or anastrozole (cited Smith et al. as reference 161). Also included data about the lack of significant difference in disease-free survival at the time of a final analysis and the lack of substantial differences in adverse events between the arms.

Added text to state that a patient-level meta-analysis, which included 36 studies of preoperative therapy in stages I–III breast cancer, indicated an improvement in event-free survival for those obtaining a pathologic complete response (pCR) versus no pCR (cited Broglio et al. as reference 73 and level of evidence 3iiiD).

Added Capecitabine as a new subsection.

Added text to state that the use of adjuvant capecitabine for breast cancer after preoperative chemotherapy and participation in clinical trials of novel therapies should be considered in patients with residual disease after preoperative therapy. Also added that the randomized, phase III, clinical trial EA1131 randomly assigned patients with residual basal-like triple-negative breast cancer (TNBC) after preoperative therapy to receive platinum-based chemotherapy or capecitabine. The phase III S1418/BR006 trial evaluated the efficacy of pembrolizumab as adjuvant therapy for patients with residual TNBC after preoperative therapy.

Metastatic Breast Cancer

Added text about the phase III, placebo-controlled, MONARCH 2 trial that tested abemaciclib in 669 randomly assigned patients with HR-positive and human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer to receive abemaciclib plus fulvestrant or placebo plus fulvestrant (cited Sledge et al. as reference 37). Also added text and statistical data about the following: the primary endpoint (added level of evidence: 1iDiii), overall survival (OS) data, adverse events in patients including diarrhea, neutropenia, nausea, fatigue, and abdominal pain in the abemaciclib and the placebo groups. Additional statistics were included about grade 1/2 diarrhea and grade 3 diarrhea in the abemaciclib versus placebo groups, and febrile neutropenia in the abemaciclib arm.

Added text to state that median OS was longer with trastuzumab emtansine versus lapatinib plus capecitabine (cited Diéras et al. as reference 47).

Added text to state that OS was significantly longer with trastuzumab emtansine versus the treatment of physician's choice (cited Krop et al. as reference 50).

Added text to state that the role of T-DM1 as first-line treatment of metastatic HER2-overexpressed breast cancer was evaluated in the phase III MARIANNE trial (cited Perez et al. as reference 51 and 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. Also added text and statistical data about the following: median progression-free survival (PFS) for three treatment groups, no significant difference in PFS in any of the groups, and none of the groups showed PFS superiority over trastuzumab plus taxane.

Added Germline BRCA Mutation as a new subsection.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of breast cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Breast Cancer Treatment are:

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Breast Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/breast/hp/breast-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389406]

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