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Suggested Citation:"5 Breast Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"5 Breast Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"5 Breast Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"5 Breast Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"5 Breast Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"5 Breast Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"5 Breast Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"5 Breast Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"5 Breast Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"5 Breast Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

5 Breast Cancer Breast cancer is the leading cause of cancer death among women glob- ally and the second leading cause of cancer death (after lung cancer) among women in the United States (DeSantis et al., 2019; Torre et al., 2017). It is also the second most frequently diagnosed cancer in women after skin cancer (DeSantis et al., 2019). Although the U.S. incidence of breast cancer for women older than 50 years has remained about same over the past 10 years, its incidence has been rising slightly in women under 40 years (Scott et al., 2020; Ward et al., 2019). However, breast cancer treatment has improved outcomes for many women, especially those with more ag- gressive subtypes and those with metastatic disease (that is, breast cancer that has spread to a distant site in the body). Fortunately, only about 6% of patients have metastatic breast cancer at the time of their initial diag- nosis (Howlader et al., 2020). Although breast cancer is also diagnosed in men, it is rare, with an incidence rate of 1.32 per 100,000 people in 2017 (Howlader et al., 2020). As of 2020, it is estimated that there are about 3.5 million adults alive who have or have had breast cancer (SEER, n.d.-a). The epidemiology of breast cancer is discussed in Chapter 3. Risk factors for breast cancer include family history (with or without an identified genetic predisposition), reproductive factors (early menarche, late menopause, late or no pregnancy), the use of exogenous hormones at menopause, radiation exposure to the chest wall in adolescence or young adult years, and regular use of alcohol. Obesity and lifetime weight gain are primarily risk factors for postmenopausal breast cancer. The identification of women who have a hereditary risk for breast cancer (e.g., BRCA1 and BRCA2 mutation carriers) but who are unaffected (do not have cancer) 107 PREPUBLICATION COPY—Uncorrected Proofs

108 DIAGNOSING AND TREATING ADULT CANCERS has potential to reduce the risk of disease through chemoprevention or prophylactic mastectomy. In this chapter the committee describes the care trajectory (see Figure 4-1) for breast cancer from initial screening and diagnosis through breast cancer staging (including its major subtypes) to the treatment options for both local and metastatic disease. These treatment options include surgery, radiation, and systemic therapies. The focus of the treatment section is on approaches that are currently standard of care for breast cancer specifically. Finally, the committee considers the long-term and late-onset impairments that may be experienced by women (and men) following the diagnosis and treatment of their breast cancer. To help manage these impairments and functional limitations as well as the adverse effects from both the cancer and its treatment, palliative and supportive care may be recommended for patients at the time of their diagnosis. As noted in Chapter 3, only about 1% of breast cancer cases are diag- nosed in men. Although this chapter focuses on breast cancer in women, men with breast cancer face similar decisions and complexity regarding the diagnosis and treatment of their disease and must take into account many of the same factors when determining appropriate treatments. The vast majority of research on breast cancer is conducted in women and this is reflected in the studies cited in this chapter. SCREENING Breast cancer is usually detected in one of two ways: as a result of a screening test (such as mammogram) in an asymptomatic individual or by a clinical evaluation of an individual who presents with symptoms such as a breast mass, bloody nipple discharge, or change in the skin of the breast. The majority of women with breast cancer are currently diagnosed while asymptomatic at the time of screening. However, younger women (i.e., those younger than 40–45 years) are not typically candidates for breast cancer screening and thus are more likely to be diagnosed when symptom- atic (usually with a mass). Several organizations (e.g., the U.S. Preventive Services Task Force and the American Cancer Society) have developed guidelines for breast cancers screening (see Table 4-1). Mammograms are typically used to screen for breast cancer. Although the timing of initiation and the intervals of screen- ing vary among the clinical guidelines, mammographic screening has been shown to reduce mortality from breast cancer compared with no screen- ing, particularly in women aged 50–69 years (Nelson et al., 2009). Studies have demonstrated that screening mammograms lead to an earlier stage of disease at diagnosis and to improved mortality. PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 109 A newer form of mammogram called digital breast tomosynthesis (also called a 3-D mammogram) is becoming more widely used. In addition, magnetic resonance imaging (MRI) is increasingly being used to supplement mammograms as a screening tool, particularly in women with high risk factors such as a pathogenic variant in a cancer susceptibility gene, such as BRCA1 or BRCA2, or who have a family history of the disease (NCCN, 2020a; Saadatmand et al., 2019). As described in Chapter 4, decisions about when to start and how often to undergo breast cancer screening should take into account a woman’s risk of breast cancer as well as how she values the specific benefits (e.g., small reductions in the likelihood of dying of breast cancer) and harms (false positive findings, unnecessary biopsies, and the potential for overdiagno- sis—detecting a cancer that would not have become clinically evident in a woman’s lifetime without screening—and related overtreatment) (Nelson et al., 2016). Some evidence suggests that screening mammography has only marginally reduced the rate at which women present with advanced cancer (Bleyer and Welch, 2012). Ongoing studies are assessing whether improve- ments in screening technologies and the ability to identify overdiagnosed cancers that do not require treatment can improve the benefit-to-harm ratio of breast cancer screening (Kanbayashi et al., 2019). DIAGNOSIS AND STAGING When a patient presents with changes to his or her breast, no matter whether the changes have been detected with a mammogram or MRI, or by presentation of symptoms such a detection of a lump in the breast tissue, a diagnosis of breast cancer requires a tissue biopsy. Image-guided biopsy— directed by mammogram, ultrasound, or MRI—is usually the first approach and is performed by radiologists or surgeons. In particular, core needle biopsy is the standard way to diagnose breast cancer and does not involve going to the operating room or undergoing general anesthesia, although sometimes a surgical biopsy is necessary. Metastasis to lymph nodes can be diagnosed either by a biopsy, such as a core needle biopsy or a fine-needle aspiration, which uses a smaller needle than a core biopsy, or by surgery. Once the biopsy tissue has been extracted, it is examined by patholo- gists who determine whether cancer is present and, if so, the type of breast cancer and the tumor grade and margins. Tumor grade is the description of how abnormal the tumor cells and the tumor tissue appear under a mi- croscope. It is an indicator of how aggressive a tumor is. Pathologists also test the biopsy tissue for specific biomarkers, par- ticularly hormone receptors (HRs) (that is, estrogen receptors [ERs] and progesterone receptors [PRs]) and human epidermal growth factor PREPUBLICATION COPY—Uncorrected Proofs

110 DIAGNOSING AND TREATING ADULT CANCERS receptor 2 (HER2). These biomarkers, along with grading and staging the tumor, help direct the treatment strategy. In data from the Surveil- lance, Epidemiology, and End Results (SEER) program from 2013–2017 (SEER, n.d.-b), 68% of breast cancers were HR-positive and HER2- negative, 10% were HR-positive and HER2-positive, 10% were triple negative (ER-, PR-, and HER2-negative), 4% were HR-negative and HER-positive, and the biomarker status was unknown for 8% of breast cancers (see Figure 5-1). Breast cancer staging describes the size of the tumor in the breast (primary tumor) and whether or how much it has spread in the body. Breast cancer is either invasive or noninvasive. Invasive breast cancers are those that have spread into surrounding breast tissue, the most common of which is invasive ductal carcinoma. In situ breast cancer (ductal carcinoma in situ, discussed below) is a noninvasive cancer that starts in a milk duct and is confined there. A cancer’s stage has implications not only for outcomes, but also for treatment decisions, such as the need for and extent of surgery (e.g., sentinel node dis- section versus axillary lymph node dissection) and the use of systemic therapy. An earlier stage at diagnosis is associated with improved outcomes. As noted in Chapter 4, the most commonly used staging system for breast cancer is that of the American Joint Committee on Cancer (AJCC). The AJCC anatomical staging system incorporates the size of the breast tumor (T), the spread to lymph nodes (N), and metastasis to distant organs (M) for a TNM stage based on information from imaging studies, physical examination, and biopsy results. The clinical stage describes the initial stage at the time of diagno- sis based on imaging studies such as mammogram or ultrasound (e.g., FIGURE 5-1 Percent of female breast cases by cancer subtype, according to SEER data, 2013–2017. SOURCE: SEER, n.d.-b. PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 111 cT1N0M0). After the patient has had surgery, the pathologic stage is based on a microscopic analysis of the tumor and lymph nodes that were removed with surgery (e.g., pT2N1). The TNM combinations can be summarized by anatomic stages from stage 0 (noninvasive cancer) to stage IV (meta- static cancer beyond the breast and regional lymph nodes) (see Table 5-1). In addition to TNM factors and the expression of the ER, PR, and HER2 biomarkers in breast cancer, genomic tests such as OncotypeDX® and Mammaprint®, are also incorporated into staging since they are known to be associated with a patient’s prognosis and responsiveness to therapy. In 2017 this change was incorporated into the AJCC staging manual eighth edition (Amin et al., 2017). The inclusion of ER, PR, HER2 biomarkers increases the complexity of the AJCC staging system and while it cannot be fully illustrated in this report, the details can be found in AJCC staging manual, which is updated periodically. TABLE 5-1 Anatomic Staging of Invasive, Non-Metastatic Breast Cancer Stage Detailed Stage TMN Stage 1 Stage 1A • T1, N0, M0 Stage 1B • T0, N1, M0 • T1, N1, M0 2 Stage 2A • T0, N1, M0 • T1, N1, M0 • T2, N0, M0 Stage 2B • T2, N1, M0 • T3, N0, M0 3 Stage 3A • T0, N2, M0 • T1, N2, M0 • T2, N2, M0 • T3, N1, M0 • T3, N2, M0 Stage 3B • T4, N0, M0 • T4, N1, M0 • T4, N2, M0 Stage 3C • Any T, N3, M0 NOTE: M = presence or absence of distant metastasis; N = extent of regional lymph node spread; T = size or extent of the primary tumor (see Chapter 4 for more information on cancer staging). SOURCES: Used with the permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) pub- lished by Springer International Publishing: the American College of Surgeons. Amin, M.B., Edge, S.B., Greene, F.L., et al. (Eds.). AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017. See https://cancerstaging.org/references-tools/deskreferences/Documents/AJCC%208th%20 Edition%20Breast%20Cancer%20Staging%20System.pdf (accessed January 15, 2021) for the AJCC cancer staging manual 8th edition breast cancer chapter. PREPUBLICATION COPY—Uncorrected Proofs

112 DIAGNOSING AND TREATING ADULT CANCERS FIGURE 5-2 Female breast cancer treatment patterns (%) by anatomical stage at diagnosis, 2016. NOTE: BCS = breast‐conserving surgery; chemo = chemotherapy, including targeted therapy and immunotherapy; RT = radiation therapy. a A small number of these patients received chemotherapy. b A small number of these patients received RT. SOURCE: Reprinted from DeSantis, C.E., J. Ma, M.M. Gaudet, L.A. Newman, K.D. Miller, A. Goding Sauer, A. Jemal, and R.L. Siegel. 2019. Breast cancer statis- tics, 2019. CA: A Cancer Journal for Clinicians 69(6):438–451; used with permis- sion from John Wiley and Sons. The staging and the treatment of breast cancer have both evolved rap- idly over the past decade. Consequently, determining the most appropriate treatment for an individual patient can be complicated and may include multiple options. In general, earlier-stage breast cancers tend to be treated with breast-conserving surgery (BCS) that is less extensive and with less chemotherapy than more advanced cancers. However, as seen in Figure 5-2, the breast cancer stage does not correlate directly with the type of treatment, which can be heterogeneous across stages. For example, some stage I and stage II patients may be treated with more extensive surgery (total mastectomy) and chemotherapy, whereas some stage III patients may be treated with BCS without chemotherapy based on tumor biological fac- tors, surgical margins, and response to therapy. Treatment decisions are ideally made in a multidisciplinary, patient-centered manner that involves the surgeon, medical oncologist, radiation oncologist, and other clinicians (such as the plastic reconstructive surgeon) as well as the patient herself (or himself). TREATMENT OF NONINVASIVE BREAST CANCER Ductal carcinoma in situ (DCIS) is the earliest form of breast cancer and refers to cancer cells that arise in the breast milk ducts but have not spread outside the duct. DCIS is considered to be noninvasive. It is also PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 113 called intraductal carcinoma, pre-invasive cancer, or stage 0 breast cancer. Between 2000 and 2017 the incidence rate of the disease ranged from about 12 to 14.5 cases per 100,00 for women younger than 50 years and from about 81.5 to 96.5 cases per 100,000 for women older than 50 years (Howlader et al., 2020). DCIS is usually detected with screening mammography. DCIS cells are not capable of metastasizing or spreading outside the breast to lymph nodes or other distant organs, so lymph node dissection is generally not needed. There is a low risk of DCIS becoming invasive, and therefore the current standard of care is to treat DCIS with BCS with or without radiation ther- apy or tamoxifen or else to treat it with a mastectomy in a manner similar to what is typical for invasive breast cancer. With complete resection and radiation treatment as indicated, the prognosis is excellent for patients with DCIS, with a 20-year mortality rate of 3.3% (Narod et al., 2015; Subhedar et al., 2015). The 20-year risk of recurrence of invasive disease in the same breast (ipsilateral) that had the initial DCIS diagnosis was 5.9% and 6.2% in the contralateral breast (Narod et al., 2015). Endocrine therapy with tamoxifen or an aromatase inhibitor is offered to patients with ER-positive, stage 0 breast cancer because although there is no survival benefit, endo- crine therapy may reduce the risk of ipsilateral and contralateral recurrence (Staley et al., 2014). TREATMENT OF INVASIVE, LOCALIZED BREAST CANCER Invasive breast cancer can be either localized, that is, it has not spread outside the breast and regional lymph nodes, or metastatic, that is, it has spread to other, often distant, parts of the body. More than 90% of breast cancer patients present with localized breast cancer. The treatment for local- ized breast cancer, while complex, is intended to cure and aims to minimize recurrences both locally (in the breast, chest wall, and lymph nodes) and systemically (e.g., liver, lungs, bone, and brain). The particular treatment given to an individual patient depends on a number of factors, particularly the cancer stage (including the tumor size and presence of involved lymph nodes), tumor grade, and HR and HER2 receptor status. Other factors that are considered when determining the treatment plan include the patient’s comorbidities and menopausal status, the response of the tumor to prior treatments, and the patient’s personal preferences. Treatment for invasive, localized breast cancer may be local (i.e., sur- gery with or without radiation), systemic (e.g., chemotherapy, endocrine therapy), or, more frequently, a combination of both (see Figure 5-3). This section begins with a discussion of the types and extent of surgery that may be used to remove the tumor and, when necessary, the affected lymph nodes. The two general surgical approaches are breast conservation with PREPUBLICATION COPY—Uncorrected Proofs

114 DIAGNOSING AND TREATING ADULT CANCERS resection and mastectomy. Following this discussion, the several types of radiation therapy that may be used to treat localized, invasive breast cancer are considered. Next is a synopsis of the various kinds of systemic therapies that are currently used based on the hormone and biomarker status of the 1. Invasive breast cancer diagnosis  Cancer grade and immunochemistry determined for HR (estrogen and/or progesterone) and HER2  Fluorescence in situ hybridization if HER2 immunochemistry is 2+ 2. Testing, imaging, and decision making with multidisciplinary team (primary care, pathology, radiology, surgery, medical oncology and radiation oncology)  Ultrasound and fine-needle aspiration of suspicious axillary nodes  Possible breast MRI with or without distant imaging (CT and PET) 3. Optimal first treatment ER-neg, PR-neg, HER2-neg ER-pos and HER2-neg HER2-pos Neoadjuvant chemotherapy Upfront surgery; or Neoadjuvant trastuzumab with neoadjuvant endocrine or without pertuzumab-based (consider neoadjuvant chemotherapy chemotherapy if locally advanced or node positive) 4. Mastectomy or lumpectomy with sentinel node biopsy or full axillary dissection 5. Adjuvant chemotherapy and genomic testing  Consider adjuvant chemotherapy if no pathologic complete response after neoadjuvant therapy or if no neoadjuvant therapy  Genomic testing on tumor to determine if chemotherapy can be omitted for ER-positive tumors 6. Adjuvant radiation therapy  Recommended for all lumpectomy patients unless they are older than 70 years with tumors that are ER-pos, low-grade, and small (≤ 2 cm)  Recommended for mastectomy patients with tumors that are large (> 5 cm) and/or node- positive 7. Additional adjuvant therapy ER-pos and/or PR-pos HER2- pos 5–10 years of adjuvant endocrine therapy  HER2-directed therapy Premenopausal at Postmenopausal  Patients with ER-pos diagnosis and/or PR-pos cancer Tamoxifen monotherapy; Aromatase inhibitor; should receive concurrent or ovarian-suppressing taxoxifen; or sequence of both adjuvant endocrine therapy medication plus tamoxifen or aromatase inhibitor FIGURE 5-3 Typical stage I to stage III invasive breast cancer care algorithm. NOTE: CT = computed tomography; ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; MRI = magnetic reso- nance imaging; PET = positron emission tomography; PR = progesterone receptor. SOURCE: Ruddy and Ganz, 2019, reproduced with permission from JAMA; copy- right © (2021), American Medical Association, all rights reserved. PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 115 cancer. Systemic and radiation therapies may be used before (neoadjuvant) or after (adjuvant) surgery. Some forms of systemic therapy, such as endo- crine therapy, may be used for HR-positive breast cancer for many years after surgery and radiation are completed. Other systemic therapies include chemotherapy and therapies that target the HER2 protein. The treatment of metastatic breast cancer, discussed after the treatment of localized breast cancer, focuses primarily on systemic therapy, although surgery and radia- tion are used in certain situations. Surgical Treatments Decisions about the surgical management of the primary breast tumor and the lymph nodes are made almost separately, depending on anatomic stage, biomarkers, and patient preferences. These decisions are often influ- enced by other treatment recommendations from the medical oncologist, radiation oncologist, breast surgeon, and plastic surgeon as well as by the patient’s preferences, reflecting the truly multidisciplinary nature of breast cancer treatment. This section discusses BSC, mastectomy, and the surgical management of axillary nodes in the breast area. The committee then considers breast reconstruction during or after surgery for cancer treatment. Breast-Conserving Surgery The options for resecting a breast tumor are (1) BCS (partial mastec- tomy, segmental mastectomy, or lumpectomy), which removes only the tu- mor and leaves the remaining breast tissue; or (2) total mastectomy, which removes the tumor along with the entire breast, possibly including the skin and nipple-areolar complex. Breast-conserving therapy often consists of BCS plus radiation therapy. Multiple randomized trials have shown that breast-conserving therapy and mastectomy are equally effective, with no difference in disease-free survival and overall survival (Fisher et al., 2002; Litiere et al., 2012; Veronesi et al., 2002). There are several relative contraindications to breast-conserving ther- apy, including a tumor that is large relative to breast size, multicentric disease (i.e., multiple tumors in different sections of the breast), and con- traindications to radiation therapy (e.g., prior chest wall irradiation). For invasive breast cancers, BCS requires a complete resection of the tumor such that the excised tissue has no cancer at the margins (i.e., negative surgical margins) (Moran et al., 2014). For in situ breast cancer, which tends toward more diffuse distribution compared with invasive breast cancer, the con- sensus guidelines recommend a 2 mm margin for optimal local control for BCS with whole-breast irradiation (Morrow et al., 2016). The effective use PREPUBLICATION COPY—Uncorrected Proofs

116 DIAGNOSING AND TREATING ADULT CANCERS of BCS depends on the relative size of the tumor compared with the native breast size. Even for fairly “small” tumors, the location of the tumor may be unfavorable (e.g., upper inner chest quadrant or superior quadrant) and can be associated with a sub-optimal cosmetic outcome after lumpectomy and radiation therapy. Finally, for multiple tumors in one breast, it may not be feasible to get an acceptable cosmetic result with BCS unless the patient has a large breast or is receiving partial-breast reconstruction. Patient preference is also a factor when deciding whether to perform breast-conserving surgery (combined with radiation) or mastectomy. De- spite equivalent survival rates for the two procedures, BSC-eligible patients are increasingly choosing to have mastectomies for several reasons, includ- ing a reluctance to undergo radiation therapy, fear of recurrence, and a desire for symmetry (DeSantis et al., 2019). In a review of 1.2 million U.S. breast cancer patients, 35.5% of patients with early-stage disease (i.e., those who are most likely to be eligible for BCS) underwent mastectomy. The rate of mastectomy increased from 2003 to 2011, when the study ended (Kum- merow et al., 2015; Lee et al., 2009). Mastectomy Mastectomy is performed for patients who are not eligible for BCS or for those who choose it. A modified radical mastectomy refers to a mastec- tomy with axillary lymph node dissection. A mastectomy can be performed with preservation of the skin or nipple or both if some form of immediate breast reconstruction is planned. A contralateral prophylactic mastectomy refers to a mastectomy performed on breasts without a diagnosis of cancer and is often offered to women with a genetic mutation that confers an in- creased risk of breast cancer (e.g., BRCA1, BRCA2, TP53, PTEN) in order to reduce that risk. Women without a known deleterious mutation or other risk factors have also elected to undergo contralateral prophylactic mastec- tomy at increasing rates (Chagpar, 2014), although there is no evidence of improved survival. The decision to undergo this surgery has been shown to be based primarily on a fear of breast cancer as well as cosmetic reasons, such as a desire for symmetry (Ager et al., 2016; Sando et al., 2018). Low physician knowledge about contralateral breast cancer and the risk of local recurrence also was found to be associated with favorable recommenda- tions about contralateral prophylactic mastectomy for patients at average risk (Kantor et al., 2019). Surgical Management of Axillary Nodes A metastasis of breast cancer to the axillary lymph nodes is determined by physical exam and imaging, commonly by ultrasound. Lymph nodes PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 117 that appear suspicious in ultrasound images can be biopsied to confirm metastasis (clinically node-positive disease). Less commonly, breast cancer can metastasize to other nodal basins such as the internal mammary, infra- clavicular, or supraclavicular lymph nodes (see Figure 5-4). For patients with breast cancer, lymph nodes may be removed for the purpose of staging and prognosis to help guide treatment recommenda- tions as well as for potentially reducing regional recurrence for patients with locally advanced disease. In order to minimize the adverse effects from lymph node removal such as lymphedema, neuropathy, and sero- mas, surgeons may perform a sentinel lymph node dissection (SLND, or sentinel lymph node biopsy) to remove only the first few axillary lymph nodes draining a breast tumor; this is performed for early-stage clinically node-negative breast cancer. Sentinel lymph nodes are the first lymph nodes to which cancer cells are most likely to spread from a primary tumor. A positive sentinel lymph node biopsy indicates that the cancer has spread to the lymph nodes, in which case an axillary lymph node dissection (ALND) may be performed. ALND entails a more complete removal of axillary lymph nodes (levels I/II, and occasionally level III) and results in higher rates of adverse effects. ALND is typically performed for patients with clinically node-positive disease. FIGURE 5-4 The lymphatic system of the breast. The sentinel lymph nodes (first lymph nodes draining a breast cancer) are found in the axilla (armpit), internal mammary chain, supraclavicular, and infraclavicular areas. SOURCE: Illustration reproduced with permission from Cancer Australia, 2021. PREPUBLICATION COPY—Uncorrected Proofs

118 DIAGNOSING AND TREATING ADULT CANCERS Breast Reconstruction Patients who undergo total mastectomy may elect to have breast re- construction to improve self-esteem and psychosocial well-being, including their emotional health, sexuality, and body image (Cordova et al., 2019). There are many options for reconstruction, including the use of a breast implant or a patient’s own tissue (autologous flap), and reconstruction may be performed at the same time as the mastectomy or delayed. Immediate breast reconstruction is often appropriate for patients who do not have significant medical comorbidities, have healthy mastectomy skin flaps, and are not expected to require radiation after mastectomy. Although the rates of breast reconstruction after mastectomy have been increasing, only about 24% of U.S. patients with invasive breast cancer undergo reconstruction at the same time as their mastectomy (Kamali et al., 2019), suggesting that breast reconstruction may be underutilized. Delayed reconstruction may be recommended if patients have risk factors for delayed wound healing (e.g., poorly controlled diabetes, smoking, or obesity) or if they are likely to be treated with postmastectomy radiation. A third approach is staged reconstruction, also referred to as “delayed-immediate” reconstruction, for patients who may need postmastectomy radiation (Kronowitz, 2010). With this approach, a temporary tissue expander is placed under the skin of the breast at the time of the mastectomy to preserve the three-dimensional shape of the breast skin envelope, and after the completion of radiation, definitive reconstruction surgery is performed. The potential benefits of the staged approach for selected patients include avoiding the complica- tions associated with radiation to the breast implant or autologous flap and an improved cosmetic result (Kronowitz, 2010). In the first 2 years after breast reconstruction with either implant or autologous flap, the most common adverse effects are wound complications (4.4–9.5%), infection (20.5–20.7%), fat necrosis (15.7%), and implant removal (24.7%). The addition of radiation increases the risks of infection and implant removal (Jagsi et al., 2016; Olsen et al., 2017). In addition to reconstruction following mastectomy, an increasing num- ber of breast cancer patients are undergoing reconstructive procedures with BCS (oncoplastic reconstruction). These patients may have tumors that are large relative to their native breast size or multiple breast lesions (multicentric), or the tumor is located in an unfavorable quadrant in the breast. These patients are not good candidates for BCS alone because a poor cosmetic outcome is anticipated following BCS and radiation (Clough et al., 2015). Oncoplastic reconstruction techniques involve rearranging the patient’s remaining native breast tissue and filling the defect resulting from the lumpectomy, a breast reduction and lift (mastopexy), or using adjacent local breast tissue to restore breast volume. This surgery is usually done on PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 119 an outpatient basis, and it has a significantly lower rate of postoperative complications than mastectomy with reconstruction (Carter et al., 2016) and rates of locoregional recurrence and survival that are similar to those following BCS without oncoplastic reconstruction or total mastectomy (Carter et al., 2016; Down et al., 2013). Adverse Effects of Breast Surgery Both BCS and mastectomy are relatively low-risk surgeries that by themselves do not commonly result in long-term adverse effects after heal- ing is complete. However, particularly when combined with radiation, sur- gery for the breast and axillary lymph nodes can result in adverse sequelae, such as recurrent seromas (fluid collections) that may require repeated drainage; wound complications such as infection, necrosis, or delayed heal- ing; breast and nipple deformities; pain or neuropathy (e.g., numbness and burning sensations); and weakness and limited movement in the affected shoulder and arm. Furthermore, lymph node resection has various potential adverse effects, including lymphedema, neuropathy, and seromas that can impair quality of life. Several of these potential long-term adverse effects are discussed later in this chapter and in Chapter 9. To reduce the risk of these adverse effects, a number of innovative approaches to axillary node surgery have been developed; these are discussed in Chapter 8. Radiation Therapy Radiation therapy is an integral component of optimal local-regional therapy for the management of stage I–III breast cancer. Decisions regarding whether a patient is likely to benefit from adjuvant radiation therapy take into account a number of factors, including the surgical approach (lumpec- tomy or mastectomy), tumor biology based on receptor status, lymph node status, and patient age. In this section the indications for radiation therapy and fractionation schedules for patients treated with lumpectomy or mas- tectomy are presented. A general overview of radiation therapy for many cancers is given in Chapter 4. Radiation Therapy After Lumpectomy The main goals of radiation therapy after lumpectomy for women with invasive breast cancer are to decrease recurrences, decrease the risk of death from breast cancer, conserve the breast with an acceptable cos- metic outcome, and avoid mastectomy in women who desire to preserve the breast. On the basis of numerous randomized clinical trials and meta- analyses, lumpectomy followed by radiation therapy to the whole breast PREPUBLICATION COPY—Uncorrected Proofs

120 DIAGNOSING AND TREATING ADULT CANCERS is considered to be equivalent to mastectomy in terms of cancer control and survival rates (Fisher et al., 2002; Poggi et al., 2003; van Dongen et al., 2000; Veronesi et al., 2002). While whole-breast irradiation has been the standard of care, other approaches include partial-breast irradiation, regional nodal irradiation, and a determination to omit radiation treatment (see Table 5-2). TABLE 5-2 Radiation Approaches for Breast Cancer Irradiation Approach Indications Comments Whole breast • Any patient that has • Hypofractionated schedules are preferred undergone lumpectomy (40–42.6 Gy in 15–16 fractions) • An additional radiation boost to the lumpectomy cavity (10–16 Gy in 4–8 fractions) is considered based on patient age and tumor biology • C o n v e n t i o n a l f r a c t i o n a t i o n c a n b e used for certain situations (e.g., connective tissue disease, very young patients [<30 years old]) Partial breast • Age ≥50 years old • Targets the tumor bed and surrounding • Tumors ≤2cm in size 1–2 cm of tissue • Lymph node negative • Can be delivered with EBRT, • (ER/PR-positive)/ brachytherapy, or IORT HER2-negative • Treatments are completed in 1.5 weeks or less Regional • Macrometastatic (>2 mm of • Previously recommended only for ≥4 nodal disease) axillary lymph node involved lymph nodes; now strongly involvement considered for 1–3 involved lymph nodes • Internal mammary, • Conventional fractionation (50 Gy/25 supraclavicular, and/ fractions) most commonly used or infraclavicular node • Hypofractionated schedules are less involvement based on frequently used but can be considered imaging or examination • Increases risk of lymphedema and other long-term effects compared to whole- breast or partial-breast irradiation Radiation • Age ≥70 years old • Omission of radiation therapy results omission • Tumors ≤2 cm in size in higher rates of in-breast recurrences • Lymph node negative but has not been shown to affect overall (clinically or pathologically) survival • ER/PR-positive and • Patient comorbidities and preferences HER2-negative must be taken into account • Patient committed to 5 years of anti-estrogen therapy NOTE: EBRT = external beam radiation therapy; ER = estrogen receptor; Gy = gray, a unit denoting the joules of radiative energy deposited per kilogram of body mass; HER2 = hu- man epidermal growth factor receptor 2; IORT = intraoperative radiation therapy; PR = progesterone receptor. PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 121 Whole-Breast Irradiation For patients who have undergone a lumpectomy, the standard of care typically involves conventionally fractionated radiation therapy (45–50.4 Gy in 25–28 fractions) over 5–5.5 weeks followed by an additional booster dose to the lumpectomy cavity with an additional 4–8 treatments (NCCN, 2020b). However, hypofractionated whole-breast radiation (see Table 5-2), has the same tumor control rate as longer courses of radiation with fewer side effects (Haviland et al., 2013; Whelan et al., 2010). Some women will receive a boost dose to the lumpectomy cavity, which can add an additional week to the treatment duration. There was some initial concern that certain types of breast cancer (triple-negative breast cancer, grade 3 tumors) were not well suited for hypofractionated whole-breast radiation therapy, but consensus guidelines now recommend it for nearly all patients receiving whole-breast radiation (ASTRO, 2018; Smith et al., 2018). Most recently, a hypofractionated schedule of 26 Gy delivered in 5 treatments given on consecutive days was shown to produce results similar to 40 Gy delivered in 15 treatments (Murray Brunt et al., 2020). As a result, this 1-week schedule of whole-breast irradiation may become more common in the near future. Partial-Breast Irradiation When patients who do not receive radiation therapy after a lumpec- tomy develop an in-breast tumor recurrence, the recurrence tends to occur near the site of the original tumor. This led to randomized clinical trials comparing whole-breast irradiation to partial-breast irradiation, which is defined as radiation therapy targeting the tumor bed (lumpectomy cavity) and approximately 2 cm of tissue surrounding the tumor bed. On the basis of these large, randomized trials comparing partial-breast irradiation to whole-breast irradiation, partial-breast irradiation results in equivalent cancer control rates to whole-breast irradiation in appropriately selected patients (Hepel and Wazer, 2020). Tumor biology and patient factors (age or a familial history) are important selection factors for partial-breast ir- radiation; specifically, the factors indicating partial-breast irradiation use include an age of greater than 50 years and lymph-node-negative and ER- positive tumors that are smaller than 2 cm. For patients who do not meet these criteria, the recurrence rates are slightly but significantly higher with partial-breast irradiation than with whole-breast irradiation. There are various partial-breast irradiation delivery methods, including external beam, brachytherapy, and intraoperative radiation therapy (see Chapter 4 for more details). The most common approach in North America is external beam radiation therapy, which is typically delivered two times per day (3.85 Gy per fraction), with each treatment separated by at least 6 PREPUBLICATION COPY—Uncorrected Proofs

122 DIAGNOSING AND TREATING ADULT CANCERS hours, for 5 consecutive days (total dose, 38.5 Gy). Alternatively, a once- per-day (6 Gy per fraction) partial-breast irradiation regimen given on non- consecutive days for a total of 5 days (30 Gy) is a good option for patients who are inconvenienced by the twice-per-day schedule (Livi et al., 2015). Regional Lymph Node Irradiation Although most patients who undergo lumpectomy will receive whole- breast irradiation or partial-breast irradiation, there are a growing number of patients who may benefit from radiation therapy that treats at-risk lymph node regions, including the axillary, supraclavicular, infraclavicular, and in- ternal mammary lymph nodes. The classic indication for radiation to these regions was for a woman to have four or more involved lymph nodes, large tumors (>5 cm), and at least one involved lymph node—that is, a woman with anatomic stage III breast cancer. However, recent studies have demon- strated that women with one to three involved lymph nodes or those with tumors that are in the inner portion of the breast (near the breast bone) may also benefit from radiation therapy that includes the lymph node regions and they may have a significantly lower risk of incurable distant metastases (Poortmans et al., 2015; Whelan et al., 2015). In women who receive neo- adjuvant chemotherapy, regional lymph node irradiation is indicated if there is lymph node involvement prior to the start of chemotherapy or if there are any pathologically involved axillary lymph nodes at the time of surgery. Omission of Radiation Therapy Omission of radiation therapy is considered mainly for women aged 70 years or older. For these women who have tumors that are ER-positive, <2 cm in size, and lymph-node-negative, data suggest that radiation provides a modest decrease in local recurrences in the breast but has no benefit in reducing mortality, provided that these women take endocrine therapy (Hughes et al., 2013). Similar results have been demonstrated in women 65 or older (with ER-positive, pathologically lymph node negative tumors up to 3 cm in size) in a separate randomized study, though mature results have not yet been reported (Kunkler et al., 2015). Therefore, provided that a patient accepts a slightly higher risk of an in-breast tumor recurrence in her lifetime with the understanding that it will not affect how long she may live, not having radiation therapy may be appropriate for these low-risk women. Radiation Therapy After Mastectomy Postmastectomy radiation is generally used for patients with stage III breast cancer (that is, 4–9 involved lymph nodes; tumors >5 cm with at least PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 123 one involved lymph node; 10 or more nodes with any tumor size; inflamma- tory breast cancer). However, new studies have demonstrated that patients with one to three involved nodes may also receive a significant benefit from radiation therapy in terms of reduced recurrences and mortality. Further- more, these studies have also shown that women who have no involved lymph nodes received no benefit from radiation therapy in terms of reduced recurrences or mortality. In women who receive neoadjuvant chemotherapy, data suggest that it is safe to omit radiation therapy only for those women who present with node negative disease; it remains unknown whether women who receive neoadjuvant chemotherapy that renders negative nodes that initially positive may omit postmastectomy radiation. Otherwise, post- mastectomy radiation therapy is indicated in women with persistent nodal disease after neoadjuvant chemotherapy. Radiation therapy after mastectomy is generally delivered over 25 treat- ments (5 weeks) (NCCN, 2020b). A booster dose of radiation (additional 5 treatments) is sometimes given to the mastectomy scar, although this has not been studied well in clinical trials. Hypofractionated radiation courses (15–16 treatments) are sometimes used for postmastectomy radiation. This approach is being investigated in a large clinical trial specifically of patients who have undergone or are planning to undergo breast reconstructive surgery. Adverse Effects of Radiation Therapy As discussed in Chapter 4, skin irritation and fatigue are among the most common acute adverse effects of radiation therapy to any part of the body. The acute and long-term adverse effects of radiation for breast cancer depend on the extent of treatment (e.g., whole-breast versus regional nodal irradiation) because the larger the volume that is irradiated, the greater the risk of adverse effects. The acute and long-term effects for radiation therapy for breast cancer are summarized in Table 5-3. Systemic Treatments Systemic treatment refers to medications given to prevent the develop- ment of recurrent breast cancer whether locally (in the same breast, op- posite breast or lymph nodes) or distantly (e.g., in the bones, liver, lungs, or brain). The decision whether to use adjuvant or neoadjuvant systemic therapy for localized breast cancer depends primarily on the tumor stage, HR status, and HER2 status, along with other factors. Each of the major types of systemic therapies—chemotherapy, endo- crine therapy, and targeted therapies—may be used for localized breast can- cer. In the section below the committee considers the use of these therapies PREPUBLICATION COPY—Uncorrected Proofs

124 DIAGNOSING AND TREATING ADULT CANCERS TABLE 5-3 Acute and Long-Term Effects Following Radiation Treatment for Breast Cancer Radiation Treatment Acute Effects Long-Term Effects Whole-breast • Fatigue • Scar tissue in the breast (fibrosis) irradiation • Skin irritation (redness, that affects breast appearance burning, itching, peeling, • Permanent changes in skin color in blistering) on the whole patchy areas breast, particularly in • Loss of hair in the armpit of the areas of skin folds affected side • Breast swelling/ • Scarring in the lung (fibrosis) discomfort • Rib fractures (exceedingly rare) • Radiation pneumonitis • Increased risk of ischemic heart (<0.2%)a disease for left-sided breast cancers compared with right-sided breast cancersb • Radiation-induced cancers (exceedingly rare) Partial-breast • Same as above except • Same as above irradiation skin reaction limited to skin in the region of the tumor bed Regional lymph node • Same as above • Same as above irradiation or post- • Pain or discomfort • Increased risk of lymphedema mastectomy radiation swallowing from (7–10% above risk from axillary therapy esophageal irritation surgery)c (particularly left-sided • Delays or complications with cases) reconstruction after mastectomy • Radiation pneumonitis • Scarring in the muscles of the upper (1–1.2%)a chest, shoulder, and back that can lead to range of motion and strength problems in the shoulder and arm • Increased risk of death from ischemic heart disease for left-sided cancers (<0.3–0.4% in non- smokers)b a Werner et al., 2019. b Wennstig et al., 2020; Cheng et al., 2017. c Shaitelman et al., 2017. for HR-positive and HR-negative and HER2-positive and HER2-negative breast cancers. Table 5-4 presents common scenarios for the use of these therapies, but whether a particular patient will receive any or all of them is dependent on his or her specific cancer staging, grade, biomarker status, comorbidities, and personal preferences. In addition, the committee consid- ers the use of systemic therapy for inflammatory breast cancer, a rare and aggressive invasive cancer. PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 125 TABLE 5-4 Systemic Therapies Use for Stage I–III (Localized) Breast Cancer HER2- Use of Breast Cancer Endocrine Directed Neoadjuvant Subtype Therapy Chemotherapy Therapy Therapy ER+, HER2– Yes If node-negative, use No Sometimes OncotypeDx® or Mammaprint® assay to determine chemotherapy use; if node-positive, often use chemotherapy ER–, HER2– No Yes No Often ER+, HER2+ Yes Yes Yes Often ER–, HER2+ No Yes Yes Often Endocrine Therapy Endocrine therapy is used to treat HR-positive cancers (see Table 5-4) by blocking the production of hormones or preventing them from work- ing. The selective estrogen receptor modulator (SERM) tamoxifen acts to block the effects of estrogen in breast tissue. Luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin and leuprolide, decrease the body’s estrogen and progesterone by suppressing the production of these hormones in the ovaries. Aromatase inhibitors, such as anastrozole, letro- zole, and exemestane, decrease the body’s estrogen by blocking an enzyme called aromatase from turning androgen into estrogen. Chemotherapy Chemotherapy regimens for breast cancer are numerous and complex (see Table 5-5) and usually involve a mixture of agents. The choice of a chemotherapy regimen for breast cancer depends on a number of factors, including the clinical status of the patient and patient preference. Unlike endocrine therapy, which typically is used after local therapies (i.e., sur- gery and radiation) are complete, chemotherapy may be used before or after local therapies. Chemotherapy agents used in the adjuvant setting are intravenous and often given as combinations; for example, doxorubicin (adriamycin) is used with cyclophosphamide. HER2-Directed Therapy There are several types of HER2-directed therapies for localized breast cancer, such as the monoclonal antibodies trastuzumab and pertuzumab, PREPUBLICATION COPY—Uncorrected Proofs

126 DIAGNOSING AND TREATING ADULT CANCERS TABLE 5-5 Examples of Systemic Therapies for Localized or Metastatic Breast Cancer Drug Class Examples Endocrine therapy SERM: tamoxifen Aromatase inhibitors: anastrazole, letrozole, exemestane SERD: fulvestrant LHRH: goserelin, leuprolide, triptorelin Chemotherapy doxorubicin, cyclophosphamide, paclitaxel, docetaxel, capecitabine, eribulin, vinorelbine, gemcitabine, and others Targeted Therapies HER2-targeted trastuzumab, pertuzumab, ado-trastuzumab-emtansine, trastuzumab deruxtecan, lapatinib, neratinib, tucatinib CDK4/6 inhibitors palbociclib, ribociclib, abemaciclib mTOR inhibitor everolimus PARP inhibitors olaparib, talazoparib PI3 kinase inhibitor alpelisib Immunotherapy atezolizumab (immune checkpoint inhibitors) NOTE: CDK = cyclin-dependent kinase; HER2 = human epidermal growth factor receptor 2; LHRH = luteinizing hormone-releasing hormone; mTOR = mammalian target of rapamycin; PARP = poly(ADP-ribose) polymerase; PI3 = phosphoinositide 3-kinases; SERD = selective estrogen receptor degrader; SERM = selective estrogen receptor modulator. the antibody conjugate ado-trastuzumab-emtansine, and the small molecule neratinib (see Table 5-5). Adjuvant treatment of HER2-positive breast can- cer includes chemotherapy in addition to HER2-directed therapies. Hormone-Receptor-Positive, HER2-Negative Breast Cancer Most breast cancer, in both women and men, is estrogen- or proges- terone-positive or both (ER+/PR+) as well as HER2-negative. Endocrine therapy is the key component of systemic treatment. Chemotherapy is con- sidered in certain situations (discussed below) but always in the context of what additional benefit it may add to endocrine therapy. In invasive breast cancer, adjuvant endocrine therapy is recommended after surgery and radiation (if used) to reduce the risk of local and systemic recurrence. The type of endocrine therapy used depends on the patient’s menopausal status (see Figure 5-3). Women who are premenopausal are treated with tamoxifen or with a combination of ovarian suppression (usually with an injection of an LHRH agonist) and tamoxifen or with an aromatase inhibitor, depending on clinical factors and patient preference. Postmenopausal women usually receive an aromatase inhibitor, although PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 127 tamoxifen is also an option for those women who are unable to tolerate the adverse effect of aromatase inhibitors. Men with breast cancer are generally treated with adjuvant tamoxifen. Previously the optimal length of endocrine therapy was considered to be 5 years; however, several studies have demonstrated some benefit from a longer duration of use. Decisions about the length of endocrine therapy (5 versus 10 years) consider the risk of recurrence as well as the patient’s tolerance of and preference for these endocrine therapies. When considering the additional benefit that using chemotherapy with endocrine therapy is likely to confer, clinicians take into account tumor stage, tumor assays, and patient age. For many years individuals with a node-negative, ER-positive tumor over 1 cm in size were offered adjuvant chemotherapy to prevent distant recurrence. However, molecular assays performed on primary breast tumors, such as OncotypeDx® and Mam- maprint®, can identify patients who will not benefit from chemotherapy and therefore should not receive it (Beumer et al., 2016; Sparano et al., 2018, 2019). Such assays are both prognostic (tumors with lower scores for recurrence have a better prognosis at baseline) and predictive (they predict the benefit of chemotherapy) and are critical components of treatment plan- ning for node-negative, ER-positive breast cancer. At present, most women with node-negative, ER-positive breast cancer do not receive chemotherapy, which is a significant change from 10 years ago. This change reflects a growing understanding of tumor biology, which in turn drives decisions on optimal treatments. In patients with node-positive, ER-positive breast cancer, the decision whether to add chemotherapy to endocrine therapy is based on the number of involved nodes and the patient’s menopausal status. In certain situations, particularly for postmenopausal women with limited nodal involvement, there appears to be little benefit from adding chemotherapy to endocrine therapy. Studies are investigating the use of the molecular assays, such as OncotypeDx®, in patients with limited lymph node involvement. Early data in postmenopausal women suggest that these assays may be helpful in determining which women may safely avoid chemotherapy, and studies are under way to try to answer this important question. The most common chemotherapy regimens used in ER-positive/ HER2-negative breast cancer include “TC” (taxotere [docetaxel] and cytoxan [cyclophosphamide]) chemotherapy given every 3 weeks for four cycles and “dd (dose-dense) AC-T” (adriamycin and cyclophosphamide given every 2 weeks for four cycles followed by taxol [paclitaxel] every 2 weeks for four cycles). Chemotherapy is often administered with white blood cell growth factors (e.g., pegfilgrastim or filgrastim) to prevent the low white blood cell counts and infection that may result from the che- motherapy alone. PREPUBLICATION COPY—Uncorrected Proofs

128 DIAGNOSING AND TREATING ADULT CANCERS Hormone-Receptor-Negative, HER2-Negative Breast Cancer (Triple- Negative Breast Cancer) Triple-negative breast cancer (TNBC) is more common in African- American women and premenopausal women. TNBC has the worst progno- sis of the three main subtypes of breast cancer (HR-positive/HER2-negative, HR-negative/HER2-negative, or HER2-positive), although, women with stage 1 (localized) TNBC still have a good prognosis, with a 5-year survival of 91%, and those with regional TNBC have a 5-year survival rate of 65% (SEER, n.d.-b). At the present time, chemotherapy is the sole systemic treatment used for early-stage disease, although clinical trials are testing other agents. Increas- ingly, neoadjuvant chemotherapy is being used for TNBC, as this approach allows for (1) clinical trials investigating new therapies in addition to standard therapies to improve the response rate and (2) risk-adapted treatment deci- sions that determine the need for additional therapy based on the response of the tumor. When chemotherapy is given prior to surgery, the pathological complete response (pCR, that is, no tumor detected after the chemotherapy) can be determined when the breast tissue is examined during the postsurgi- cal pathology assessment. A pCR is associated with improved disease-free survival in TNBC. Studies indicate that adding carboplatin to taxol in the dd AC-T chemotherapy regimen described above for HR-positive/HER2-negative breast cancer can improve pCR for TNBC (Loibl et al., 2018). Clinical trials have suggested that neoadjuvant immune therapy (including pembrolizumab) may also improve pCR, but these drugs are not approved by the U.S. Food and Drug Administration (FDA) for this cancer at this time. If there is residual tumor following chemotherapy, administration of capecitabine for 6 months can reduce the risk of recurrent disease. The com- bination of chemotherapy, surgery, possible radiation, and then 6 months of capecitabine means that TNBC treatment may extend for more than 1 year. Numerous clinical trials are under way to assess whether there are benefits of treating women with residual TNBC, including, for example, studies of women who have received capecitabine (or chemotherapy) therapy with either pembrolizumab (Lewis, 2019) or with atezolizumab (Keenan and Tolaney, 2020). HER2-Positive Breast Cancer The central component of HER2-positive breast cancer treatment, whether it is HR-positive or HR-negative, is HER2-directed therapy, spe- cifically trastuzumab in conjunction with chemotherapy. Depending on the underlying biological risk of recurrence of the tumor, there are various chemotherapy regimens can be used with trastuzumab, including paclitaxel, PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 129 TC (taxotere [docetaxel] and carboplatin), and dd AC-T (see above). An additional HER2-targeted therapy, pertuzumab, is added in cases in which tumors are at higher risk of recurrence. Neoadjuvant chemotherapy is increasingly being used in HER2 positive cancers. The antibody drug conjugate trastuzumab–emtansine significantly reduces the risk of distant disease in patients for whom neoadjuvant che- motherapy did not result in a pCR of the tumor. If HER2 positive tumors are also ER-positive, then the hormone targeted therapies described earlier are also used. Bisphosphonates and Denosumab Bone-acting agents such as bisphosphonates and denosumab have been studied in women with breast cancer to determine their effect on cancer recurrence. Adjuvant bisphosphonates have been recommended for post- menopausal women who have had breast cancer to reduce the risk of re- currence (Curigliano et al., 2017). Postmenopausal women with early-stage invasive breast cancer treated with bisphosphonates for 2 to 5 years had highly significant reductions in recurrence, distant recurrence, bone recur- rence, and breast cancer mortality; however, in premenopausal women, bisphosphonates had no effect on any of these outcomes (EBCTCG, 2015). Another study of women with early-stage breast cancer showed that bisphosphonates not only significantly decreased the risks of locoregional or distant recurrence, new primary breast cancers, and breast cancer mor- tality, but that these risk reductions were seen in both pre/peri and post- menopausal women, in both ER-negative and ER-positive breast cancers, and for both earlier and later recurrences (Korde et al., 2018). Inflammatory Breast Cancer Inflammatory breast cancer is a rare (1–5% of all breast cancers) and very aggressive disease, which is characterized by the skin of the breast hav- ing a discolored and thickened appearance (ACS, 2019). It is diagnosed as a locally advanced disease (stage III). It is more common in African-American women, younger women, and women who are overweight or obese. The treatment of inflammatory breast cancer includes chemotherapy (with the exact chemotherapy dependent on HER2 status), mastectomy, and postmastectomy chest wall radiation. It may also include endocrine therapy if the cancer is HR-positive. Despite aggressive multimodality treatment, in- flammatory breast cancer has a poor prognosis, with a 5-year survival rate of 52% for women with regional disease and 18% for those with distant disease (ACS, 2019). PREPUBLICATION COPY—Uncorrected Proofs

130 DIAGNOSING AND TREATING ADULT CANCERS Adverse Effects of Systemic Treatments Although some adverse effects may be more common with specific sys- temic treatments, in general the following effects are seen with adjuvant che- motherapy: hair loss, mouth sores, diarrhea, constipation, fatigue, difficulty concentrating, induction of menopause, infertility, low blood counts, fever, infection, bone pain, and neuropathy, along with others. Long-term adverse effects, described in the section on Life After Breast Cancer Diagnosis and in Chapter 9, include cardiotoxicity, chronic fatigue, and chemotherapy- induced peripheral neuropathy. The toxicity of HER2-directed therapy in- cludes infusion reactions, cardiotoxicity, pneumonitis, and diarrhea. The adverse effects of tamoxifen include hot flashes and night sweats; vaginal dryness, discharge, or bleeding; uterine cancer; blood clots; and cataracts. The adverse effects of aromatase inhibitors include muscle aches and pains (arthralgias and myalgias), bone loss and bone fractures, vaginal dryness, and hot flashes. Treatment-related new primary cancers are relatively rare. Lung cancer from radiation, uterine cancer from tamoxifen, and leukemia from anthra- cyclines and other chemotherapy agents such as cytoxan have been reported (Bhatia et al., 1996; Dracham et al., 2018; Travis et al., 1999, 2000). See Chapter 4 for more discussion of treatment-related cancers. TREATMENT OF METASTATIC BREAST CANCER Metastatic breast cancer at diagnosis (stage IV) is infrequent; most metastatic disease occurs several years after initial diagnosis of earlier stage disease and represents a recurrence of the original breast cancer that has spread to another part of the body, most commonly the liver, brain, bones, or lungs. Although the length of time that individuals live with metastatic breast cancer has been increasing with improved therapies, metastatic dis- ease is generally felt to be incurable. About 6% of all women and about 9% of Black women are diagnosed with metastatic breast cancer at the time of their initial diagnosis (Howlader et al., 2020). Most women and men who develop metastatic disease do so at some point after the diagnosis of a potentially curable breast cancer which then recurs outside the breast (see section on recurrence). For example, among women with ER-positive breast cancer who received 5 years of adjuvant endocrine therapy, the risk of distant metastases ranged from 10% to 41% in the 15 years after cessa- tion of endocrine therapy, with the risk being strongly correlated with the original TN status and tumor grade (Pan et al., 2017). While firm estimates of the number of women living with recurrent or metastatic disease breast cancer are not available, some reports suggest it may be more than 150,000 individuals (Mariotto et al., 2017) (see Figure 5-5). This is an important PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 131 FIGURE 5-5 Number of U.S. women alive as of January 1, 2017, who had previ- ously been diagnosed with de novo or recurrent metastatic breast cancer (MBC), by time since diagnosis. SOURCE: Mariotto et al., 2017, with permission from the American Association for Cancer Research. population of patients, as these individuals are now living for extended periods of time on chronic cancer therapies, including many new investiga- tional agents that are effectively targeting HR-positive and HER2-positive disease. See Chapter 10 for a discussion of the palliative and supportive care needs of cancer patients and survivors. Younger women are more likely to be diagnosed with de novo meta- static disease, likely due to the absence of screening and delays in early diagnosis. This diagnosis has with significant implications for the prognosis and treatment of these women. However, most women who die from breast cancer are initially diagnosed with localized disease and subsequently have a systemic recurrence (i.e., metastatic disease). The treatment goals for metastatic disease are to improve longevity and quality of life. The National Comprehensive Cancer Network and other organizations encourage enrollment in clinical trials whenever possible as the best choice for treatment. Treatment for metastatic breast cancer, as with localized disease, is determined by HR and HER2 status, the timing and type of prior therapies, the presence of visceral crisis (i.e., the need to achieve a therapeutic response quickly because of impending or actual organ damage), and patient preference. TNBC is more likely to recur than the other subtypes, with a 5-year survival rate of approximately 77% for triple-negative tumors versus 90–94% for HR-positive and HER2-positive cancers (SEER, n.d.-b). Once breast cancer is metastatic, the median 5-year survival is estimated to be 27% (SEER, n.d.-a). However, due to the in- creasing number of effective medications for metastatic breast cancer, the PREPUBLICATION COPY—Uncorrected Proofs

132 DIAGNOSING AND TREATING ADULT CANCERS median survival of stage IV breast cancer is increasing, particularly for HER2-positive and ER-positive disease. In this section, the systemic treatments and radiation therapy used for metastatic breast cancer are discussed. Systemic Treatments Systemic treatments for metastatic breast cancer include the use of endocrine therapies and chemotherapy as well as targeted therapies. In general, treatments are used until there is too much toxicity to continue or until the cancer grows. Breaks from therapy are often considered in the context of shared decision making with the patient. Endocrine Therapy Individuals with metastatic HR-positive tumors will generally receive a sequence of endocrine therapies until the time of toxicity or disease pro- gression (Caswell-Jin et al., 2018; Cristofanilli et al., 2016). These therapies include tamoxifen, aromatase inhibitors, and fulvestrant (see Table 5-5). Often these endocrine therapies are used in combination with targeted therapies (see below) such as CDK4/6 inhibitors, everolimus, or alpelisib (see Table 5-5). When all endocrine options have been tried or if the clini- cal situation warrants, chemotherapy may then be used. Some metastatic tumors respond extremely well to endocrine therapies, and individuals can be on these medications for years or, rarely, even decades. Chemotherapy The choice of chemotherapy for metastatic breast cancer depends on a number of factors, including the clinical status of the patient and patient preference. For example, capecitabine is an oral chemotherapy medication that does not generally cause hair loss. Although sequential single che- motherapy agents are generally used for metastatic disease, combination chemotherapy with two of more agents is sometimes used, particularly if the patient has significant visceral disease and a rapid response to therapy is felt to be necessary. FDA has approved an extensive list of chemotherapy agents for metastatic breast cancer (NCI, 2020). Targeted Therapies Targeted therapies are frequently used in metastatic breast cancer. It is standard of care to combine endocrine therapy with other forms of targeted therapy. HER2-directed therapy is, by its nature, targeted therapy. Thus, PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 133 in both HER2-positive and HR-positive metastatic breast cancer, targeted therapies are frequently used either alone or in combination with other treatments. HER2-Directed Therapy For HER2-positive metastatic disease, many treatment options are available (see Table 5-5). There has been an explosion in available HER2- targeted treatments in the last 10 years, which have led to an improvement in the overall survival for metastatic breast cancer. Some of these therapies are administered on their own (e.g., ado-trastuzumab-emtansine or trastu- zumab deruxtecan), and some are administered in combination with che- motherapy agents such as lapatinib and tucatinib. Patients can be on these therapies for extended periods of time. PARP Inhibitors Multiple poly (ADP-ribose) polymerase (PARP) inhibitors have been approved by FDA as cancer therapeutics. Tumors in which there are de- fects in homologous DNA repair, such as those associated with mutations in BRCA1 and BRCA2, appear particularly susceptible to PARP inhibitors (Domchek et al., 2020). About 60% of women who inherit either a BRCA1 or BRCA2 mutation develop breast cancer by age 66 years (Kuchenbaecker et al., 2017). Approximately 5–10% of all breast cancers are associated with hereditary factors such as BRCA1/2 mutations (PDQ® Adult Treat- ment Editorial Board, 2020). FDA approved the PARP inhibitors talazopa- rib and olaparib for BRCA1/2-associated metastatic breast cancer (Litton et al., 2018; Robson et al., 2017). The side effects of PARP inhibitors include nausea, fatigue, and low blood counts. CDK4/6 Inhibitors FDA has approved cyclin-dependent kinase 4/6 inhibitors (CDKIs) in combination with endocrine therapy for both first-line and second-line treatment of HR-positive, HER2-negative, advanced or metastatic breast cancer. Cyclin-dependent kinase is an enzyme important in cell prolifera- tion, and therefore these drugs work by targeting the cell cycle machinery. These oral medications include palbociclib, ribociclib, and abemaciclib and are given in combination with endocrine therapy such as aromatase inhibitors, tamoxifen, or fulvestrant (Cristofanilli et al., 2016; Goetz et al., 2017; Johnston et al., 2019; Turner et al., 2015, 2018). Multiple studies have demonstrated that CDK4/6 inhibitors plus endocrine therapy have significantly higher progression-free survival than endocrine therapy alone. PREPUBLICATION COPY—Uncorrected Proofs

134 DIAGNOSING AND TREATING ADULT CANCERS Patients can be on these for a prolonged period of time, with median time of progression-free survival in the range of 2 years. mTOR Inhibitor Everolimus is a mammalian target of rapamycin (mTOR) inhibitor ap- proved for use in metastatic breast cancer in combination with endocrine therapy. mTOR is a protein that helps control cell division. PI3K Kinase Inhibitors Approximately 40% of ER-positive, HER2-negative metastatic breast cancers have a detectable PI3K (phosphoinositide 3-kinase) mutation. Al- pelisib is a cyclin-dependent kinase inhibitor which, in combination with endocrine therapy, improves progression-free survival for metastatic breast cancer patients. The side effects of alpelisib include elevated blood sugars, diarrhea, and rash (André et al., 2019). Immunotherapy Atezolizumab is a PD-1 (programmed cell death-1) inhibitor used to treat metastatic breast cancer. Atezolizumab in combination with the chemotherapeutic agent nab-paclitaxel (abraxne) has been shown to im- prove disease progression-free survival in patients with TNBC and PD-L1 (programmed death ligand-1) expression when administered as a first-line treatment. Immune side effects (such as thyroiditis, pneumonitis, colitis, and myocarditis) are common and can be serious (Schmid et al., 2018). In November, 2020, FDA approved pembrolizumab, another PD-L1 inhibitor to treat locally recurrent unresectable or metastatic TNBC (FDA, 2020). Bisphosphonates and Denosumab A review by the Cochrane Collaborative found that in women with metastatic breast cancer with bone metastases, bisphosphonates reduced the risk of skeletal-related events by 14%, but had no effect on overall survival. Denosumab was slightly more effective in reducing the risk of skeletal- related events (22%), but also had no effect on survival (O’Carrigan et al., 2017). Surgical Treatment Occasionally surgery is used for the treatment of metastatic breast cancer. Situations in which surgery may be considered include the PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 135 removal of a single focus of metastatic breast cancer, the prevention of severe complications of metastatic breast cancer (such as malignant cord compression or pathological fracture of the leg), or the management of an existing complication of metastatic breast cancer (such as a pathologi- cal fracture of the leg). However, a recent clinical study has shown that compared with optimal systemic therapy, early local therapy with BCS followed by radiation therapy or mastectomy (with or without radiation therapy) does not improve survival in patients with de novo metastatic breast cancer and an intact primary tumor. Although there was an in- creased risk of local disease progression without local therapy, surgical removal of the intact primary tumor did not lead to improved quality of life (Khan et al., 2020). Radiation Treatment Palliative Radiation Therapy Although the first-line treatment of metastatic breast cancer is systemic therapy, local treatments such as radiation therapy can be used to help im- prove or palliate a symptom caused by the disease, particularly pain from bone metastases. Radiation therapy reduces pain from bone metastases in over 60% of patients and has been shown to eliminate pain completely in 21–25% of patients (Chow et al., 2007; Spencer et al., 2018). Most palliative radiation therapy treatment courses involve 1–10 treatments (Hartsell et al., 2005; Howell et al., 2013; Lutz et al., 2011). Most palliative radiation therapy courses are delivered using standard 3-D- conformal radiation therapy. Stereotactic body radiation therapy (SBRT), which delivers an ablative dose of radiation in 1–5 fractions, is sometimes used to treat painful bone metastases in the spine, particularly if the me- tastasis has already received prior palliative radiation therapy. Compared with standard palliative radiation therapy doses and techniques, the data on using SBRT to treat a de novo bone metastasis are mixed (Loi et al., 2019; Spencer et al., 2019) and clinical studies are under way. The biology of the breast cancer and the disease course are important for determining how many treatments a patient will receive. For instance, a patient with ER- positive breast cancer receiving endocrine therapy and a CDK4/6 inhibitor who is experiencing pain in a rib bone would most likely benefit from 10 radiation treatments instead of one treatment because her life expectancy is on the order of years and the likelihood of re-treatment for pain in that rib is high. By contrast, the optimum treatment for a patient with TNBC with the same degree of rib pain but whose cancer has progressed after three prior types of therapy may be only one radiation treatment because her life expectancy is much shorter. PREPUBLICATION COPY—Uncorrected Proofs

136 DIAGNOSING AND TREATING ADULT CANCERS Stereotactic Body Radiation Therapy for Oligometastatic Breast Cancer In addition to its role in palliating painful bone metastases, SBRT is in- creasingly being used in patients with very limited (“oligometastatic”) can- cers with the goal of completely eradicating the known sites of disease and potentially curing patients with limited metastatic disease (see Chapter 4). The approach of ablating oligometastases is commonly used in lung cancer on the basis of small, randomized studies, some of which included patients with breast cancer (see Chapter 6). In some cases, surgery can also be used to ablate sites of metastatic disease. SBRT has an advantage over surgery because there is less disruption in the delivery of systemic therapy and less acute morbidity. While the treatment of up to four metastases with SBRT has been deemed safe in a clinical trial (Chmura et al., 2019), SBRT can be associated with significant toxicities depending on the proximity of the me- tastasis to normal tissues, and some of these toxicities can be fatal (Palma et al., 2019). The results of a randomized clinical trial (NCT02364557) comparing SBRT to standard-of-care therapy (systemic therapy and pallia- tive radiation, if indicated) are pending, and if SBRT proves to be beneficial by improving disease outcomes, it may become the standard of care for pa- tients with limited metastatic breast disease (Chmura et al., 2019). Selecting patients with oligometastatic breast cancer for SBRT should carefully weigh the risks of treating the metastases against the potential benefits. Recurrence For women who have HR-positive cancers—the vast majority of breast cancer—treatment may result in a cure, but there is a continuing risk of cancer recurrence in the decades following the initial diagnosis (see Figure FIGURE 5-6 Hazard rate of relapse by tumor subtype in (A) 3,589 women diag- nosed with breast cancer between 1986 and 1992 and (B) 3,589 women diagnosed with breast cancer between mid-2004 and 2008. NOTE: ER = estrogen. SOURCE: Cosetti et al., 2015, reprinted with permission © (2015) American Soci- ety of Clinical Oncology, all rights reserved. PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 137 5-6). These women may have recurrent metastatic cancer 10 to 25 years after their initial diagnosis, and these recurrent cancers can lead to morbid- ity, impairments, and functional limitations. In such cases the treatment for recurrence adds to any toxicity and morbidity that may have resulted from the initial cancer treatments. LIFE AFTER BREAST CANCER DIAGNOSIS Physical and mental impairment following a diagnosis of breast cancer can be due to the toxicity of the treatments used to cure a person or caused by the development of incurable metastatic disease. Thus, looking solely at the prognosis and expected mortality from breast cancer is an incomplete measure of the impairments and subsequent functional limitations that can result from a diagnosis of the disease. To a large extent the post-treatment experience of early-stage breast can- cer survivors is influenced by the specific local treatments they receive, such as the extent of breast surgery or radiation treatment. Many of the long-term and late-onset effects of cancer treatment, such as fatigue or cognitive complaints, may result from a variety of treatments used for local disease. For women with de novo metastatic or recurrent breast cancer, the physical effects often dominate and are influenced by the specific sites of metastatic disease (e.g., bone, lung, liver, or brain). Thus, the experience for survivors after a diagnosis of breast cancer is heterogeneous and cannot be easily categorized. The impacts of cancer and its treatment on survivor functioning can be classified into two types: (1) long-term effects, which are symptoms or difficulties that begin during treatment and persist for some time after treatment ends (e.g., pain, fatigue, insomnia, neuropathy) (see Chapter 9); and (2) late-onset effects, which are problems that are not evident during active treatment but that emerge months and years after treatment ends (e.g., new-onset lymphedema, congestive heart failure, osteoporosis, and fracture). While these two categories of problems seem distinct, they often overlap, and their time of origin may not be easy to delineate. Long-term effects are more common and sometimes reflect the “new normal” for can- cer survivors, while the late-onset effects are often rarer and more serious and can take the survivor by surprise, as they occur at a time that may be distant from the initial treatment. Furthermore, long-term and late-onset effects may occur individually, as clusters, or be synergistic; all of these ef- fects may increase the likelihood of impairments and functional limitations. In the sections below the committee briefly summarizes some of the long-term and late-onset effects that may result from breast cancer and its treatments. More information on many of these effects that result not only from breast cancer but other cancers considered in this report may also be found in Chapter 9. PREPUBLICATION COPY—Uncorrected Proofs

138 DIAGNOSING AND TREATING ADULT CANCERS Common Long-Term Effects of Breast Cancer Treatment The most direct effects of treatment result from breast cancer surgery and radiation treatment, if given, and include pain, lymphedema, fatigue, cognitive impairments, and depression. Other late-onset and long-term ef- fects include chemotherapy-induced peripheral neuropathy and reproduc- tive system dysfunction. Pain Pain in the residual breast tissue and chest wall is common after breast surgery. Although this pain is most severe in the early months after surgery, for 25% of women it can persist indefinitely after surgery (Miaskowski et al., 2012). Pain often extends into the ipsilateral arm (i.e., the arm adjacent to the breast undergoing surgery) and axilla. Breast surgery may also limit the range of motion and result in a frozen shoulder if physical therapy is not performed early in the course of postoperative pain (Stubblefield and Custodio, 2006). Lumpectomy with radiation was expected to reduce the likelihood of these post-treatment physical effects, but that has not been observed (Shimozuma et al., 1999). Women may also have difficulty sleeping and resuming some physi- cal activities, such as lifting, as a result of their chronic chest and breast pain. Lymphedema Lymphedema (swelling of the arm) on the side associated with breast surgery is more likely to occur in women who had more extensive axillary node surgery (axillary lymph node dissection versus sentinel lymph node dis- section) in combination with radiation to the axillary area (Erickson et al., 2001; Naoum et al., 2020). Swelling of the breast can also be a problem if radiation is carried out after BCS. Other risk factors for lymphedema include weight gain, cellulitis, skin injury, and trauma. Edema may occur early in the postoperative period and can be helped by physical therapy interventions, such as manual lymphatic drainage, but it can become chronic, causing pain and arm dysfunction. Edema of the arm can also occur as a late-onset effect, ap- pearing months to years after the end of treatment. Patients who have SLND are at much lower risk for arm pain and lymphedema in the year after surgery than those undergoing ALND. Nevertheless, a small number of survivors un- dergoing either surgery may have persistent pain and lymphedema out to 36 months (Land et al., 2010). Fatigue Fatigue is one of the most common acute side effects of cancer treat- ment and is generally most severe in those who receive multimodal therapy PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 139 (i.e., surgery, radiation, and chemotherapy). It often takes months to 1 year or more after treatment ends for the fatigue to resolve. In about 20% of breast cancer survivors, treatment-associated fatigue does not resolve and may persist for years (Bower et al., 2000, 2006). Fatigue after breast cancer treatment appears to be associated with persistent levels of inflam- mation, and some individuals appear to be genetically predisposed to have more difficulty recovering from that inflammation (Bower, 2014; Bower and Ganz, 2015; Bower et al., 2002, 2005). Because patients often appear well and have no laboratory evidence that explains the fatigue (i.e., normal chemistries, no anemia, normal thyroid function), the diagnosis of fatigue must be based on patient reports; given the lack of laboratory tests for fa- tigue, this complaint may be underreported and underappreciated (Bower, 2019). Fatigue patients are often unable to resume normal activities, must carefully manage their energy expenditure during the day, and have less time for leisure activities. Fatigue often co-occurs with cognitive difficulties (Bower and Ganz, 2015). A recent study that examined the trajectory for post-treatment fatigue in breast cancer survivors found that women with depressive symptoms and childhood adversity were at a higher risk of fa- tigue out to 6 years of follow-up (Bower et al., 2018). Because of the prevalence of fatigue in breast cancer survivors, a num- ber of interventions have been tested to address this ongoing problem. For example, integrative medicine interventions, such as yoga, have been found to be beneficial in addressing cancer-related fatigue in breast cancer survivors and may be effective in reducing inflammation (Bower et al., 2012, 2014). Other treatments for cancer-related fatigue are discussed in Chapter 9. Cognitive Impairment Cognitive impairment after breast cancer treatments can be associated with fatigue or may be an independent complaint. While only 15–20% of women may experience this problem, many are unable to do their usual home and professional work due to having difficulty remembering, plan- ning, and multitasking. The issue was often referred to as “chemobrain” or “chemofog” because when early reports of this problem first appeared in the 1990s it was at a time when many women were receiving adjuvant chemotherapy for breast cancer, and high-dose chemotherapy with stem cell transplants was being used in an attempt to cure women with metastatic or locally advanced breast cancer (Ganz, 1998; van Dam et al., 1998). Since then it has been found that various treatments other than chemotherapy, in- cluding the endocrine therapies that are the mainstay of treatment for HR- positive breast cancer, may be causing the cognitive complaints reported by breast cancer patients (Ganz and Van Dyk, 2020; Ganz et al., 2014; Wagner et al., 2020). Premature menopause, a common result of adjuvant PREPUBLICATION COPY—Uncorrected Proofs

140 DIAGNOSING AND TREATING ADULT CANCERS chemotherapy in younger women, and also ovarian suppression therapy, now widely used in premenopausal breast cancer patients, may exacerbate the cognitive changes associated with adjuvant chemotherapy. Individuals who are having persistent cognitive difficulties in association with breast cancer treatments should be evaluated by a neuropsychologist who is familiar with this complication of cancer treatment. While standard- ized neurocognitive test batteries can be used, there are some specific areas of potential deficit that should be investigated. In addition, uncontrolled depressive symptoms and insomnia may be important co-factors that need to be excluded or managed. Interventions that have been found to be help- ful include cognitive rehabilitation and cognitive behavioral therapy (CBT). More information on the treatment of cognitive impairments from cancer treatments may be found in Chapter 9. Depression In addition to the disruptive physical symptoms faced by younger and mid-life women, the psychosocial impact of breast cancer can be substantial and can affect all aspects of life. Many women may have persistent anxiety, depression, and associated insomnia after a diagnosis of breast cancer or its treatment (IOM, 2004). These symptoms are often not identified by the cancer care team during clinical visits, and psychosocial counseling services for cancer patients may be unavailable. Although cancer survivors may appear to have recovered (e.g., their hair has grown back), they may still have mental health issues; this is particularly true for younger breast cancer survivors (Howard-Anderson et al., 2012). Depression occurs at a high rate in breast cancer survivors, and it can be lead to functional limitations. One study of newly diagnosed women found that 38% had elevated symptoms of depression at a 16-month follow-up (Stanton et al., 2015). While most women with breast cancer will recover from the psychosocial impact of the diagnosis and treatment, clinical interventions and medications may be needed for those with persistent symptoms (Stanton and Bower, 2015). Concomitant problems often include anxiety and insomnia, both of which may benefit from specific medications and behavioral interventions, such as CBT, or from supportive therapies such as Tai Chi Chih (Irwin et al., 2017). More information on depression may be found in Chapter 9. Chemotherapy-Induced Peripheral Neuropathy For the past two decades, taxane chemotherapy has been increasingly used as a component of adjuvant chemotherapy. While highly effective in the treatment of breast cancer, this class of drugs may result in seri- ous chemotherapy-induced peripheral neuropathy (CIPN), which can then PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 141 become a dose-limiting toxicity. CIPN is common after breast cancer treat- ments end and does not resolve in a substantial number of breast cancer survivors (Rivera et al., 2018). This persistent CPIN can lead to impaired quality of life and functioning (Rivera et al., 2018) as well as an increased risk of falls (Winters-Stone et al., 2017). More information on CIPN may be found in Chapter 9. Other Long-Term and Late-Onset Effects Other important physical effects of cancer treatments relate to disrup- tions in the endocrine or menopausal status of women. Specifically, younger premenopausal women who are treated with cytotoxic chemotherapy may have an abrupt cessation of menses and the subsequent onset of vasomo- tor (hot flashes, night sweats, palpitations) and vaginal (dryness, pain with intercourse) symptoms, along with the potential for infertility (Barton and Ganz, 2015; Knobf, 2006). The cessation of menses may be temporary or permanent, with the latter more common in women aged 40 years or older (Ganz et al., 2011). If endocrine therapy with tamoxifen is used following chemotherapy-induced amenorrhea, then the amenorrhea is likely to persist much longer, although menses may return (Ganz et al., 2011; Knobf, 2006). However, endocrine therapy may cause the same vasomotor symptoms and lead to substantial impacts on quality of life. This therapy is given for 5–10 years and is difficult for many women to tolerate. There may be other complications from breast cancer treatment, such as blood clots from tamoxifen or osteoporosis and fracture risk from premature menopause or endocrine therapy. New primary or subsequent cancers, such as endometrial cancer, can result from tamoxifen, especially in postmenopausal women. Some of the menopausal symptoms can be man- aged with medications. Rarely, women may experience serious depression in association with these hormonal changes. Impaired fertility is another loss these women face, and although there are opportunities to preserve fertility by the pretreatment collection of oocytes from the ovaries, which can be preserved with or without fertilization to create an embryo, the costs may be prohibitive for many women (Howard-Anderson et al., 2012; Pinto and de Azambuja, 2011). For women with de novo or recurrent metastatic breast cancer, treat- ments may be chronic as long as the woman is alive, perhaps for as many as 15–20 years. This may include multiple episodes of recurrent/progressive disease, with use of radiation at various time points to control pain or other symptoms, along with systemic treatments. Late-onset effects of cancer treatments that include cardiac toxicity from chemotherapy and radiation as well as osteoporosis and fractures may lead to additional functional limitations beyond the presence of metastatic disease itself. PREPUBLICATION COPY—Uncorrected Proofs

142 DIAGNOSING AND TREATING ADULT CANCERS FINDINGS AND CONCLUSIONS Findings 1. As of 2020 there are an estimated 3.5 million women and men with a past or current diagnosis of breast cancer alive in the United States. 2. More than 90% of breast cancer patients present with localized disease that has not spread outside of the breast and regional lymph nodes. Most breast cancer is hormone (estrogen and/or progesterone)-receptor positive and HER2 negative (68%); about 10% of breast cancer is hormone-receptor negative and HER2 negative (triple-negative breast cancer); 10% is hormone-receptor positive and HER2 positive; and about 4% of breast cancer is hormone-receptor negative and HER2 positive. 3. Triple-negative breast cancer is more common in African American women as well as premenopausal women and has the worst prog- nosis of the subtypes of breast cancer; it is also the most likely to recur. 4. Treatment is determined by guidelines that are based on clinical and biological factors, stage of cancer, family history, patient age, and patient preferences, and include a combination of local treat- ments (i.e., surgery and radiation therapy) or local treatments with systemic therapy. 5. For localized breast cancer, lumpectomy followed by radiation therapy to the whole breast is considered equivalent to mastectomy in terms of cancer control and survival rates. 6. Lymph node dissection has potential adverse effects including lymphedema, neuropathy, and seromas that can impair a survivor’s quality of life. 7. For breast cancer that is hormone-receptor positive and HER2 negative, endocrine therapy (tamoxifen or an aromatase inhibi- tor) is a key component of systemic treatment. Adverse effects of aromatase inhibitors that may cause impairments include muscle aches and pains (arthralgias and myalgias) and bone loss. 8. The long-term and late-onset effects of intensive chemotherapy in- clude leukemia, cardiac dysfunction, chronic fatigue, and neuropa- thy, which can be life threatening and lead to functional limitations. 9. The post-treatment experience of early-stage breast cancer which may relate to impairments and functional limitations is influenced by the specific local treatments, such as the extent of breast surgery or radiation therapy. PREPUBLICATION COPY—Uncorrected Proofs

BREAST CANCER 143 10. The impairments resulting from breast cancer and from its treat- ment fall into two main groups: long-term effects, which are symp- toms or problems that start during treatment and persist long after treatment ends (e.g., pain, fatigue, insomnia, neuropathy, and cognitive complaints); and late-onset effects (i.e., impairments that emerge months to years after treatment ends—lymphedema, congestive heart failure, osteoporosis, and fracture). 11. Most women who die from breast cancer are initially diagnosed with localized disease but subsequently have a systemic recurrence, resulting in metastatic disease. 12. Women who present with de novo metastatic breast cancer at the time of their initial diagnosis are more likely to be younger. Meta- static breast cancer has significant implications for their prognosis and treatment. For women with de novo metastatic or recurrent metastatic breast cancer, the physical effects often dominate and are influenced by the sites of the metastatic disease (e.g., bone, lung, liver, or brain); however, these women may also have sub- stantial ongoing psychosocial concerns. Conclusions 1. The 5-year survival for people with early-stage breast cancer (specif- ically, stage I, hormone-receptor positive, and HER2-negative), the most commonly diagnosed breast cancer, is excellent, at 94–99%. 2. Impairments associated with breast cancer and its treatment, even early-stage breast cancer, are highly variable and depend on many individual characteristics and the specific treatments the patient receives. 3. There are many impairments that may result from breast cancer and its treatment, especially pain, fatigue, cognitive complaints, neuropathy, psychological issues, and lymphedema, which are of- ten untreated and may lead to persistent functional limitations. REFERENCES ACS (American Cancer Society). 2019. Inflammatory breast cancer. https://www.cancer.org/ cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/types-of-breast-cancer/ inflammatory-breast-cancer.html (accessed August 11, 2020). Ager, B., P. Butow, J. Jansen, K.-A. Phillips, D. Porter, and CPM DA Advisory Group. 2016. Contralateral prophylactic mastectomy (CPM): A systematic review of patient reported factors and psychological predictors influencing choice and satisfaction. The Breast 28:107–120. AJCC (American Joint Committee on Cancer). 2017. AJCC cancer staging manual, eighth edition. New York: Springer International Publishing. PREPUBLICATION COPY—Uncorrected Proofs

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Diagnosing and Treating Adult Cancers and Associated Impairments Get This Book
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Cancer is the second leading cause of death among adults in the United States after heart disease. However, improvements in cancer treatment and earlier detection are leading to growing numbers of cancer survivors. As the number of cancer survivors grows, there is increased interest in how cancer and its treatments may affect a person's ability to work, whether the person has maintained employment throughout the treatment or is returning to work at a previous, current, or new place of employment. Cancer-related impairments and resulting functional limitations may or may not lead to disability as defined by the U.S. Social Security Administration (SSA), however, adults surviving cancer who are unable to work because of cancer-related impairments and functional limitations may apply for disability benefits from SSA.

At the request of SSA, Diagnosing and Treating Adult Cancers and Associated Impairments provides background information on breast cancer, lung cancer, and selected other cancers to assist SSA in its review of the listing of impairments for disability assessments. This report addresses several specific topics, including determining the latest standards of care as well as new technologies for understanding disease processes, treatment modalities, and the effect of cancer on a person's health and functioning, in order to inform SSA's evaluation of disability claims for adults with cancer.

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