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Breast Cancer TABLE 2. Breast Cancer Risk F. rs Breast Cancer Risk Factor Breast Cancer Risk Factors Increase in Breast Cancer Risk or Category Lifetime Breast Cancer Risk Reproductive factors Early menarche, late menopause, first full-term RR, 1.2-3.5 pregnancy after age 30 years, nulliparity Lifestyle Obesity (BMI 30), lack of regular exercise, alcohol intake RR, 1.2-1.62¢ Treatment related: radiation Prior chest wall irradiation in patients younger than RR, 5.09 30 years (e.g., mantle irradiation for Hodgkin lymphoma) Treatment related: HRT Combination estrogen and progesterone HRT after RR, 1.2-1.48 menopause Breast density® Increased breast density Risk increases with each category of breast density; for >75% density, RR is 4.7 compared with <10% density‘ Atypical breast lesions Atypical ductal or lobular hyperplasia, LCIS RR, 3.8-5.39 RR, 5.4-8.0° Family history of breast cancerand BRCA1/2 mutation represents the most common familial RR, 3.0-7.0 familial breast cancer syndromes breast cancer syndrome (5%-10% of all breast cancer tumors); others are rare BRCA1/2 = breast cancer susceptibility 1 or breast cancer susceptibility 2 genes; HRT= hormone replacement therapy; LCIS = lobular carcinoma in situ; RR = relative risk.

Family history of breast cancerand BRCA1/2 mutation represents the most common familial RR, 3.0-7.0 familial breast cancer syndromes breast cancer syndrome (5%-10% of all breast cancer tumors); others are rare BRCA1/2 = breast cancer susceptibility 1 or breast cancer susceptibility 2 genes; HRT= hormone replacement therapy; LCIS = lobular carcinoma in situ; RR = relative risk. *Data from Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001 Jan 25;344 (4):276-85. Erratum in: N Engl J Med. 2001 Jun 7;344(23):1804. [PMID: 11172156] Data from Lynch BM, Neilson HK, Friedenreich CM. Physical activity and breast cancer prevention. Recent Results Cancer Res. 2011;186:13-42. [PMID: 21113759] Data from Bagnardi V, Rota M, Botteri E, et al. Light alcohol drinking and cancer: a meta-analysis. Ann Oncol. 2013 Feb;24(2):301-8. [PMID: 22910838] and Smith-Warner SA, Spiegelman D, Yaun SS, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA. 1998 Feb 18;279(7):535-40. [PMID: 9480365] 4Data from Swerdlow AJ, Cooke R, Bates A, et al. Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin's lymphoma in England and Wales: a National Cohort Study. J Clin Oncol. 2012 Aug 1;30(22):2745-52. [PMID: 22734026] °Breast density refers to the amount of radiologically dense breast tissue appearing on a mammogram. ‘Data from Boyd NF, Guo H, Martin LJ, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007 Jan 18;356(3):227-36. [PMID: 17229950] SData from Degnim AC, Cisscher DW, Berman HK, et al. Stratifications of breast cancer risk in women with atypia: a Mayo cohort study. J Clin Oncol. 2007 Jul 1;25(19):2671-77. [PMID: 17563394] and Marshall LM, Hunter DJ, Connolly JL, et al. Risk of breast cancer associated with atypical hyperplasia of lobular and ductal types. Cancer Epidemiol Biomarkers Prev. 1997 May;6(5):297-301. [PMID: 9149887] Data from Bodian CA, Perzin KH, Lattes R. Lobular neoplasia. Long-term risk of breast cancer and relation to other factors. Cancer. 1996 Sep 1;78(5):1024-34. [PMID: 8780540] TABLE 3. Highlights of NCCN? Recommendations for Breast and Ovarian Cancer Syndrome Genetic Testing Individuals with a Personal History of Breast or Ovarian Cancer

Data from Bodian CA, Perzin KH, Lattes R. Lobular neoplasia. Long-term risk of breast cancer and relation to other factors. Cancer. 1996 Sep 1;78(5):1024-34. [PMID: 8780540] TABLE 3. Highlights of NCCN? Recommendations for Breast and Ovarian Cancer Syndrome Genetic Testing Individuals with a Personal History of Breast or Ovarian Cancer Breast cancer diagnosed at or before age 45 years Breast cancer diagnosed at age 46-50 years with one or more relatives® with breast, ovarian, prostate, or pancreatic cancer at any age Women with two primary breast cancers, with the first diagnosed at or before age 50 years Breast cancer diagnosed at any age with one or more relatives® diagnosed with ovarian cancer, breast cancer diagnosed at or before age 50 years, male breast cancer, metastatic prostate cancer, pancreatic cancer Triple-negative breast cancer‘ diagnosed at or before age 60 years Breast cancer in women of Ashkenazi (Eastern European) Jewish ancestry Men with breast cancer diagnosed at any age Ovarian cancer diagnosed at any age Individuals without a Personal History of Breast or Ovarian Cancer Family history of a known deleterious BRCA1/2 mutation BRCA1/2 pathogenic or likely pathogenic variant detected by tumor profiling on any tumor type Any individual with one or more first- or second-degree relatives meeting the above criteria BRCA1/2 = breast cancer susceptibility 1 or breast cancer susceptibility 2 genes; NCCN = National Comprehensive Cancer Network; USPSTF = U.S. Preventive Services Task Force. *Full testing guidelines can be accessed at https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf First-, second-, or third-degree relatives on the same side of the family. ‘Negative for estrogen and progesterone receptors and HER2 amplification.

Breast Cancer TABLE 4. American Cancer Society Recommendations for MRI Breast Cancer Screening Women with BRCA1/2 mutations Women who are a first-degree relative of a BRCA1/2 carrier but are untested? Women with a strong family history of breast cancer with a lifetime breast cancer risk of >20% to 25% as calculated by models? largely dependent on family history Women who had radiation to the chest wall between ages 10 and 30 years (e.g., mantle radiation therapy for Hodgkin lymphoma) Women with a history of other rare familial breast cancer syndromes BRCA1/2 = breast cancer susceptibility 1 or breast cancer susceptibility 2 genes. *Testing for the BRCA1 or BRCA2 mutation that is present in the family is strongly recommended, but some patients decide to defer testing. In this situation when their carrier status is unknown, breast MRI screening is recommended. If they are later tested and do not carry the mutation, MRI screening should be stopped. ’Models that can be used to estimate lifetime risk of breast cancer to determine if MRI screening is appropriate (please note that the Gail Model is not recommended for this use): * BRCAPRO: www4.utsouthwestern.edu/breasthealth/cagene/default.asp * Claus model: Claus EB, Risch N, Thompson WD. The calculation of breast cancer risk for women with a first-degree family history of ovarian cancer. Breast Cancer Res Treat. 1993 Nov;28(2):115-20. [PMID: 8173064] * Tyrer-Cuzik (also called IBIS Breast Cancer Risk Evaluation Tool): www.ems-trials.org/riskevaluator/

* BRCAPRO: www4.utsouthwestern.edu/breasthealth/cagene/default.asp * Claus model: Claus EB, Risch N, Thompson WD. The calculation of breast cancer risk for women with a first-degree family history of ovarian cancer. Breast Cancer Res Treat. 1993 Nov;28(2):115-20. [PMID: 8173064] * Tyrer-Cuzik (also called IBIS Breast Cancer Risk Evaluation Tool): www.ems-trials.org/riskevaluator/ Cancer Society recommends screening certain women at high risk using annual mammography and breast MRI e Women at high risk for breast cancer should be screened (Table 4). with annual mammography and breast MRI; this includes The National Comprehensive Cancer Network recom- women with gene mutations who have a high risk of mends that women with a 5-year risk of breast cancer of breast cancer including BRCA1 or BRCA2, women with a 1.67% or greater are candidates for breast cancer chemopre- strong family history of breast cancer, and those with a vention with antiestrogens. A recommended tool for estimat- history of chest irradiation at a young age. ing 5-year and lifetime risks of breast cancer is the Gail Model e Women with an elevated 5-year risk of breast cancer or Risk Assessment Tool (https://www.cancer.gov/bcrisktool/). with lobular carcinoma in situ or atypical hyperplasia All patients with atypical hyperplasia or lobular carcinoma in should be considered for breast cancer chemoprophylaxis. situ are candidates for chemoprophylaxis. Contrary to the National Comprehensive Cancer Network, the U.S. Preventive e Surgical prophylaxis options for BRCA1 and BRCA2 Services Task Force advises against using any hard cut-off mutation carriers include prophylactic bilateral mastec-

Cancer Society recommends screening certain women at high risk using annual mammography and breast MRI e Women at high risk for breast cancer should be screened (Table 4). with annual mammography and breast MRI; this includes The National Comprehensive Cancer Network recom- women with gene mutations who have a high risk of mends that women with a 5-year risk of breast cancer of breast cancer including BRCA1 or BRCA2, women with a 1.67% or greater are candidates for breast cancer chemopre- strong family history of breast cancer, and those with a vention with antiestrogens. A recommended tool for estimat- history of chest irradiation at a young age. ing 5-year and lifetime risks of breast cancer is the Gail Model e Women with an elevated 5-year risk of breast cancer or Risk Assessment Tool (https://www.cancer.gov/bcrisktool/). with lobular carcinoma in situ or atypical hyperplasia All patients with atypical hyperplasia or lobular carcinoma in should be considered for breast cancer chemoprophylaxis. situ are candidates for chemoprophylaxis. Contrary to the National Comprehensive Cancer Network, the U.S. Preventive e Surgical prophylaxis options for BRCA1 and BRCA2 Services Task Force advises against using any hard cut-off mutation carriers include prophylactic bilateral mastec- point for defining increased risk but suggests focusing instead tomy and prophylactic bilateral salpingo-oophorectomy. on each woman’s values and priorities in weighing the reduced risk of breast cancer with increased likelihood of adverse effects. Staging and Prognosis of Tamoxifen and raloxifene are selective estrogen receptor Early-Stage Breast Cancer modifiers that block estrogen uptake in breast tissue. Breast cancer staging and prognosis are presented in Table 6. Exemestane and anastrozole are aromatase inhibitors that In addition to the excellent prognosis for patients with small prevent the conversion of androgens into estrogens. These tumors with neither lymph node involvement nor distant agents proportionally decrease the risk of breast cancer by 28% metastases, the presence of hormone receptors and absence of to 65% and are given for 5 years. Table 5 summarizes these human epidermal growth factor 2 (HER2) overexpression also chemoprophylaxis options. favorably affect prognosis. Hormone receptor positivity also For women with BRCA1 or BRCA2 mutations, breast predicts risk reduction from antiestrogen therapy. Monoclonal cancer screening with breast MRI should start at age 25 years antibodies such as trastuzumab that block HER2 receptors are and with mammography added at age 30 years. Prophylactic effective therapies and have markedly improved the prognosis bilateral mastectomies for BRCA1 or BRCA2 mutation carri- for those with HER2-positive breast cancer. ers decrease the risk of breast cancer by greater than 90%, For asymptomatic patients with newly diagnosed stage 0 to whereas prophylactic bilateral salpingo-oophorectomy II (early-stage) breast cancer, current guidelines recommend decreases the risk of ovarian, fallopian tube, and primary against using imaging studies such as PET, CT, bone scan, or peritoneal cancers by greater than 80% and all-cause mor- measuring serum markers such as CA15-3 or CA27-29, for stag- tality to age 70 years by 77%. Premenopausal prophylactic ing, as the incidence of asymptomatic metastases is low. However, bilateral salpingo-oophorectomy also decreases the risk of imaging studies for staging are recommended in patients with breast cancer by 50% and is recommended after completion stage III disease or in those with earlier-stage disease who have of childbearing. signs or symptoms suggestive of metastatic disease.

Breast Cancer TABLE Primary Chemoprevention for Breast Cancer Considerations Tamoxifen Raloxifene Exemestane Anastrozole Mechanism of action SERM SERM Aromatase inhibitor Aromatase inhibitor Breast cancer risk 43% at 7 years? As effective astamoxifen 65% at 3 years? 53% at 5 years® reduction 6 b at reducing the risk of 28% at 10 years invasive cancers, but less effective at reducing noninvasive cancers* Important toxicities Vasomotor symptoms, Vasomotor symptoms, Vasomotor symptoms, Vasomotor symptoms, cataracts, vascular events cataracts, vascular vaginal dryness, sexual vaginal dryness, sexual (stroke, TIA, VTE), and events (25% lower risk dysfunction, arthralgia, dysfunction, arthralgia, endometrial cancer and of vascular events than headaches, and carpal tunnel syndrome, uterine sarcoma in with tamoxifen) insomnia dry eyes, and postmenopausal women hypertension

Important toxicities Vasomotor symptoms, Vasomotor symptoms, Vasomotor symptoms, Vasomotor symptoms, cataracts, vascular events cataracts, vascular vaginal dryness, sexual vaginal dryness, sexual (stroke, TIA, VTE), and events (25% lower risk dysfunction, arthralgia, dysfunction, arthralgia, endometrial cancer and of vascular events than headaches, and carpal tunnel syndrome, uterine sarcoma in with tamoxifen) insomnia dry eyes, and postmenopausal women hypertension Indicated for use in Yes Not studied; should not Not effective in Not effective in premenopausal women be used unless part of a premenopausal women premenopausal women clinical trial Other Contraindicated in Contraindicated in At 3-year follow-up, no At 5-year follow-up, no women with prior women with prior increase in osteoporosis, increase in thromboem- thromboembolic events; thromboembolic events fractures, endometrial bolic events, fractures, 32% reduction in cancer, vascular events, cerebrovascular events, osteoporotic fractures? or cardiac disease or myocardial infarction

Other Contraindicated in Contraindicated in At 3-year follow-up, no At 5-year follow-up, no women with prior women with prior increase in osteoporosis, increase in thromboem- thromboembolic events; thromboembolic events fractures, endometrial bolic events, fractures, 32% reduction in cancer, vascular events, cerebrovascular events, osteoporotic fractures? or cardiac disease or myocardial infarction SERM = selective estrogen receptor modulator; TIA=transient ischemic attack; VTE = venous thromboembolism. *Fisher B, Constantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005 Nov 16;97(22):1652-62. [PMID: 16288118] ’Cuzick J, Sestak |, Cawthorn S, et al; IBIS-I Investigators. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol. 2015 Jan;16(1):67-75. [PMID: 25497694] “Vogel VG, Costantino JP, Wickerham DL, et al; National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA. 2006 Jun 21;295(23):2727-41. Erratum in: JAMA. 2006 Dec 27;296(24):2926. [PMID: 16754727] 9Goss PE, Ingle JN, Alés-Martinez JE, et al; NCIC CTG MAP.3 Study Investigators. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011 Jun 23;364(25):2381-91. Erratum in: N Engl J Med. 2011 Oct 6;365(14):1361. [PMID: 21639806]

“Vogel VG, Costantino JP, Wickerham DL, et al; National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA. 2006 Jun 21;295(23):2727-41. Erratum in: JAMA. 2006 Dec 27;296(24):2926. [PMID: 16754727] 9Goss PE, Ingle JN, Alés-Martinez JE, et al; NCIC CTG MAP.3 Study Investigators. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011 Jun 23;364(25):2381-91. Erratum in: N Engl J Med. 2011 Oct 6;365(14):1361. [PMID: 21639806] *Cuzick J, Sestak |, Forbes JF, et al; IBIS-II Investigators. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014 Mar 22;383(9922):1041-48. Erratum in: Lancet. 2014 Mar 22;383(9922):1040. [PMID: 24333009] TABLE 6. Staging and Prognosis of Invasive Breast Cancer Stage Definition 5-Year Relative Survival? Rates 0 Ductal carcinoma in situ (negative lymph nodes) 100% Localized IA: Tumor <2 cm and negative lymph nodes 98.9% IB: Tumor <2 cm and 1 to 3 micrometastatic positive lymph nodes (0.2-2 mm) Regional IIA: Tumor <2 cm with 1 to 3 positive lymph nodes (>2 mm) OR 85.7% Tumor 2-5 cm with negative lymph nodes IIB: Tumor 2-5 cm with 1 to 3 positive lymph nodes OR Tumor >5 cm with negative lymph nodes IITA: Tumor <5 cm with 4 to 9 positive lymph nodes OR Tumor >5 cm with 1 to 9 positive lymph nodes IIIB: Tumors with skin or chest wall involvement with 0 to 9 positive lymph nodes IIIC: Tumors with 10 or more positive lymph nodes Distant Distant metastatic disease 28.1%

Tumor >5 cm with 1 to 9 positive lymph nodes IIIB: Tumors with skin or chest wall involvement with 0 to 9 positive lymph nodes IIIC: Tumors with 10 or more positive lymph nodes Distant Distant metastatic disease 28.1% mie oe is the ratio of the proportion of observed survivors in a cohort of patients with cancer to the proportion of expected survivors in a comparable set of cancer-free Individuals. Data from Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2017, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2017/, based on November 2019 SEER data submission, posted to the SEER web site, April 2020. Accessed January 1, 2021.

Breast Cancer Breast cancer survival has improved dramatically. American lumpectomy, often followed by breast irradiation, or mastec- Cancer Society data from 1989 to 2017 show a 40% decrease in tomy. Irradiation may be omitted in some cases of estrogen deaths from breast cancer. The 5-year relative survival for all receptor—positive DCIS. Mastectomy is recommended if the invasive breast cancer stages in patients diagnosed from 2010 to DCIS is more extensive and cannot be fully removed by a 2016 is 91.4%. wide excision. Post-lumpectomy irradiation and mastectomy improve disease-free survival but not breast cancer-specific mortality. ¢ Clinical features associated with a more favorable prog- In women with estrogen receptor—positive DCIS, tamox- nosis of early-stage breast cancer include hormone ifen and aromatase inhibitors decrease the risks of local recur- receptor—positive cancer, small tumor size, low tumor rence and contralateral breast cancers. Tamoxifen is the grade, negative lymph nodes, and the absence of HER2 appropriate treatment in premenopausal women. For post- overexpression. menopausal women, both tamoxifen and anastrozole are effec- HVC e Imaging studies such as PET, CT, or bone scan for stag- tive options; antiestrogen treatment of DCIS does not increase ing are not recommended in asymptomatic patients survival. Adjuvant endocrine therapy is not indicated. with newly diagnosed stage 0 to II breast cancer. Patients with DCIS should undergo annual mammogra- phy starting 6 to 12 months after radiation therapy, if given, and follow-up visits every 6 to 12 months for 5 years after Primary Breast Cancer Therapy diagnosis.

Breast cancer survival has improved dramatically. American lumpectomy, often followed by breast irradiation, or mastec- Cancer Society data from 1989 to 2017 show a 40% decrease in tomy. Irradiation may be omitted in some cases of estrogen deaths from breast cancer. The 5-year relative survival for all receptor—positive DCIS. Mastectomy is recommended if the invasive breast cancer stages in patients diagnosed from 2010 to DCIS is more extensive and cannot be fully removed by a 2016 is 91.4%. wide excision. Post-lumpectomy irradiation and mastectomy improve disease-free survival but not breast cancer-specific mortality. ¢ Clinical features associated with a more favorable prog- In women with estrogen receptor—positive DCIS, tamox- nosis of early-stage breast cancer include hormone ifen and aromatase inhibitors decrease the risks of local recur- receptor—positive cancer, small tumor size, low tumor rence and contralateral breast cancers. Tamoxifen is the grade, negative lymph nodes, and the absence of HER2 appropriate treatment in premenopausal women. For post- overexpression. menopausal women, both tamoxifen and anastrozole are effec- HVC e Imaging studies such as PET, CT, or bone scan for stag- tive options; antiestrogen treatment of DCIS does not increase ing are not recommended in asymptomatic patients survival. Adjuvant endocrine therapy is not indicated. with newly diagnosed stage 0 to II breast cancer. Patients with DCIS should undergo annual mammogra- phy starting 6 to 12 months after radiation therapy, if given, and follow-up visits every 6 to 12 months for 5 years after Primary Breast Cancer Therapy diagnosis. Ductal Carcinoma in Situ Ductal carcinoma in situ (DCIS), classified as stage 0 breast e Mastectomy or post-lumpectomy irradiation decreases cancer, is a noninvasive breast cancer that usually presents as the risk for local recurrence in women with ductal car- calcifications on mammography (Figure 1). Its incidence has cinoma in situ but does not improve overall 10-year increased greatly, from 3% of breast cancers before the era of survival. mammographic screening to 20% to 25% of breast cancers e In estrogen receptor-—positive ductal carcinoma in situ, today. Patients with DCIS infrequently present with a palpable tamoxifen and aromatase inhibitors further decrease mass or with Paget disease of the breast (see Invasive Breast Cancer). the risks of local recurrence and contralateral breast cancer but do not improve overall survival. Because half of local recurrences of DCIS are invasive cancers, the goal of treatment is to eradicate the area of DCIS and decrease the risks of local recurrence and deaths Invasive Breast Cancer from breast cancer. Surgical treatment involves either Most early-stage invasive breast cancers are treated with initial excision followed by irradiation and adjuvant systemic ther- apy. There are two surgical options for invasive breast cancer.

Ductal Carcinoma in Situ Ductal carcinoma in situ (DCIS), classified as stage 0 breast e Mastectomy or post-lumpectomy irradiation decreases cancer, is a noninvasive breast cancer that usually presents as the risk for local recurrence in women with ductal car- calcifications on mammography (Figure 1). Its incidence has cinoma in situ but does not improve overall 10-year increased greatly, from 3% of breast cancers before the era of survival. mammographic screening to 20% to 25% of breast cancers e In estrogen receptor-—positive ductal carcinoma in situ, today. Patients with DCIS infrequently present with a palpable tamoxifen and aromatase inhibitors further decrease mass or with Paget disease of the breast (see Invasive Breast Cancer). the risks of local recurrence and contralateral breast cancer but do not improve overall survival. Because half of local recurrences of DCIS are invasive cancers, the goal of treatment is to eradicate the area of DCIS and decrease the risks of local recurrence and deaths Invasive Breast Cancer from breast cancer. Surgical treatment involves either Most early-stage invasive breast cancers are treated with initial excision followed by irradiation and adjuvant systemic ther- apy. There are two surgical options for invasive breast cancer. Breast conservation therapy involves wide excision followed by breast irradiation and is typically used in patients with cancers 5 cm or less in size, without skin involvement, and

Breast conservation therapy involves wide excision followed by breast irradiation and is typically used in patients with cancers 5 cm or less in size, without skin involvement, and with clear margins after excision. Mastectomy is recom- mended for cancers that are too large to allow a lumpectomy with an acceptable cosmetic outcome, cancers with skin involvement, and inflammatory breast cancers. Mastectomy may also be chosen in situations when irradiation is contrain- dicated, or in women with BRCA1 or BRCA2 mutations or strong family histories of breast cancer in which there is a high risk of new breast cancers. For some patients with large tumors, neoadjuvant chemotherapy or endocrine therapy can be given before surgery to shrink the tumor to facilitate breast conservation. A sentinel node biopsy is done at the time of breast sur- gery in patients with clinically negative axillary lymph nodes. In patients undergoing breast conservation surgery who will

with clear margins after excision. Mastectomy is recom- mended for cancers that are too large to allow a lumpectomy with an acceptable cosmetic outcome, cancers with skin involvement, and inflammatory breast cancers. Mastectomy may also be chosen in situations when irradiation is contrain- dicated, or in women with BRCA1 or BRCA2 mutations or strong family histories of breast cancer in which there is a high risk of new breast cancers. For some patients with large tumors, neoadjuvant chemotherapy or endocrine therapy can be given before surgery to shrink the tumor to facilitate breast conservation. A sentinel node biopsy is done at the time of breast sur- gery in patients with clinically negative axillary lymph nodes. In patients undergoing breast conservation surgery who will receive chemotherapy or antiestrogen therapy as well as whole breast irradiation, axillary dissection is not required if no more

with clear margins after excision. Mastectomy is recom- mended for cancers that are too large to allow a lumpectomy with an acceptable cosmetic outcome, cancers with skin involvement, and inflammatory breast cancers. Mastectomy may also be chosen in situations when irradiation is contrain- dicated, or in women with BRCA1 or BRCA2 mutations or strong family histories of breast cancer in which there is a high risk of new breast cancers. For some patients with large tumors, neoadjuvant chemotherapy or endocrine therapy can be given before surgery to shrink the tumor to facilitate breast conservation. A sentinel node biopsy is done at the time of breast sur- gery in patients with clinically negative axillary lymph nodes. In patients undergoing breast conservation surgery who will receive chemotherapy or antiestrogen therapy as well as whole breast irradiation, axillary dissection is not required if no more than two sentinel nodes are involved. For patients with clini- FIGURE 1. Ductal carcinoma in situ presenting as calcifications on mammography. cally involved axillary nodes or three or more positive sentinel

receive chemotherapy or antiestrogen therapy as well as whole breast irradiation, axillary dissection is not required if no more than two sentinel nodes are involved. For patients with clini- FIGURE 1. Ductal carcinoma in situ presenting as calcifications on mammography. cally involved axillary nodes or three or more positive sentinel 9

Breast Cancer nodes, an axillary dissection is recommended. An axillary distant recurrence. The type of adjuvant therapy used depends dissection is also performed if the sentinel nodes are not iden- on the biology and stage of the breast cancer. tified, which occurs in 5% of cases. The sentinel node proce- dure has a lower risk of lymphedema, sensory loss, and Adjuvant Endocrine Therapy shoulder abduction defects than axillary dissection. Approximately 75% of breast cancers are hormone receptor— Primary breast irradiation usually consists of irradiation positive (positive for the estrogen receptor, progesterone recep- to the whole breast, although partial breast irradiation is an tor, or both). Patients with hormone receptor-positive breast option in some patients. Postmastectomy irradiation is gener- ally recommended for tumors larger than 5 cm, positive mar- cancers should receive adjuvant antiestrogen therapy for at least 5 years. The Early Breast Cancer Trialists Collaborative gins or skin involvement, inflammatory breast cancers, or four or more positive axillary nodes and often for women with one Group meta-analysis of adjuvant tamoxifen showed a 39% pro- portional reduction in breast cancer recurrence at 15 years and to three positive axillary nodes. Postmastectomy irradiation decreases both the risk of local recurrence and the risk of dis- a 30% proportional reduction in breast cancer mortality. In postmenopausal women, aromatase inhibitors are superior to tant metastases and increases overall survival. For women older than age 70 years with cancers less than tamoxifen, with a further 29% proportional decrease in breast

nodes, an axillary dissection is recommended. An axillary distant recurrence. The type of adjuvant therapy used depends dissection is also performed if the sentinel nodes are not iden- on the biology and stage of the breast cancer. tified, which occurs in 5% of cases. The sentinel node proce- dure has a lower risk of lymphedema, sensory loss, and Adjuvant Endocrine Therapy shoulder abduction defects than axillary dissection. Approximately 75% of breast cancers are hormone receptor— Primary breast irradiation usually consists of irradiation positive (positive for the estrogen receptor, progesterone recep- to the whole breast, although partial breast irradiation is an tor, or both). Patients with hormone receptor-positive breast option in some patients. Postmastectomy irradiation is gener- ally recommended for tumors larger than 5 cm, positive mar- cancers should receive adjuvant antiestrogen therapy for at least 5 years. The Early Breast Cancer Trialists Collaborative gins or skin involvement, inflammatory breast cancers, or four or more positive axillary nodes and often for women with one Group meta-analysis of adjuvant tamoxifen showed a 39% pro- portional reduction in breast cancer recurrence at 15 years and to three positive axillary nodes. Postmastectomy irradiation decreases both the risk of local recurrence and the risk of dis- a 30% proportional reduction in breast cancer mortality. In postmenopausal women, aromatase inhibitors are superior to tant metastases and increases overall survival. For women older than age 70 years with cancers less than tamoxifen, with a further 29% proportional decrease in breast 2 cm in size, no clinically involved lymph nodes, and estrogen cancer recurrence. Both tamoxifen and aromatase inhibitors also decrease the risk of contralateral breast cancer. receptor-positive breast cancer, wide excision followed by antiestrogen therapy alone is an acceptable treatment option. Tamoxifen is a selective estrogen receptor modulator that

2 cm in size, no clinically involved lymph nodes, and estrogen cancer recurrence. Both tamoxifen and aromatase inhibitors also decrease the risk of contralateral breast cancer. receptor-positive breast cancer, wide excision followed by antiestrogen therapy alone is an acceptable treatment option. Tamoxifen is a selective estrogen receptor modulator that Whole breast irradiation in this situation decreases the risk of blocks estrogen uptake by breast cancer cells. It is effective in both premenopausal and postmenopausal women. The aro- local recurrence from 9% to 2% at 12 years but has no impact on the risk of distant metastases, breast cancer-specific sur- matase inhibitors letrozole, anastrozole, and exemestane have vival, or overall survival. similar efficacy and prevent conversion of adrenal androgens Paget disease of the breast is an uncommon manifestation to estrogen but do not inhibit ovarian estrogen production. of breast cancer, characterized by a scaly or red rash or ulcera- They are thus not effective in premenopausal women unless tion occurring on the nipple and spreading to the areola. It may ovarian suppression is given concomitantly. have a similar appearance to atopic or contact dermatitis. Paget For postmenopausal women, 5 years of an aromatase disease usually occurs in association with an underlying ductal inhibitor or 2 years of tamoxifen followed by 3 years of an breast cancer and is diagnosed througha skin biopsy or scrape aromatase inhibitor is associated with a significantly lower cytology, which shows involvement of the epidermis by neo- risk of recurrence and with improved survival in women with plastic cells. Upon diagnosis, patients should undergo diagnos- higher-grade ductal cancers or lobular cancers. Extended aro- tic breast imaging and, if no abnormalities are detected, breast matase therapy up to 10 years reduces disease-free survival in MRI should be considered to evaluate for occult disease. patients with high-risk features but does not have an impact Prognosis and management are determined by the standard on overall survival. Decisions regarding extended aromatase

tic breast imaging and, if no abnormalities are detected, breast matase therapy up to 10 years reduces disease-free survival in MRI should be considered to evaluate for occult disease. patients with high-risk features but does not have an impact Prognosis and management are determined by the standard on overall survival. Decisions regarding extended aromatase features of an in situ or invasive carcinoma. Depending on the inhibitor therapy should be tailored to patient risk and comor- extent of disease within the breast, breast-conserving therapy bidities that may affect tolerability, including bone health and may be appropriate, although all patients require nipple- history of venous thromboembolic disease. areolar resection. Endocrine therapy options for premenopausal women with estrogen receptor-positive breast cancer include tamox- ifen, ovarian function suppression (OFS) with tamoxifen, or e Breast-conserving therapy is effective for many women OFS with an aromatase inhibitor. For those with low recur- with small (<5 cm) tumors, no skin involvement, and rence risk, tamoxifen alone for 5 years may be appropriate. clear margins after resection; breast irradiation is rec- Extended tamoxifen therapy to 10 years is associated with a ommended subsequently in most patients. reduction in recurrence risk (3.7%) and breast cancer mortal- e Postmastectomy irradiation is recommended for can- ity (2.8%). Disease-free survival is improved in premenopausal cers greater than 5 cm in size, positive margins or skin women with higher-risk cancers with the addition of OFS. involvement, inflammatory breast cancers, and most Patients treated with OFS had more hot flushes, vaginal dry-

e Postmastectomy irradiation is recommended for can- ity (2.8%). Disease-free survival is improved in premenopausal cers greater than 5 cm in size, positive margins or skin women with higher-risk cancers with the addition of OFS. involvement, inflammatory breast cancers, and most Patients treated with OFS had more hot flushes, vaginal dry- patients with positive axillary lymph nodes. ness, decreased libido, insomnia, depression, arthralgia, hypertension, glucose intolerance, and osteoporosis. Adverse effects of tamoxifen and aromatase inhibitors are shown in Table 5. Up to one third of women treated with aro- Adjuvant Systemic Therapy for matase inhibitors develop aromatase inhibitor-associated Nonmetastatic Breast Cancer symmetric arthralgia, joint stiffness, and bone pain. This mus- Patients with stage I to III (potentially curable) breast cancer culoskeletal syndrome is managed with NSAIDs or duloxetine, receive adjuvant systemic therapy to eradicate occult micro- a treatment break and changing to an alternate aromatase scopic foci of breast cancer and decrease the risk of local and inhibitor, or a change to tamoxifen. 10

Breast Cancer cancers, typically two or three agents are given for four to eight cycles. The most common chemotherapies used for e Endocrine therapy in women with hormone receptor- adjuvant treatment are anthracyclines (doxorubicin or epi- positive breast cancer substantially reduces the risk of rubicin), cyclophosphamide, and the taxanes (paclitaxel or recurrence and improves overall survival. docetaxel). e Endocrine therapy options for premenopausal women Adjuvant chemotherapy combined with HER2-targeted include tamoxifen, ovarian function suppression (OFS) treatment such as the monoclonal antibody trastuzumab or plus tamoxifen, or OFS plus an aromatase inhibitor; the combination of trastuzumab and pertuzumab is recom- women at low recurrence risk may be treated with mended for HER2-positive cancers that are greater than tamoxifen alone. 5 mm in size, node positive, or both. The addition of trastu- e Five years of an aromatase inhibitor or 2 years of tamox- zumab to chemotherapy decreases the risk of cancer recur- ifen followed by 3 years of an aromatase inhibitor is rence by 53% and the risk of death by 34%. Trastuzumab is associated with a significantly lower risk of recurrence generally given for 12 months in total. For patients with node- and with improved survival in postmenopausal women negative HER2-positive breast cancers smaller than 3 cm in with higher-grade ductal cancers or lobular cancers. size, weekly paclitaxel and trastuzumab is a well-tolerated e Extended aromatase inhibitor treatment up to 10 years regimen with a 7-year recurrence-free survival rate of 97.5%.

cancers, typically two or three agents are given for four to eight cycles. The most common chemotherapies used for e Endocrine therapy in women with hormone receptor- adjuvant treatment are anthracyclines (doxorubicin or epi- positive breast cancer substantially reduces the risk of rubicin), cyclophosphamide, and the taxanes (paclitaxel or recurrence and improves overall survival. docetaxel). e Endocrine therapy options for premenopausal women Adjuvant chemotherapy combined with HER2-targeted include tamoxifen, ovarian function suppression (OFS) treatment such as the monoclonal antibody trastuzumab or plus tamoxifen, or OFS plus an aromatase inhibitor; the combination of trastuzumab and pertuzumab is recom- women at low recurrence risk may be treated with mended for HER2-positive cancers that are greater than tamoxifen alone. 5 mm in size, node positive, or both. The addition of trastu- e Five years of an aromatase inhibitor or 2 years of tamox- zumab to chemotherapy decreases the risk of cancer recur- ifen followed by 3 years of an aromatase inhibitor is rence by 53% and the risk of death by 34%. Trastuzumab is associated with a significantly lower risk of recurrence generally given for 12 months in total. For patients with node- and with improved survival in postmenopausal women negative HER2-positive breast cancers smaller than 3 cm in with higher-grade ductal cancers or lobular cancers. size, weekly paclitaxel and trastuzumab is a well-tolerated e Extended aromatase inhibitor treatment up to 10 years regimen with a 7-year recurrence-free survival rate of 97.5%. reduces recurrence risk relative to 5 years in patients Neoadjuvant chemotherapy is generally recommended for

cancers, typically two or three agents are given for four to eight cycles. The most common chemotherapies used for e Endocrine therapy in women with hormone receptor- adjuvant treatment are anthracyclines (doxorubicin or epi- positive breast cancer substantially reduces the risk of rubicin), cyclophosphamide, and the taxanes (paclitaxel or recurrence and improves overall survival. docetaxel). e Endocrine therapy options for premenopausal women Adjuvant chemotherapy combined with HER2-targeted include tamoxifen, ovarian function suppression (OFS) treatment such as the monoclonal antibody trastuzumab or plus tamoxifen, or OFS plus an aromatase inhibitor; the combination of trastuzumab and pertuzumab is recom- women at low recurrence risk may be treated with mended for HER2-positive cancers that are greater than tamoxifen alone. 5 mm in size, node positive, or both. The addition of trastu- e Five years of an aromatase inhibitor or 2 years of tamox- zumab to chemotherapy decreases the risk of cancer recur- ifen followed by 3 years of an aromatase inhibitor is rence by 53% and the risk of death by 34%. Trastuzumab is associated with a significantly lower risk of recurrence generally given for 12 months in total. For patients with node- and with improved survival in postmenopausal women negative HER2-positive breast cancers smaller than 3 cm in with higher-grade ductal cancers or lobular cancers. size, weekly paclitaxel and trastuzumab is a well-tolerated e Extended aromatase inhibitor treatment up to 10 years regimen with a 7-year recurrence-free survival rate of 97.5%. reduces recurrence risk relative to 5 years in patients Neoadjuvant chemotherapy is generally recommended for with higher-risk cancer but does not improve overall patients with larger or node-positive tumors and involves

e Extended aromatase inhibitor treatment up to 10 years regimen with a 7-year recurrence-free survival rate of 97.5%. reduces recurrence risk relative to 5 years in patients Neoadjuvant chemotherapy is generally recommended for with higher-risk cancer but does not improve overall patients with larger or node-positive tumors and involves survival. multiple chemotherapy agents along with trastuzumab and pertuzumab. Patients with no residual disease at surgery have an excellent prognosis. Patients with residual disease follow- Adjuvant Chemotherapy ing preoperative chemotherapy have a greater recurrence Increasingly, the use of adjuvant chemotherapy for early risk, and subsequent use of ado-trastuzumab-emtansine breast cancer is based more on tumor biology rather than (an antibody-drug conjugate that links trastuzumab to on stage. Hormone receptor-negative and HER2-positive the microtubule inhibitor emtansine) reduces recurrence cancers are associated with greater recurrence as well as risk by 50% relative to trastuzumab. The main toxicities of greater risk reduction from chemotherapy. Adjuvant che- trastuzumab are infusion reactions such as fever, chills, and motherapy is recommended for women with cancers of cardiomyopathy. these subtypes that are either greater than 5 mm or lymph Acute adverse effects of adjuvant chemotherapy include node positive. bone marrow suppression, alopecia, allergic reactions, neu- For hormone receptor—positive, HER2-negative breast ropathy, nausea, and premature menopause and infertility in cancers with zero to three positive axillary nodes, the use of premenopausal women (see Effects of Cancer Therapy and multigene assays (e.g., the 21-gene recurrence score assay) that Survivorship). Women of childbearing age who wish to pre- predict the risk of recurrence with antiestrogen therapy alone serve fertility may undergo oocyte or embryo banking before has significantly decreased the use of adjuvant chemotherapy. chemotherapy. Serious long-term toxicities include cardio- Women with node-negative breast cancer and low and inter- myopathy, neuropathy, myelodysplasia, and acute myelocytic mediate recurrence scores have a favorable prognosis with leukemia. The risk of cardiomyopathy after four cycles of an antiestrogen therapy alone and do not benefit from the addi- anthracycline is 1.5%. The risk of acute leukemia after regi- tion of chemotherapy. Similar findings have been seen for mens containing an anthracycline or cyclophosphamide is women with one to three positive nodes with low and inter- 0.5%. mediate risk recurrence scores, but these conclusions remain For women of advanced age with higher-risk early breast controversial. cancer, it is important to consider estimated life expectancy, Clinicopathologic factors that suggest benefit from adju- functional status, and medical comorbidities before adminis- vant chemotherapy include high tumor grade, extensive lym- tering adjuvant chemotherapy. There is a higher risk of cardio- phatic invasion, larger tumor size, skin or chest wall toxicity in older women. involvement, and involvement of more than four axillary nodes. Women with hormone receptor-negative, HER2-negative e Patients with hormone receptor-positive, node-negative cancers (triple-negative breast cancer) have a 50% propor- breast cancer and low or intermediate risk recurrence tional reduction in the risk of recurrence and of breast cancer scores have a favorable prognosis with antiestrogen mortality with adjuvant chemotherapy. Adjuvant chemother- therapy and do not benefit from chemotherapy. apy is recommended for patients with triple-negative cancers e Adjuvant chemotherapy is appropriate for patients with larger than 5 mm in size or with positive lymph nodes. triple-negative or HER2-positive tumors greater than When adjuvant chemotherapy is given for high-risk 5 mm in size or with positive axillary lymph nodes. hormone receptor-positive cancers or triple-negative

survival. multiple chemotherapy agents along with trastuzumab and pertuzumab. Patients with no residual disease at surgery have an excellent prognosis. Patients with residual disease follow- Adjuvant Chemotherapy ing preoperative chemotherapy have a greater recurrence Increasingly, the use of adjuvant chemotherapy for early risk, and subsequent use of ado-trastuzumab-emtansine breast cancer is based more on tumor biology rather than (an antibody-drug conjugate that links trastuzumab to on stage. Hormone receptor-negative and HER2-positive the microtubule inhibitor emtansine) reduces recurrence cancers are associated with greater recurrence as well as risk by 50% relative to trastuzumab. The main toxicities of greater risk reduction from chemotherapy. Adjuvant che- trastuzumab are infusion reactions such as fever, chills, and motherapy is recommended for women with cancers of cardiomyopathy. these subtypes that are either greater than 5 mm or lymph Acute adverse effects of adjuvant chemotherapy include node positive. bone marrow suppression, alopecia, allergic reactions, neu- For hormone receptor—positive, HER2-negative breast ropathy, nausea, and premature menopause and infertility in cancers with zero to three positive axillary nodes, the use of premenopausal women (see Effects of Cancer Therapy and multigene assays (e.g., the 21-gene recurrence score assay) that Survivorship). Women of childbearing age who wish to pre- predict the risk of recurrence with antiestrogen therapy alone serve fertility may undergo oocyte or embryo banking before has significantly decreased the use of adjuvant chemotherapy. chemotherapy. Serious long-term toxicities include cardio- Women with node-negative breast cancer and low and inter- myopathy, neuropathy, myelodysplasia, and acute myelocytic mediate recurrence scores have a favorable prognosis with leukemia. The risk of cardiomyopathy after four cycles of an antiestrogen therapy alone and do not benefit from the addi- anthracycline is 1.5%. The risk of acute leukemia after regi- tion of chemotherapy. Similar findings have been seen for mens containing an anthracycline or cyclophosphamide is women with one to three positive nodes with low and inter- 0.5%. mediate risk recurrence scores, but these conclusions remain For women of advanced age with higher-risk early breast controversial. cancer, it is important to consider estimated life expectancy, Clinicopathologic factors that suggest benefit from adju- functional status, and medical comorbidities before adminis- vant chemotherapy include high tumor grade, extensive lym- tering adjuvant chemotherapy. There is a higher risk of cardio- phatic invasion, larger tumor size, skin or chest wall toxicity in older women. involvement, and involvement of more than four axillary nodes. Women with hormone receptor-negative, HER2-negative e Patients with hormone receptor-positive, node-negative cancers (triple-negative breast cancer) have a 50% propor- breast cancer and low or intermediate risk recurrence tional reduction in the risk of recurrence and of breast cancer scores have a favorable prognosis with antiestrogen mortality with adjuvant chemotherapy. Adjuvant chemother- therapy and do not benefit from chemotherapy. apy is recommended for patients with triple-negative cancers e Adjuvant chemotherapy is appropriate for patients with larger than 5 mm in size or with positive lymph nodes. triple-negative or HER2-positive tumors greater than When adjuvant chemotherapy is given for high-risk 5 mm in size or with positive axillary lymph nodes. hormone receptor-positive cancers or triple-negative 11