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医療専門家向け Breast Cancer Treatment (Adult) (PDQ®)

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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult 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.

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).

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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 2020:[ 1 ]

Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 48,530 cases of female breast ductal carcinoma in situ and 276,480 cases of invasive disease in 2020.[ 1 ] Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 63,220 American women will die of lung cancer in 2020.[ 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 [DCIS] section in the Pathologic Evaluation of Breast Tissue section in the PDQ summary on Breast Cancer Screening for more information.) Population studies from the United States [ 2 ] and the United Kingdom [ 3 ] 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.[ 4 ]

Anatomy

Drawing of female breast anatomy showing the lymph nodes, nipple, areola, chest wall, ribs, muscle, fatty tissue, lobe, ducts, and lobules.

画像を拡大する

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.[ 22 ][ 23 ]

Of all women with breast cancer, 5% to 10% may have a germline mutation of the genes BRCA1 and BRCA2.[ 24 ] Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry.[ 25 ] 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.[ 26 ] Male BRCA2 mutation carriers also have an increased risk of breast cancer.[ 27 ]

Mutations in either the BRCA1 or the BRCA2 gene also confer an increased risk of ovarian cancer [ 27 ][ 28 ] or other primary cancers.[ 27 ][ 28 ] Once a BRCA1 or BRCA2 mutation has been identified, other family members can be referred for genetic counseling and testing.[ 29 ][ 30 ][ 31 ][ 32 ] (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.[ 51 ][ 52 ][ 53 ] The development of a contralateral breast cancer is associated with an increased risk of distant recurrence.[ 54 ] 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.[ 55 ][ 56 ]

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.[ 57 ][ 58 ][ 59 ]

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):[ 60 ]

The use of molecular profiling in breast cancer includes the following:[ 64 ]

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.[ 65 ][ 66 ]

Gene profile tests include the following:

The following trials describe the prognostic and predictive value of multigene assays in early breast cancer:

  1. The prognostic ability of the Oncotype DX 21-gene assay was assessed in two randomized trials.
  2. The use of Oncotype Dx to predict benefit from chemotherapy in patients with node-negative, ER-positive breast cancer was initially assessed in a prospective-retrospective way using the tamoxifen alone (n = 227) and the combination arms (n = 424) of the NSABP B-20 trial.[ 72 ] Patients in the NSABP B-20 trial were randomly assigned to receive tamoxifen alone or tamoxifen concurrently with methotrexate and fluorouracil (MF) or cyclophosphamide with MF (CMF).[ 75 ]
  3. Similar findings were reported in the prospective-retrospective evaluation of the Southwestern Oncology Group (SWOG-8814 [NCT00929591]) trial in hormone receptor–positive lymph node-positive postmenopausal patients treated with tamoxifen with or without cyclophosphamide, doxorubicin, and fluorouracil.[ 77 ] 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 prospective, randomized TAILORx (NCT00310180) trial indicate that chemotherapy is unlikely to provide substantial benefit to patients older than 50 years with ER-PR–positive and node-negative disease and a recurrence score of 11 to 25.[ 78 ] In this study, a low-risk score was defined as less than 11, an intermediate score was 11 to 25, and a 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 ]

    In the middle-risk group in the TAILORx study (recurrence score, 11–25), 6,907 women were randomly assigned to endocrine therapy alone or endocrine therapy plus chemotherapy.[ 78 ] Of these, 3,399 women on the endocrine therapy-alone arm and 3,312 women on the endocrine therapy-plus-chemotherapy arm were available for an analysis according to the randomized treatment assignments. After a median follow-up of 90 months, the difference in invasive DFS, the main study endpoint, met the prespecified noninferiority criterion (P > .10 for a test of no difference after 835 events had occurred) suggesting the noninferiority of endocrine therapy compared with endocrine therapy plus chemotherapy.

  5. The MINDACT (NCT00433589) trial tested whether adding MammaPrint genomic risk to a clinical-risk classification (modified from Adjuvant! Online) might guide more appropriate choices of chemotherapy in women with node negative- or 1-to-3 node-positive disease.[ 81 ][Level of evidence: 3iiiDii] Unlike the TAILORx study, which only had hormone receptor–positive patients, this trial included hormone receptor–negative patients. In this prospective study, women with both genomic and clinical high-risk classification received chemotherapy, while those with both genomic and clinical low-risk classification did not receive chemotherapy. Participants with discordant results (clinical high-risk- with genomic low-risk classification, or clinical low-risk- with genomic high-risk classification) were randomly assigned to receive or not receive chemotherapy. A total of 1,550 women with high clinical risk and low genomic risk, and 592 women with low clinical risk and high genomic risk, were randomly assigned to receive or not receive chemotherapy. The primary goal of the study was to determine whether patients with high clinical risk, but low genomic risk, who did not receive chemotherapy had a 5-year survival rate without distant metastases (primary study endpoint) of 92% or lower (a noninferiority design).

Results from the prospective, randomized 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 recurrence score 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:

参考文献
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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
NOS = not otherwise specified.
Carcinoma, NOS  
Ductal Intraductal (in situ)
Invasive with predominant component
Invasive, NOS
Comedo
Inflammatory
Medullary with lymphocytic infiltrate
Mucinous (colloid)
Papillary
Scirrhous
Tubular
Other
Lobular Invasive with predominant in situ component
Invasive [ 2 ]
Nipple Paget disease, NOS
Paget disease with intraductal carcinoma
Paget disease with invasive ductal carcinoma
Other Undifferentiated carcinoma
Metaplastic

The following tumor subtypes occur in the breast but are not considered typical breast cancers:

参考文献
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  4. Carter BA, Page DL: Phyllodes tumor of the breast: local recurrence versus metastatic capacity. Hum Pathol 35 (9): 1051-2, 2004.[PUBMED Abstract]
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 also according to other clinical factors such as the following, some of which are included in the determination of stage:

The standards used to define biomarker status are described as follows:

TNM Definitions

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define breast cancer.[ 3 ] The grade of the tumor is determined by its morphologic features, such as tubule formation, nuclear pleomorphism, and mitotic count.

Table 2. Definition of Primary Tumor (T) – Clinical and Pathologicala
T Category T Criteria
DCIS = ductal carcinoma in situ.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bLobular carcinoma in situ is a benign entity and is removed from TNM staging in the AJCC Cancer Staging Manual, 8th ed.
cRules for Classification - The anatomic TNM system is a method for coding extent of disease. This is done by assigning a category of extent of disease for the tumor (T), regional lymph nodes (N), and distant metastases (M). T, N, and M are assigned by clinical means and by adding surgical findings and pathological information to the clinical information. The documented prognostic impact of postneoadjuvant extent of disease and response to therapy warrant clear definitions of the use of the yp prefix and response to therapy. The use of neoadjuvant therapy does not change the clinical (pretreatment) stage. As per TNM rules, the anatomic component of clinical stage is identified with the prefix c (e.g., cT). In addition, clinical staging can include the use of fine-needle aspiration (FNA) or core-needle biopsy and sentinel lymph node biopsy before neoadjuvant therapy. These are denoted with the postscripts f and sn, respectively. Nodal metastases confirmed by FNA or core-needle biopsy are classified as macrometastases (cN1), regardless of the size of the tumor focus in the final pathological specimen. For example, if, prior to neoadjuvant systemic therapy, a patient with a 1 cm primary has no palpable nodes but has an ultrasound-guided FNA biopsy of an axillary lymph node that is positive, the patient will be categorized as cN1 (f) for clinical (pretreatment) staging and is assigned to Stage IIA. Likewise, if the patient has a positive axillary sentinel node identified before neoadjuvant systemic therapy, the tumor is categorized as cN1 (sn) (Stage IIA). As per TNM rules, in the absence of pathological T evaluation (removal of the primary tumor), which is identified with prefix p (e.g., pT), microscopic evaluation of nodes before neoadjuvant therapy, even by complete removal such as sentinel node biopsy, is still classified as clinical (cN).
TX Primary tumor cannot be assessed.
T0 No evidence of primary tumor.
Tisb DCIS.
Tis (Paget) Paget disease of the nipple NOT associated with invasive carcinoma and/or DCIS in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.
T1 Tumor ≤20 mm in greatest dimension.
–T1mi Tumor ≤1 mm in greatest dimension.
–T1a Tumor >1 mm but ≤5 mm in greatest dimension (round any measurement >1.0–1.9 mm to 2 mm).
–T1b Tumor >5 mm but ≤10 mm in greatest dimension.
–T1c Tumor >10 mm but ≤20 mm in greatest dimension.
T2 Tumor >20 mm but ≤50 mm in greatest dimension.
T3 Tumor >50 mm in greatest dimension.
T4 Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4.
–T4a Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4.
–T4b Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d'orange) of the skin that does not meet the criteria for inflammatory carcinoma.
–T4c Both T4a and T4b are present.
–T4d Inflammatory carcinoma (see Rules for Classificationc).
Table 3. Definition of Regional Lymph Nodes – Clinical (cN)a,b
cN Category cN Criteria
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
b(sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine-needle aspiration/core needle biopsy, respectively.
cThe cNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no documentation of physical examination of the axilla.
dcN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in cases treated with neoadjuvant therapy.
cNXc Regional lymph nodes cannot be assessed (e.g., previously removed).
cN0 No regional lymph node metastases (by imaging or clinical examination).
cN1 Metastases to movable ipsilateral Level I, II axillary lymph nodes(s).
–cN1mid Micrometastases (approximately 200 cells, >0.2 mm, but ≤2.0 mm).
cN2 Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or matted;
or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases.
–cN2a Metastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structures.
–cN2b Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases.
cN3 Metastases in ipsilateral infraclavicular (Level Ill axillary) lymph node(s) with or without Level l, II axillary lymph node involvement; or in ipsilateral internal mammary lymph node(s) with Level l, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement.
–cN3a Metastases in ipsilateral infraclavicular lymph node(s).
–cN3b Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s).
–cN3c Metastases in ipsilateral supraclavicular lymph node(s).
Table 4. Definition of Regional Lymph Nodes – Pathological (pN)a,b
pN Category pN Criteria
ITCs = isolated tumor cells; RT-PCR = reverse transcriptase-polymerase chain reaction.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
b(sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine-needle aspiration/core needle biopsy, respectively, with NO further resection of nodes.
pNX Regional lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed).
pN0 No regional lymph node metastasis identified or ITCs only.
–pN0(i+) ITCs only (malignant cell clusters ≤0.2 mm) in regional lymph node(s).
–pN0(mol+) Positive molecular findings by RT-PCR; no ITCs detected.
pN1 Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsy.
–pN1mi Micrometastases (~200 cells, >0.2 mm, but ≤2.0 mm).
–pN1a Metastases in 1–3 axillary lymph nodes, at least one metastasis >2.0 mm.
–pN1b Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs.
–pN1c pN1a and pN1b combined.
pN2 Metastases in 4–9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases.
–pN2a Metastases in 4–9 axillary lymph nodes (at least 1 tumor deposit >2.0 mm).
–pN2b Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary nodes.
pN3 Metastases in ≥10 axillary lymph nodes; or in infraclavicular (Level Ill axillary) lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive Level l, II axillary lymph nodes; or in >3 axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes.
–pN3a Metastases in ≥10 axillary lymph nodes (at least 1 tumor deposit >2.0 mm); or metastases to the infraclavicular (Level III axillary lymph) nodes.
–pN3b pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging);
or pN2a in the presence of pN1b.
–pN3c Metastases in ipsilateral supraclavicular lymph nodes.
Table 5. Definition of Distant Metastasis (M)a
M Category M Criteria
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bNote that imaging studies are not required to assign the cM0 category.
M0 No clinical or radiographic evidence of distant metastases.b
cM0(i+) No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits ≤0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastases.
cM1 Distant metastases detected by clinical and radiographic means.
pM1 Any histologically proven metastases in distant organs; or if in nonregional nodes, metastases >0.2 mm.
Table 6. Definition of Histologic Grade (G)a
G G Definition
SBR = Scarff-Bloom-Richardson grading system, Nottingham Modification.
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
GX Grade cannot be assessed.
G1 Low combined histologic grade (favorable), SBR score of 3–5 points.
G2 Intermediate combined histologic grade (moderately favorable); SBR score of 6–7 points.
G3 High combined histologic grade (unfavorable); SBR score of 8–9 points.
Table 7. Ductal Carcinoma in situ: Nuclear Gradea
G G Definition
aReprinted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
GX Grade cannot be assessed.
G1 Low nuclear grade.
G2 Intermediate nuclear grade.
G3 High nuclear grade.

AJCC Anatomic and Prognostic Stage Groups

There are three stage group tables for invasive cancer:[ 3 ]

In the United States, cancer registries and clinicians must use the Clinical and Pathological Prognostic Stage Group tables for reporting. It is expected that testing is performed for grade, HER2, ER, and PR status and that results are reported for all cases of invasive cancer in the United States.

AJCC Anatomic Stage Groups

Table 8. Definition of Anatomic Stage Groupsa
Stage TNM
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
Notes:
1. T1 includes T1mi.
2. T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB.
3. T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category.
4. M0 includes M0(i+).
5. The designation pM0 is not valid; any M0 is clinical.
6. If a patient presents with M1 disease before receiving neoadjuvant systemic therapy, the stage is Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.
7. Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided the studies are performed within 4 months of diagnosis in the absence of disease progression, and provided the patient has not received neoadjuvant therapy.
8. Staging following neoadjuvant therapy is denoted with a yc or ypn prefix to the T and N classification. There is no anatomic stage group assigned if there is a complete pathological response (pCR) to neoadjuvant therapy, for example, ypT0, ypN0, cM0.
0 Tis, N0, M0
IA T1, N0, M0
IB T0, N1mi, M0
T1, N1mi, M0
IIA T0, N1, M0
T1, N1, M0
T2, N0, M0
IIB T2, N1, M0
T3, N0, M0
IIIA T0, N2, M0
T1, N2, M0
T2, N2, M0
T3, N1, M0
T3, N2, M0
IIIB T4, N0, M0
T4, N1, M0
T4, N2, M0
IIIC Any T (Tis, T1, T0, T2, T3, T4; N3, M0)
IV Any T (Tis, T1, T0, T2, T3, T4; Any N = N0, N1mi, N1, N2, N3, M1)

AJCC Prognostic Stage Groups

The Clinical Prognostic Stage is used for clinical classification and staging of patients in the United States with invasive breast cancer. It uses TNM information based on the patient’s history, physical examination, imaging results (not required for clinical staging), and biopsies.

Table 9. Definition of Clinical Prognostic Stage Groupsa
TNM Grade HER2 Status ER Status PR Status Stage Group
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bT1 includes T1mi.
cN1 does not include N1mi. T1, N1mi, M0, and T0, N1mi, M0 cancers are included for prognostic staging with T1, N0, M0 cancers of the same prognostic factor status.
dN1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2, N1; T3, N1; and T4, N1, respectively.
Notes:
1. Because N1mi categorization requires evaluation of the entire node, and cannot be assigned on the basis of an fine-needle aspiration or core biopsy, N1mi can only be used with Clinical Prognostic Staging when clinical staging is based on a resected lymph node in the absence of resection of the primary cancer, such as in the situation where sentinel node biopsy is performed before receiving neoadjuvant chemotherapy or endocrine therapy.
2. For cases with lymph node involvement with no evidence of primary tumor (e.g., T0, N1, etc.) or with breast ductal carcinoma in situ (e.g.,Tis, N1, etc.), the grade, human epidermal growth factor receptor 2 (HER2), estrogen receptor, and progesterone receptor information from the tumor in the lymph node should be used for assigning stage group.
3. For cases where HER2 is determined to be equivocal by in situ hybridization (fluorescence in situ hybridization or chromogenic in situ hybridization) testing under the 2013 American Society of Clinical Oncologists/College of American Pathologists HER2 testing guidelines, the HER2-negative category should be used for staging in the Pathological Prognostic Stage Group table.[ 4 ][ 5 ]
4. The prognostic value of these Prognostic Stage Groups is based on populations of persons with breast cancer that have been offered and mostly treated with appropriate endocrine and/or systemic chemotherapy (including anti–HER2 therapy).
Tis, N0, M0 Any (refer to Table 6 and Table 7) Any Any Any 0
T1b, N0, M0 G1 Positive Positive Positive IA
Negative IA
T0, N1mi, M0 Negative Positive IA
Negative IA
T1b, N1mi, M0 Negative Positive Positive IA
Negative IA
Negative Positive IA
Negative IB
G2 Positive Positive Positive IA
Negative IA
Negative Positive IA
Negative IA
Negative Positive Positive IA
Negative IA
Negative Positive IA
Negative IB
G3 Positive Positive Positive IA
Negative IA
Negative Positive IA
Negative IA
Negative Positive Positive IA
Negative IB
Negative Positive IB
Negative IB
T0, N1c, M0; T1b, N1c, M0; T2, N0, M0 G1 Positive Positive Positive IB
Negative IIA
Negative Positive IIA
Negative IIA
Negative Positive Positive IB
Negative IIA
Negative Positive IIA
Negative IIA
G2 Positive Positive Positive IB
Negative IIA
Negative Positive IIA
Negative IIA
Negative Positive Positive IB
Negative IIA
Negative Positive IIA
Negative IIB
G3 Positive Positive Positive IB
Negative IIA
Negative Positive IIA
Negative IIA
Negative Positive Positive IIA
Negative IIB
Negative Positive IIB
Negative IIB
T2, N1d, M0; T3, N0, M0 G1 Positive Positive Positive IB
Negative IIA
Negative Positive IIA
Negative IIB
Negative Positive Positive IIA
Negative IIB
Negative Positive IIB
Negative IIB
G2 Positive Positive Positive IB
Negative IIA
Negative Positive IIA
Negative IIB
Negative Positive Positive IIA
Negative IIB
Negative Positive IIB
Negative IIIB
G3 Positive Positive Positive IB
Negative IIB
Negative Positive IIB
Negative IIB
Negative Positive Positive IIB
Negative IIIA
Negative Positive IIIA
Negative IIIB
T0, N2, M0; T1b, N2, M0; T2, N2, M0; T3, N1d, M0; T3, N2, M0 G1 Positive Positive Positive IIA
Negative IIIA
Negative Positive IIIA
Negative IIIA
Negative Positive Positive IIA
Negative IIIA
Negative Positive IIIA
Negative IIIB
G2 Positive Positive Positive IIA
Negative IIIA
Negative Positive IIIA
Negative IIIA
Negative Positive Positive IIA
Negative IIIA
Negative Positive IIIA
Negative IIIB
G3 Positive Positive Positive IIB
Negative IIIA
Negative Positive IIIA
Negative IIIA
Negative Positive Positive IIIA
Negative IIIB
Negative Positive IIIB
Negative IIIC
T4, N0, M0; T4, N1d, M0; T4, N2, M0; Any T, N3, M0 G1 Positive Positive Positive IIIA
Negative IIIB
Negative Positive IIIB
Negative IIIB
Negative Positive Positive IIIB
Negative IIIB
Negative Positive IIIB
Negative IIIC
G2 Positive Positive Positive IIIA
Negative IIIB
Negative Positive IIIB
Negative IIIB
Negative Positive Positive IIIB
Negative IIIB
Negative Positive IIIB
Negative IIIC
G3 Positive Positive Positive IIIB
Negative IIIB
Negative Positive IIIB
Negative IIIB
Negative Positive Positive IIIB
Negative IIIC
Negative Positive IIIC
Negative IIIC
Any T, Any N, M1 Any (refer to Table 6 and Table 7) Any Any Any IV

AJCC Pathological Prognostic Stage Groups

The Pathological Prognostic Stage applies to patients with invasive breast cancer initially treated with surgery. It includes all information used for clinical staging, surgical findings, and pathological findings following surgery to remove the tumor. Pathological Prognostic Stage is not used for patients treated with neoadjuvant therapy before surgery to remove the tumor.[ 3 ]

Table 10. Definition of Pathological Prognostic Stage Groupsa
TNM Grade HER2 Status ER Status PR Status Stage Group
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted with permission from AJCC: Breast, revised version. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 4–96.
bT1 includes T1mi.
cN1 does not include N1mi. T1, N1mi, M0 and T0, N1mi, M0 cancers are included for prognostic staging with T1, N0, M0 cancers of the same prognostic factor status.
dN1 includes N1mi. T2, T3, and T4 cancers and N1mi are included for prognostic staging with T2, N1; T3, N1; and T4, N1, respectively.
Notes:
1. For cases with lymph node involvement with no evidence of primary tumor (e.g., T0, N1, etc.) or with breast ductal carcinoma in situ (e.g.,Tis, N1, etc.), the grade, human epidermal growth factor receptor 2 (HER2), estrogen receptor, and progesterone receptor information from the tumor in the lymph node should be used for assigning stage group.
2. For cases where HER2 is determined to be equivocal by in situ hybridization (fluorescence in situ hybridization or chromogenic in situ hybridization) testing under the 2013 American Society of Clinical Oncologists/College of American Pathologists HER2 testing guidelines, the HER2-negative category should be used for staging in the Pathological Prognostic Stage Group table.[ 4 ][ 5 ]
3. The prognostic value of these Prognostic Stage Groups is based on populations of persons with breast cancer that have been offered and mostly treated with appropriate endocrine and/or systemic chemotherapy (including anti–HER2 therapy).
Tis, N0, M0 Any (refer to Table 6 and Table 7) Any Any Any 0
T1b, N0, M0; T0, N1mi, M0; T1b, N1mi, M0 G1 Positive Positive Positive IA
Negative IA
Negative Positive IA
Negative IA
Negative Positive Positive IA
Negative IA
Negative Positive IA
Negative IA
G2 Positive Positive Positive IA
Negative IA
Negative Positive IA
Negative IA
Negative Positive Positive IA
Negative IA
Negative Positive IA
Negative IB
G3 Positive Positive Positive IA
Negative IA
Negative Positive IA
Negative IA
Negative Positive Positive IA
Negative IA
Negative Positive IA
Negative IB
T0, N1c , M0; T1b, N1c, M0; T2, N0, M0 G1 Positive Positive Positive IA
Negative IB
Negative Positive IB
Negative IIA
Negative Positive Positive IA
Negative IB
Negative Positive IB
Negative IIA
G2 Positive Positive Positive IA
Negative IB
Negative Positive IB
Negative IIA
Negative Positive Positive IA
Negative IIA
Negative Positive IIA
Negative IIA
G3 Positive Positive Positive IA
Negative IIA
Negative Positive IIA
Negative IIA
Negative Positive Positive IB
Negative IIA
Negative Positive IIA
Negative IIA
T2, N1c, M0; T3, N0, M0 G1 Positive Positive Positive IA
Negative IIB
Negative Positive IIB
Negative IIB
Negative Positive Positive IA
Negative IIB
Negative Positive IIB
Negative IIB
G2 Positive Positive Positive IB
Negative IIB
Negative Positive IIB
Negative IIB
Negative Positive Positive IB
Negative IIB
Negative Positive IIB
Negative IIB
G3 Positive Positive Positive IB
Negative IIB
Negative Positive IIB
Negative IIB
Negative Positive Positive IIA
Negative IIB
Negative Positive IIB
Negative IIIA
T0, N2, M0; T1b, N2, M0; T2, N2, M0, T3, N1d, M0; T3, N2, M0 G1 Positive Positive Positive IB
Negative IIIA
Negative Positive IIIA
Negative IIIA
Negative Positive Positive IB
Negative IIIA
Negative Positive IIIA
Negative IIIA
G2 Positive Positive Positive IB
Negative IIIA
Negative Positive IIIA
Negative IIIA
Negative Positive Positive IB
Negative IIIA
Negative Positive IIIA
Negative IIIB
G3 Positive Positive Positive IIA
Negative IIIA
Negative Positive IIIA
Negative IIIA
Negative Positive Positive IIB
Negative IIIA
Negative Positive IIIA
Negative IIIC
T4, N0, M0; T4, N1d, M0; T4, N2, M0; Any T, N3, M0 G1 Positive Positive Positive IIIA
Negative IIIB
Negative Positive IIIB
Negative IIIB
Negative Positive Positive IIIA
Negative IIIB
Negative Positive IIIB
Negative IIIB
G2 Positive Positive Positive IIIA
Negative IIIB
Negative Positive IIIB
Negative IIIB
Negative Positive Positive IIIA
Negative IIIB
Negative Positive IIIB
Negative IIIC
G3 Positive Positive Positive IIIB
Negative IIIB
Negative Positive IIIB
Negative IIIB
Negative Positive Positive IIIB
Negative IIIC
Negative Positive IIIC
Negative IIIC
Any T, Any N, M1 Any (refer to Table 6 and Table 7) Any Any Any IV
参考文献
  1. Barnes DM, Harris WH, Smith P, et al.: Immunohistochemical determination of oestrogen receptor: comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer 74 (9): 1445-51, 1996.[PUBMED Abstract]
  2. Wolff AC, Hammond MEH, Allison KH, et al.: Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 36 (20): 2105-2122, 2018.[PUBMED Abstract]
  3. Breast. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 589–628.[PUBMED Abstract]
  4. Wolff AC, Hammond ME, Hicks DG, et al.: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31 (31): 3997-4013, 2013.[PUBMED Abstract]
  5. Wolff AC, Hammond ME, Hicks DG, et al.: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Arch Pathol Lab Med 138 (2): 241-56, 2014.[PUBMED Abstract]
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 lymph node (SLN) biopsy with or without axillary lymph node dissection for positive 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

Stages 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 trial of the European Organization for Research and Treatment of Cancer (EORTC) (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 after 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 ]

Because 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]

Because 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]

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

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

Table 12. Adjuvant Systemic Treatment Options for Women With Stages I, II, IIIA, and Operable IIIC Breast Cancer
Patient Group Treatment Options
ER = estrogen receptor; PR = progesterone receptor.
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

Chemotherapy

Adjuvant chemotherapy 1970s to 2000: Anthracycline-based regimens versus cyclophosphamide, methotrexate, and 5-FU (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 5-FU). 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 5-FU, 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 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 5-FU (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 5-FU(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 non–anthracycline-containing regimens.[ 86 ]

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

Several 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 [NT00897026]) 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 (NCT01420185) 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 5-FU) 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 meta-analysis of 26 randomized trials that included 37,298 women treated with anthracycline- and taxane-containing chemotherapy compared standard regimens (administered every 3–4 weeks) with more dose-intense regimens. Regimens that increased dose intensity by shortening the interval between cycles (i.e., dose-dense therapy or administration of the same dose over a shorter time period) and regimens that increased dose intensity by administering individual drugs in sequence to allow for higher doses (i.e., sequential scheduling).[ 98 ]
  5. A randomized, phase III, double-blinded study (NCT01519700) demonstrated noninferiority for the duration of severe neutropenia of a biosimilar filgrastim, EP2006, compared with the U.S.-licensed product.[ 99 ][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.[ 100 ][ 101 ][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.[ 101 ]
    2. Patients had fewer cardiac-related toxic effects with TC than with AC, but they had more myalgia, arthralgia, edema, and febrile neutropenia.[ 100 ]

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.[ 102 ][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 Nausea and Vomiting Related to Cancer Treatment; 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.[ 105 ][ 106 ] 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).[ 107 ]

Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens.[ 108 ] 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%.[ 109 ]

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.[ 110 ]

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.[ 111 ][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.[ 112 ][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.[ 113 ] 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.[ 114 ][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.[ 115 ]

    1. One year of trastuzumab versus observation:
    2. One year versus 2 years of trastuzumab:
    3. Symptomatic cardiac events occurred in 1% of the patients on trastuzumab and in 0.1% of the observation group.
  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 non–anthracycline-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. Several studies have compared 6 months of trastuzumab administration to 12 months.[ 121 ][ 122 ][ 123 ]
    1. In an interim analysis of the PHARE (NCT00381901) trial, the 2-year DFS rate was 93.8% (95% CI, 92.6–94.9) in the 12-month group and 91.1% (89.7–92.4) in the 6-month group (HR, 1.28; 95% CI, 1.05–1.56; noninferiority, P = .29).[ 121 ][Level of evidence: 1iiA]
    2. Similar results were noted in a much smaller study of 481 patients led by the Hellenic Oncology Research Group.[ 122 ][Level of evidence: 1iiA]
    3. In contrast, the PERSEPHONE (NCT00712140) trial, which enrolled 4,088 patients who experienced 512 DFS events at the time of analysis, excluded its prespecified noninferiority margin (HR, 1.07; 90% CI, 0.93−1.24; noninferiority, P = .011).[ 123 ][Level of evidence: 1iiA]

Several 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.[ 126 ][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.[ 127 ]

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 neoadjuvant trastuzumab up to 2 years before randomization. Patients received neratinib 240 mg oral daily for 1 year or a placebo.[ 128 ][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.[ 130 ] Five years of adjuvant endocrine therapy has been shown to substantially reduce the risks of locoregional and distant recurrence, contralateral breast cancer, and death from breast cancer.

The optimal duration of endocrine therapy is unclear, with the preponderance of evidence supporting at least 5 years of endocrine therapy. A meta-analysis of 88 clinical trials involving 62,923 women with hormone receptor–positive breast cancer who were disease free after 5 years of endocrine therapy showed a steady risk of late recurrence 5 to 20 years after diagnosis.[ 131 ][Level of evidence: 3iiiD] The risk of distant recurrence correlated with the original tumor (T) and node (N) status, with risks ranging from 10% to 41%.

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.[ 132 ] 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 ][ 133 ][ 134 ][ 135 ][ 136 ] 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:[ 136 ][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:

    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.[ 136 ] Women who have become menopausal after 5 years of tamoxifen may also be treated with AIs. (Refer to the Aromatase inhibitors section in the Hormone receptor–positive therapy section of this summary for more information.)

Tamoxifen and chemotherapy

Because of 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.[ 137 ]

Ovarian ablation, tamoxifen, and chemotherapy

Evidence suggests ovarian ablation alone is not an effective substitute for other systemic therapies.[ 138 ][ 139 ][ 140 ][ 141 ][ 142 ] Further, the addition of ovarian ablation to chemotherapy and/or tamoxifen has not been found to significantly improve outcomes.[ 140 ][ 142 ][ 143 ][ 144 ][ 145 ]

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.[ 146 ][Level of evidence: 1iiDii]
    1. Upon initial report, with a median follow-up of 5.6 years, 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. However, updated results with a median follow-up of 8 years, demonstrated improved DFS with tamoxifen plus ovarian suppression compared with tamoxifen alone (HR, 0.76; 95% CI, 0.62–0.93, P = .009); the 8-year DFS was 83.2% in the tamoxifen-plus-ovarian-suppression group versus 78.9% in the tamoxifen-alone group. In addition, OS at 8 years was improved with tamoxifen plus ovarian suppression compared with tamoxifen alone (HR, 0.67; 95% CI, 0.48–0.92; P = .01); 8-year OS was 93.3% in the tamoxifen-plus-ovarian-suppression group versus 91.5% in the tamoxifen-alone group.

      Despite overall negative initial results, subgroup analysis suggested a benefit with ovarian suppression in women who underwent chemotherapy and remained premenopausal afterwards. Follow-up results at 8 years, however, did not demonstrate heterogeneity of treatment effect according to whether chemotherapy was administered, although recurrences were more frequent among patients who received chemotherapy.

Aromatase inhibitors (AIs)

Premenopausal women

AIs 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.[ 147 ]
  2. In two unblinded studies that were analyzed together (TEXT [NCT00066703] and SOFT [NCT00066690]), exemestane was also compared with tamoxifen in 4,690 premenopausal women who underwent ovarian ablation.[ 148 ]
    1. The use of exemestane resulted in a significant difference in DFS (HR, 0.77; 95% CI, 0.67–0.90; P < .001; 8-year DFS, 86.8% in the exemestane-ovarian suppression group vs. 82.8% in the tamoxifen-ovarian-suppression group).[ ][Level of evidence: 1iDii]
    2. The 8-year rate of freedom from distant recurrence was also higher in the exemestane-ovarian-suppression group (HR, 0.80; 95% CI, 0.66–0.96; P = .02); 8-year rate of freedom from distant recurrence was 91.8% in the exemestane-ovarian-suppression group versus 89.7% in the tamoxifen-ovarian-suppression group.
    3. Despite improvements in DFS and freedom from distant recurrence, no difference in OS was observed with the use of exemestane in combination with ovarian suppression compared with tamoxifen in combination with ovarian suppression (HR, 0.98; 95% CI, 0.79–1.22; P = .84; 8-year OS, 93.4% in the exemestane-ovarian suppression group vs. 93.3% in the tamoxifen-ovarian-suppression group).[ ][Level of evidence: 1iiA]
    4. 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):[ ]

Postmenopausal women

In postmenopausal women, the use of AIs 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.[ 150 ]

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 lymph node-negative or lymph node-positive disease. Most (84%) of the patients in the study were hormone receptor-positive. Slightly more than 20% had received chemotherapy.[ 151 ]; [ 152 ][Level of evidence: 1iDii]
  2. A large, double-blinded, randomized trial of 8,010 postmenopausal women with hormone receptor-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.[ 153 ] 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.[ 154 ][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).[ 150 ][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.[ 155 ][ 156 ][ 157 ] 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.[ 157 ][Level of evidence: 1iiA]
  2. Two other trials were reported together.[ 156 ] 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% CI for the switched arm vs. 96% CI for the tamoxifen-alone arm; P = .16).[ 157 ][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.[ 158 ][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).[ 150 ][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.[ 160 ][Level of evidence: 1iDii]
  2. Similarly in the IBCSG 1-98 (NCT00004205) trial, two sequential arms were compared with 5 years of letrozole.[ 161 ][Level of evidence: 1iDii]
  3. The FATA-GIM3 (NCT00541086) trial, which was not included in the meta-analysis, compared 2 years of tamoxifen followed by 3 years of one of the three AIs with 5 years of an AI. No significant difference in 5-year DFS was found between the two approaches (88.5% for switching; 89.8% for upfront AI; HR, 0.89; 95% CI, 0.73–1.08; P = .23).[ 162 ]

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).[ 150 ][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 hormone receptor-positive breast cancer.[ 163 ][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 hormone receptor-positive disease were randomly assigned to receive either letrozole or anastrozole.[ 165 ]
  3. In the FATA-GIM3 trial, 3,697 patients with HR-positive disease were randomly assigned among the three AIs either for 5 years or after 2 years of tamoxifen. No significant difference in 5-year DFS (90.0% for anastrozole, 88.0% for exemestane, and 89.4% for letrozole; P = .24) was noted among the three AIs.[ 162 ]

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 years (range, 4.5–6.0) years.[ 166 ][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.[ 170 ][Level of evidence: 1iDii]

Duration of AI therapy

The optimal duration of AI therapy is uncertain, and multiple trials have evaluated courses longer than 5 years.

Evidence regarding extension of endocrine therapy beyond 5 years of initial AI-based adjuvant therapy:

  1. A double-blind, randomized, phase III 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.[ 171 ] Patients who received previous tamoxifen therapy were included. Most 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%.[ ][Level of evidence: 1iDii]
    2. OS rates showed no difference (HR, 0.97; 95% CI, 0.73–1.28; P = .83). More patients on letrozole had fractures (14%) than did patients on placebo (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.
  2. A randomized phase III study assessed the effect of an additional 2.5 years of letrozole versus 5 years of letrozole in 1,824 women who received 5 years of an AI.[ 172 ][Level of evidence: 1iiDii]
  3. A phase III trial (NSABP-B42 [NCT00382070]) randomly assigned, in a double-blind fashion, 3,966 women who received 5 years of initial adjuvant therapy with an AI or received tamoxifen for 2 to 3 years followed by an AI to receive 5 mg of letrozole or placebo for 5 additional years.[ 173 ][Level of evidence: 1iDii] The planned analysis of DFS was carried out after a median follow-up of 6.9 years.
  4. A phase III trial conducted by the IBCSG (SOLE [NCT00553410]) randomly assigned 4,851 eligible receptor-positive postmenopausal women who had completed 5 years of adjuvant therapy with an AI, a selective estrogen receptor modulator, or both, to receive 2.5 mg of letrozole daily for 5 years or to an intermittent schedule in which there was a 3-month break at the end of each of the first 4 years, but not in the final year.[ 174 ]
  5. A phase III trial conducted by the Dutch Breast Cancer Study Group (DATA [NCT00301457]) randomly assigned 1,860 eligible receptor-positive postmenopausal women who had received 2 to 3 years of tamoxifen to receive either 3 or 6 years of anastrozole (1 mg daily).[ 175 ]
  6. The phase III ABCSG-16 study, published in abstract form, enrolled 3,484 postmenopausal women with hormone receptor–positive breast cancer who had completed 5 years of endocrine therapy with tamoxifen and/or an AI to either 2 or 5 years of extended therapy with anastrozole. The primary endpoint was DFS. Secondary endpoints included OS, time to contralateral breast cancer, time to second primary cancer, fractures, and toxicity.[ 176 ]

Bone-modifying therapy

Both bisphosphonates and denosumab have been evaluated as adjuvant therapies for early-stage breast cancer; however, the role of these agents as adjuvant therapy for early-stage breast cancer is unclear. Compared with denosumab, the amount of evidence supporting bisphosphonates is greater, and there is evidence supporting breast cancer mortality—an endpoint that is more clinically relevant.

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.[ 177 ] 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).
  2. The ABCSG-18 (NCT00556374) trial randomly assigned 3,435 postmenopausal women with receptor-positive breast cancer who were receiving an AI to receive denosumab or a placebo every 6 months during AI therapy.[ 178 ] The patients were unblinded when results related to bone events were reported, and patients on placebo were allowed to cross over to the active drug.

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 to reduce tumor volume and allow for definitive surgery. In addition, preoperative chemotherapy is being used for some patients with primary operable stage II or stage III breast cancer. A meta-analysis of multiple, randomized clinical trials performed in 2005 demonstrated that preoperative chemotherapy is associated with identical DFS and OS compared with the administration of the same therapy in the adjuvant setting.[ 179 ][Level of evidence: 1iiA]

In 2019, the Early Breast Cancer Trialists’ Collaborative Group performed a meta-analysis using individual patient data from 4,756 women who participated in 10 trials that compared neoadjuvant chemotherapy with the same regimen given in the adjuvant setting.[ 180 ] Compared with adjuvant therapy, neoadjuvant therapy was associated with an increased frequency of breast conservation (65% vs. 49%). There were no differences between neoadjuvant chemotherapy and adjuvant therapy in distant recurrence, breast cancer mortality, or death from any cause; however, neoadjuvant therapy was associated with higher 15-year local recurrence (21.4% vs. 15.9%; rate ratio, 1.37; 95% CI, 1.17−1.61; P = .001).[ 180 ][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).[ 181 ][ 182 ][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).[ 183 ] pCR could not be validated in this study as a surrogate endpoint for improved EFS and OS.[ 183 ][Level of evidence: 3iiiD] Because 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 hormone-receptor 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:[ 184 ]

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.[ 189 ][ 190 ] 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.[ 191 ][ 192 ][ 193 ][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.[ 194 ][Level of evidence: 1iiA]

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 NSABP (NSABP B-27 [NCT00002707]) trial was conducted.[ 181 ][Level of evidence: 1iiD]
  2. Data from NSABP B-27 and the Aberdeen Breast Group Trial support the use of anthracycline-taxane–based regimens in women with initial response or with relative resistance to anthracyclines.[ 189 ]
  3. Alternative anthracycline-taxane schedules have also been evaluated (concurrent TAC) and appear similar in efficacy to the sequential approach described above.[ 195 ][Level of evidence: 1iiDiv]
  4. The phase III GeparSepto (NCT01583426) trial investigated an alternative taxane (nab-paclitaxel) in patients with untreated primary breast cancer.[ 196 ] 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%).[ 196 ][Level of evidence: 1iiDiv]
  5. The incorporation of many additional cytotoxic agents to anthracycline-taxane–based regimens has not offered a significant additional benefit to breast conservation or pCR rate in unselected breast cancer populations.[ 197 ][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.[ 198 ][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.[ 199 ][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]).[ 200 ][ 201 ][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-taxane–based regimens.[ 202 ][Level of evidence: 1iiDiv] This has been confirmed in phase III studies.[ 203 ][ 204 ]

Trastuzumab

Evidence (trastuzumab):

  1. The phase III NeOAdjuvant Herceptin (NOAH) study randomly assigned patients with HER2-positive locally advanced or inflammatory breast cancers to undergo preoperative chemotherapy with or without 1 year of trastuzumab therapy.[ 204 ][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 (5-FU, epirubicin, cyclophosphamide) of the preoperative chemotherapy regimen.[ 206 ][Level of evidence: 1iiDiv]

A subcutaneous formulation of trastuzumab has also been approved.

The SafeHer (NCT01566721) trial evaluated the safety and tolerability of self-administered versus clinician-administered SQ trastuzumab in stage I to stage III HER2-positive breast cancer.[ 207 ] Chemotherapy was administered concurrently or sequentially.

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.[ 208 ][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. EFS and OS were secondary endpoints. Six-year EFS was 65% in both arms (HR, 0.98; 95% CI, 0.74−1.29). Six-year OS was 84% in both arms (HR, 0.94; 95% CI, 0.61−1.45).[ 209 ]

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.[ 210 ][ 211 ]

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 to improve on the pCR rates observed with trastuzumab and chemotherapy.

Evidence (pertuzumab):

  1. In the open-label, randomized, phase II NeoSPHERE (NCT00545688) trial,[ 210 ] 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:[ 210 ][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.[ 213 ][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:

Because of these studies, the FDA-granted accelerated approval for the use of pertuzumab as part of a preoperative treatment for women with early-stage, HER2-positive breast cancer whose tumors are larger than 2 cm or node-positive.

The FDA approval of pertuzumab was subsequently converted to regular approval following the results of the confirmatory APHINITY (NCT01358877) trial, a randomized, phase III, adjuvant study for women with HER2-positive breast cancer, which demonstrated improved invasive DFS with the combination of chemotherapy and dual HER2-targeted therapy with pertuzumab plus trastuzumab compared with chemotherapy and trastuzumab alone.[ 127 ] Pertuzumab is now approved both in combination with trastuzumab and chemotherapy for the neoadjuvant therapy of locally advanced, inflammatory, or early-stage HER2-positive breast cancer, which is larger than 2 cm or node-positive, as part of a complete treatment regimen and in combination with chemotherapy and trastuzumab as adjuvant treatment for HER2-positive early breast cancer at a high risk of recurrence.

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 (against the use of lapatinib for HER2-positive early breast cancer):

  1. The role of lapatinib in the preoperative setting was examined in the GeparQuinto [NCT00567554] trial.[ 201 ] 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.[ 201 ][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.[ 214 ] [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.[ 126 ] 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.[ 216 ][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.[ 217 ][Level of evidence: 3iiiD]

Preoperative endocrine therapy

Preoperative endocrine therapy may be an option for postmenopausal women with hormone receptor-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.[ 218 ][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.[ 219 ] 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).[ 182 ][Level of Evidence: 1iiDiv]

AIs have also been compared with tamoxifen in the preoperative setting. Overall objective response and breast-conserving therapy rates with 3 to 4 months of preoperative therapy were either statistically significantly improved in the AI-treated women [ 218 ] or comparable to tamoxifen-associated outcomes.[ 182 ] 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.[ 220 ] The study was terminated because of the results of a planned interim analysis, and a final analysis was done.

Trastuzumab emtansine (T-DM1)

Evidence (T-DM1):

  1. In a phase III trial (KATHERINE [NCT01772472]), 1,486 women with HER2-positive disease who received a preoperative taxane-containing chemotherapy (with or without an anthracycline) along with trastuzumab with or without a second HER2 targeted agent, but who had residual disease after surgery, were randomly assigned to receive 14 cycles of adjuvant trastuzumab or T-DM1.[ 221 ][Level of evidence: 1iDii]

These approaches 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 hormone receptor-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.[ 222 ][ 223 ][ 224 ] Even when these tests permit earlier detection of recurrent disease, patient survival is unaffected.[ 223 ] 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.

参考文献
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  214. 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.[PUBMED Abstract]
  215. 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.[PUBMED Abstract]
  216. 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.[PUBMED Abstract]
  217. 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.[PUBMED Abstract]
  218. 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.[PUBMED Abstract]
  219. 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.[PUBMED Abstract]
  220. Masuda N, Lee SJ, Ohtani S, et al.: Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med 376 (22): 2147-2159, 2017.[PUBMED Abstract]
  221. von Minckwitz G, Huang CS, Mano MS, et al.: Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 380 (7): 617-628, 2019.[PUBMED Abstract]
  222. Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicenter randomized controlled trial. The GIVIO Investigators. JAMA 271 (20): 1587-92, 1994.[PUBMED Abstract]
  223. Rosselli Del Turco M, Palli D, Cariddi A, et al.: Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA 271 (20): 1593-7, 1994.[PUBMED Abstract]
  224. 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.[PUBMED Abstract]
Locally Advanced or Inflammatory Breast Cancer

Treatment Option Overview for Locally Advanced or Inflammatory Breast Cancer

On the basis of the 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 way 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.

参考文献
  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.[PUBMED Abstract]
  2. Berg CD, Swain SM: Results of Concomitantly Administered Chemoradiation for Locally Advanced Noninflammatory Breast Cancer. Semin Radiat Oncol 4 (4): 226-235, 1994.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
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.

参考文献
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  13. Wapnir IL, Price KN, Anderson SJ, et al.: Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial. J Clin Oncol 36 (11): 1073-1079, 2018.[PUBMED Abstract]
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 overall,[ 1 ] survival varies according to subtype. The longest median outcomes have been observed in patients with human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor–positive metastatic breast cancer, and less favorable outcomes have been observed in patients with triple-negative metastatic breast cancer.[ 2 ]

Treatment options for metastatic breast cancer include the following:

  1. Hormone therapy (tamoxifen, aromatase inhibitors).
  2. HER2 targeted therapy.
  3. CDK 4/6 inhibitors.
  4. mTOR inhibitors.
  5. PIK3CA inhibitors.
  6. Chemotherapy.
  7. Immunotherapy.
  8. Surgery, for patients with limited symptomatic metastases.
  9. Radiation therapy, for patients with limited symptomatic metastases.
  10. Bone-modifying therapy, for patients with bone metastases.

In many cases, these therapies are given in sequence and used in various combinations.

Cytologic or histologic documentation of metastatic disease, with testing of estrogen receptor (ER), progesterone receptor, and HER2 status, should be obtained whenever possible.

All patients with metastatic breast cancer are considered candidates for ongoing clinical trials.

Hormone Receptor–Positive Breast Cancer

Endocrine therapy and cyclin-dependent kinase inhibitor therapy

CDK4 and CDK6 have been implicated in the continued proliferation of hormone receptor–positive breast cancer resistant to endocrine therapy. CDK inhibitors have been approved by the U.S. Food and Drug Administration (FDA) in combination with endocrine therapy in both first-line and later-line treatment of advanced hormone receptor–positive HER2-negative breast cancer. Three oral CDK4/6 inhibitors are currently available: palbociclib, ribociclib, and abemaciclib.

Overall, the addition of CDK 4/6 inhibitors to endocrine therapy is associated with improved breast cancer outcomes and, in general, either maintained or improved quality of life.[ 3 ][ 4 ][ 5 ][ 6 ][ 7 ][ 8 ]

First-line palbociclib and endocrine therapy

Evidence (first-line palbociclib and endocrine therapy):

  1. PALOMA-2 (NCT01740427) confirmed the results of the phase II PALOMA-1 trial.[ 9 ] 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).[ 10 ]

First-line ribociclib and endocrine therapy

Ribociclib, another CDK4/6 inhibitor, has also been tested in the first-line setting for postmenopausal patients and premenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer.

Evidence (first-line ribociclib and endocrine therapy):

  1. The phase III, placebo-controlled MONALEESA-2 trial (NCT01958021) randomly assigned 668 patients to receive first-line ribociclib plus letrozole or placebo plus letrozole.[ 11 ]
    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.[ 11 ][Level of evidence: 1iDiii]
    2. OS data were immature at the time of publication.
    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%).
  2. Ribociclib has also been tested in combination with fulvestrant in postmenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer. The MONALEESA-3 (NCT02422615) trial included patients receiving first-line or second-line therapy. This phase III, placebo-controlled trial randomly assigned 726 patients in a 2:1 ratio to receive ribociclib plus fulvestrant or placebo plus fulvestrant.[ 12 ]
    1. The primary endpoint (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 20.5 months versus 12.8 months in the placebo group (HR, .593; 95% CI, .480–.732; P <.001).[ 12 ][Level of evidence: 1iDiii]
    2. OS was superior in the ribociclib group (HR, 0.724; 95% CI, 0.568–0.924; P = .004). The result crossed the prespecified stopping boundary (P = .011) for superior efficacy. Results were similar in all subgroups.[ 13 ][Level of evidence: 1iA]
    3. Adverse events were similar to those in other studies of CDK4/6 inhibitors.
  3. Ribociclib was also assessed in the first-line setting in a study conducted solely in premenopausal or perimenopausal women receiving either tamoxifen or a nonsteroidal aromatase inhibitor (AI) plus goserelin.[ 14 ] In the MONALEESA-7 (NCT02278120) trial, 672 premenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer, who had not received endocrine therapy for advanced disease, were randomly assigned in a 1:1 ratio to ribociclib or placebo.
    1. The primary endpoint (investigator-assessed PFS) was met. At the time of final analysis for PFS, the median PFS for the ribociclib group was 23.8 months versus 13.0 months in the placebo group (HR, .55; 95% CI, 0.44–0.69; P < .0001).[ 14 ][Level of evidence: 1iC]
    2. OS was a secondary endpoint. The combination of ribociclib plus endocrine therapy was associated with longer OS than was endocrine therapy alone (42-month OS, 70.2% vs. 46%; HRdeath, 0.71; 95% CI, 0.54−0.95, P = .01).[ 15 ][Level of evidence: 1iA] The survival benefit was observed both in patients who received an AI plus goserelin and in those who received tamoxifen, but it was not statistically significant in the much-smaller tamoxifen group.
    3. Adverse events were similar to those in other studies of CDK4/6 inhibitors.

First-line abemaciclib and endocrine therapy

Abemaciclib, another CDK4/6 inhibitor, has also been tested in the first-line setting for postmenopausal patients with hormone receptor–positive and HER2-negative recurrent or metastatic breast cancer.

Evidence (first-line abemaciclib and endocrine therapy):

  1. MONARCH 3 (NCT02246621) was a randomized, double-blind, phase III trial that evaluated first-line abemaciclib or placebo plus a nonsteroidal AI in 493 postmenopausal women with hormone receptor–positive and HER2-negative advanced breast cancer.[ 16 ]

Second-line palbociclib and endocrine therapy

Evidence (second-line palbociclib and endocrine therapy):

  1. 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 after or progressed on previous endocrine therapy and were randomly assigned to receive either fulvestrant plus placebo or fulvestrant plus palbociclib. Premenopausal and postmenopausal patients were eligible. Premenopausal patients received goserelin.[ 5 ][Level of Evidence: 1iC]

Second-line ribociclib and endocrine therapy

The MONALEESA-3 trial included patients receiving second-line therapy. (Refer to the evidence on first-line ribociclib and endocrine therapy above for more information.)

Second-line abemaciclib and endocrine therapy

Evidence:

  1. The MONARCH 2 (NCT02107703) study tested abemaciclib (CDK4/6 inhibitor) in a phase III, placebo-controlled trial that randomly assigned 669 patients with hormone receptor–positive and HER2-negative advanced breast cancer (with previous progression on endocrine therapy) to receive abemaciclib plus fulvestrant or placebo plus fulvestrant.[ 19 ]
    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).[ 19 ][Level of evidence: 1iDiii]
    2. OS data are mature and demonstrate an improvement in OS for patients receiving abemaciclib, and showed a median OS of 46.7 months for abemaciclib plus fulvestrant versus 37.3 months for placebo (HR, 0.757; 95% CI, 0.606–0.945; P = .01).[ 20 ][Level of Evidence: 1iA]
    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%).

Single-agent cyclin-dependent kinase inhibitor therapy

Evidence (single-agent cyclin-dependent kinase inhibitor therapy):

  1. Single-agent abemaciclib was approved by the FDA for use in hormone receptor–positive, HER2-negative breast cancer with disease progression on or after endocrine therapy and chemotherapy on the basis of results of the MONARCH 1 (NCT02102490) trial.[ 21 ] Abemaciclib is the only CDK4/6 inhibitor approved as a single agent. MONARCH 1 was a single-arm phase II study of single-agent abemaciclib in 132 women with hormone receptor–positive and HER2-negative advanced breast cancer that had progressed on at least one line of previous endocrine therapy and at least two lines of previous chemotherapy. The study population was heavily pretreated, and most participants had visceral disease. Patients who had previous CDK inhibitors were excluded.

Mammalian target of rapamycin (mTOR) inhibitor therapy plus endocrine therapy

Preclinical models and clinical studies suggest that mTOR inhibitors might overcome endocrine resistance.

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.[ 22 ][Level of evidence: 1iDiii]
  2. TAMRAD (NCT01298713) was an open-label randomized phase II trial comparing tamoxifen to tamoxifen plus everolimus in postmenopausal women whose disease had progressed after receiving an AI in the adjuvant or metastatic setting. The trial randomly assigned 57 women to receive tamoxifen and 54 women to receive the combination therapy.[ 24 ]
  3. PrE0102 (NCT01797120) was a double-blind randomized phase II trial comparing fulvestrant to fulvestrant plus everolimus in postmenopausal women whose disease had progressed after receiving an AI in the adjuvant or metastatic setting. Sixty-six women were randomly assigned to the combination arm and 65 to fulvestrant alone.[ 25 ]
  4. The SWISH trial (NCT02069093) was a single-arm trial assessing the efficacy of a dexamethasone oral solution (0.5 mg per 5 mL) in the prevention of stomatitis in women receiving exemestane plus everolimus.[ 26 ] The incidence of grade 2 or worse stomatitis was 2% in the 85 evaluable patients in this study compared with 33% in the BOLERO-2 trial.

Alpelisib plus endocrine therapy

Activating mutations in PIK3CA are identified in approximately 40% of hormone receptor–positive and HER2-negative breast cancers. Alpelisib is an alpha-specific PI3K inhibitor.

Evidence (alpelisib plus endocrine therapy):

  1. SOLAR-1 (NCT02437318) was a randomized phase III trial comparing alpelisib plus fulvestrant to placebo plus fulvestrant in 572 postmenopausal women with hormone receptor–positive and HER2-negative advanced breast cancer who had received previous endocrine therapy.[ 27 ][Level of evidence: 1iiDiii]

    PIK3CA mutations were confirmed in 341 participants. The primary endpoint was PFS in the cohort of patients with PIK3CA mutations.

  2. Evidence of mTOR inhibitor activity in HER2-positive breast cancer was shown in the double-blind, placebo-controlled, phase III BOLERO-3 (NCT01007942) trial.[ 28 ][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.

Endocrine therapy alone

With the PFS and OS advantages associated with combination therapy with targeted agents and endocrine therapy as discussed above, single-agent endocrine therapy is less frequently used, especially in the first-line setting. However, its use remains appropriate in select cases as first-line therapy and in later-line therapy after progression on targeted therapies and before the use of chemotherapy in cases in which endocrine-sensitive disease is still thought to be present.

Commonly used single-agent endocrine therapies include tamoxifen, nonsteroidal AI (letrozole, anastrozole), the steroidal AI exemestane, and fulvestrant. In general, premenopausal women with metastatic breast cancer undergo ovarian suppression or ablation and are treated in the same manner as postmenopausal women.

Tamoxifen and AI therapy

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 PFS for the AI compared with tamoxifen.[ 29 ][ 30 ][ 31 ][Level of evidence: 1iiDiii]

Evidence (tamoxifen and AI therapy):

  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).[ 32 ][Level of evidence: 1iA]

Fulvestrant

Fulvestrant is a selective estrogen receptor degrader that has been studied in the first-line and second-line setting in women with advanced or metastatic breast cancer.

First-line fulvestrant

Evidence (first-line fulvestrant):

  1. FALCON (NCT01602380) was a phase III double-blind randomized trial that compared fulvestrant (500 mg) to anastrozole (1 mg) in patients with advanced or metastatic receptor-positive breast cancer who had not received previous endocrine therapy.[ 33 ] The trial randomly assigned 230 patients to receive fulvestrant and 232 patients to receive anastrozole.

Second-line fulvestrant

Evidence (second-line fulvestrant):

  1. 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.[ 34 ][ 35 ] The proper sequence of these therapies is not known.[ 36 ][ 37 ]
  2. EFECT (NCT00065325) was a phase III double-blind randomized trial that compared fulvestrant given in a loading-dose regimen (500 mg day 0, 250 mg days 14 and 28, and 250 mg every 28 days thereafter) to exemestane (25 mg) in women who had developed progressive disease after previous nonsteroidal AI (anastrozole or letrozole) therapy.[ 38 ] The trial randomly assigned 351 women to receive fulvestrant and 342 women to receive exemestane.
  3. CONFIRM (NCT00099437) was a double-blind phase III trial that compared two doses of fulvestrant (500 mg vs. 250 mg, each given in a loading-dose schedule) in 736 women whose disease had progressed on previous endocrine therapy.[ 39 ]

Combination endocrine therapy with an AI and fulvestrant

Conflicting results were found in two trials that compared the combination of the antiestrogen fulvestrant (refer to the section on Fulvestrant for more information about this drug) and anastrozole with anastrozole alone in the first-line treatment of hormone receptor–positive postmenopausal patients with recurrent or metastatic disease.[ 40 ][ 41 ] 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.[ 40 ][ 41 ]

Evidence (combination endocrine therapy with an AI and fulvestrant):

  1. The SWOG trial (SWOG-0226 [NCT00075764]), which enrolled 707 patients, demonstrated a statistically significant difference in PFS (HR, 0.80; 95% CI, 0.68–0.94; P = .007) and OS (HR, 0.81; 95% CI, 0.65–1.00; P = .05).[ 40 ][Level of evidence: 1iA]
  2. In an analysis done after 5 more years of follow-up, the observed benefits of combined therapy were still present, and the level of significance with respect to OS was greater (HR, 0.82; 95% CI, 0.69–0.98; P = .03).[ 42 ][Level of evidence: 1iA]
  3. In contrast, the FACT trial , which enrolled 514 patients, found no difference in either disease-free survival (DFS) (HR, 0.99; 95% CI, 0.81–1.20; P = .91) or OS (HR, 1.0; 95% CI, 0.76–1.32; P = 1.00).[ 41 ][Level of evidence: 1iA]

Sequencing Therapy for Hormone Receptor–Positive Metastatic Breast Cancer

The optimal sequence of therapies for hormone receptor–positive metastatic breast cancer is not known. In general, in the absence of a visceral crisis, most patients receive sequential endocrine-based regimens before transitioning to chemotherapy. On the basis of the PFS and OS improvements mentioned above, a combination of a CDK4/6 inhibitor therapy and endocrine therapy in the first line is an appropriate choice.

Hormone Receptor–Negative Breast Cancer

The treatment for hormone receptor–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. Several 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.[ 43 ] Trastuzumab is a humanized monoclonal antibody that binds to the HER2/neu receptor.[ 43 ] 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%.[ 44 ][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.[ 45 ][Level of evidence: 1iiA]

Notably, when combined with doxorubicin, trastuzumab is associated with significant cardiac toxicity.[ 46 ]

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.[ 49 ][ 50 ][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.[ 51 ][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.[ 53 ][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.[ 54 ][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.[ 56 ][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.

Trastuzumab deruxtecan

Trastuzumab deruxtecan is an antibody-drug conjugate that combines trastuzumab with a topoisomerase inhibitor. A phase I study demonstrated antitumor activity in patients with advanced HER2-positive breast cancer who received the drug conjugate.[ 57 ]

Evidence (trastuzumab deruxtecan):

  1. A non-blinded single-arm phase II trial (NCT03248492) examined the response rate to trastuzumab deruxtecan at a dose of 5.4 mg/kg in 184 patients with HER2-positive breast cancer who had previously received trastuzumab and trastuzumab emtansine.[ 57 ][Level of evidence: 3iiiDiv]

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 [NCT00078572]) 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.[ 58 ][Level of evidence: 1iiA]

Tucatinib

Tucatinib is an oral tyrosine kinase inhibitor highly selective for the kinase domain of HER2 that minimally inhibits the epidermal growth factor receptor. A phase Ib trial in pretreated patients demonstrated activity when tucatinib was combined with trastuzumab and capecitabine.

Evidence (tucatinib):

  1. The HER2CLIMB trial (NCT02614794) compared trastuzumab, capecitabine, and tucatinib with trastuzumab, capecitabine, and placebo in 632 patients who had previously been treated with trastuzumab, pertuzumab, and trastuzumab emtansine and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with and without brain metastases were included.[ 59 ][Level of evidence:1iA]

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.

Olaparib

Evidence (olaparib):

  1. 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).[ 60 ] All patients had received anthracycline and taxane previously in either the adjuvant or metastatic setting, and those with hormone receptor–positive disease had also received endocrine therapy previously.

Talazoparib

Evidence (talazoparib):

  1. The EMBRACA (NCT01945775) trial was a randomized, open label, phase III trial that assigned 431 patients with a deleterious germline BRCA or BRCA2 mutation and locally advanced or metastatic breast cancer in a 2:1 ratio to talazoparib (1 mg PO qd) or standard single-agent chemotherapy of the physician’s choice (eribulin, capecitabine, gemcitabine, or vinorelbine).[ 61 ] All patients had received previous treatment with an anthracycline, taxane, or both. Patients had received three or fewer lines of cytotoxic chemotherapy for advanced breast cancer. Previous platinum therapy in the setting of early breast cancer was permitted if it was completed at least 6 months before progressive disease or if there was no objective progression while on platinum therapy in the advanced-disease setting. Hormone receptor–positive and hormone receptor–negative patients were enrolled.

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

Chemotherapy

Patients receiving 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 hormone receptor–negative tumors and those with visceral metastases or symptomatic disease are also candidates for cytotoxic agents.[ 62 ]

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 ECOG intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin, given both as a combination and sequentially.[ 91 ] Although response rate and time to disease progression were both better for the combination, survival was the same in both groups.[ 91 ][Level of evidence: 1iiA]; [ 92 ][ 93 ]

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

Currently, 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 ][ 94 ] 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.[ 95 ][Level of evidence: 1iiA]

Decisions regarding the duration of chemotherapy may consider 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.[ 96 ][ 97 ][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,[ 97 ] 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 [ 98 ] or a different chemotherapy regimen given at higher versus lower doses.[ 99 ][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.[ 100 ][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.

Chemotherapy plus immunotherapy

The addition of atezolizumab, an anti-programmed death ligand 1 (PD-L1)–positive antibody, to first-line chemotherapy for patients with hormone receptor–negative and HER2-negative advanced breast cancer was evaluated in the phase III randomized placebo-controlled IMpassion130 trial (NCT02425891).[ 101 ] Participants (N = 902) were randomly assigned 1:1 to atezolizumab plus nanoparticle albumin-bound (nab)-paclitaxel or to placebo plus nab-paclitaxel. Participants were stratified according to the presence of liver metastases (yes/no), receipt of previous taxane therapy (yes/no), and PD-L1 status (positive or negative). PD-L1 score of 1% or greater was defined as positive. Co-primary endpoints included PFS and OS, both of which were evaluated in the intention-to-treat population and in the PD-L1–positive population (n = 369).

  1. PFS data are final with a median follow-up of 12.9 months and included the following:
  2. OS data are not yet mature. Results of the first interim analysis for OS, performed at the time of the final PFS analysis, included the following:
  3. Adverse events occurred as expected. Adverse events that were potentially immune-related were more frequent in the atezolizumab arm.

Atezolizumab was granted accelerated approval by the FDA for use in combination with protein-bound paclitaxel for patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1.

Sacituzumab govitecan

  1. Sacituzumab govitecan is an antibody drug conjugate that combines an anti–trophoblast cell-surface antigen 2 antibody with an active metabolite of irinotecan.[ 102 ] In a phase I/II trial, 108 women with triple-negative breast cancer who had received at least two previous chemotherapy regimens (median, three) were treated with sacituzumab govitecan at a dose of 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle.

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.[ 103 ][ 104 ][ 105 ][ 106 ] The risk of cardiac toxicity may also be reduced by administering doxorubicin as a continuous intravenous infusion.[ 107 ] 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.[ 108 ] Dexrazoxane has a similar protective effect in patients receiving epirubicin.[ 109 ]

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.[ 110 ] 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.[ 111 ][ 112 ]

Bone-Modifying Therapy

The use of bone-modifying therapy to reduce skeletal morbidity in patients with bone metastases should be considered.[ 113 ] Results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity.[ 114 ][ 115 ][ 116 ][Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate.[ 117 ]

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.[ 118 ] 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).[ 118 ][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.[ 119 ]

(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.[ 120 ] The study enrolled 462 patients who had received previous anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab.[ 120 ][Level of evidence: 1iiA]
  2. ECOG-2100 (NCT00028990), an open-label, randomized, phase III trial, compared paclitaxel alone with paclitaxel and bevacizumab.[ 121 ][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.[ 122 ][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.[ 123 ][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.[ 124 ][Level of evidence: 1iA]

In November 2011, because 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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  97. 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.[PUBMED Abstract]
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  121. 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.[PUBMED Abstract]
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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 2020, DCIS is expected to account for about 18% 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 because 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 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 months). 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 years).

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 years).[ 20 ] Positive or unknown surgical margins were present in 23% of patients. Approximately 80% of the lesions measured 1 cm or smaller, 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 smaller, 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.

参考文献
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  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
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  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
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  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
  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.[PUBMED Abstract]
Changes to This Summary (07/22/2020)

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.

Editorial changes were made to this summary.

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 adult 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.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Breast Cancer Treatment (Adult). 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]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.