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Correct staging of breast cancer patients is of extraordinary importance. Not only does it permit an accurate prognosis, but in many cases, therapeutic decision making is based largely on the TNM (primary tumor, regional nodes, metastasis) classification. Comparison with historic series should be undertaken with caution, as the staging has changed several times in the past 20 years. The current staging is complex and results in significant changes in outcome by stage as compared with prior staging systems.
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NONINVASIVE BREAST CANCER
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Breast cancer develops as a series of molecular changes in the epithelial cells that lead to ever more malignant behavior. Increased use of mammography has led to more frequent diagnoses of noninvasive breast cancer. These lesions fall into two groups: ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (lobular neoplasia or LCIS). The management of both entities is controversial.
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Ductal Carcinoma In Situ
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Proliferation of cytologically malignant breast epithelial cells within the ducts is termed ductal carcinoma in situ (DCIS). Atypical hyperplasia may be difficult to differentiate from DCIS. At least one-third of patients with untreated DCIS develop invasive breast cancer within 5 years. However, many low-grade DCIS lesions do not appear to progress over many years; therefore, many patients are overtreated. Unfortunately, there is no reliable means of distinguishing patients who require treatment from those who may be safely observed.
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For many years, the standard treatment for DCIS was mastectomy. Although no studies have compared breast-preserving therapy to mastectomy, the ~100% ten year survival rates with the former suggest that it is a satisfactory strategy. Breast-preserving surgery alone may also be acceptable. However, although survival was identical in the two arms of a randomized trial comparing wide excision plus or minus irradiation, the latter caused a substantial reduction in the local recurrence rate as compared with wide excision alone. Addition of tamoxifen or an aromatase inhibitor (AI) to any DCIS surgical/radiation therapy regimen further improves local control. However, in the largest trial comparing the two in DCIS, anastrozole did not improve distant disease-free or overall survival compared to tamoxifen.
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Several prognostic features may help to identify patients at high risk for local recurrence after either lumpectomy alone or lumpectomy with radiation therapy, and therefore might provide an indication for mastectomy. These include extensive disease; age <40; and cytologic features such as necrosis, poor nuclear grade, and comedo subtype with overexpression of erbB2. In summary, it is reasonable to recommend breast-preserving surgery for patients who have a localized focus of DCIS with clear margins followed by breast irradiation and tamoxifen or anastrozole. For patients with localized DCIS, axillary lymph node dissection is unnecessary.
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More controversial is the question of what management is optimal when there is any degree of invasion. Because of a significant likelihood (10–15%) of axillary lymph node involvement even when the primary lesion shows only microscopic invasion, it is prudent to do at least a sentinel lymph node sampling for all patients with any degree of invasion. Further management is dictated by the presence of nodal spread.
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Proliferation of cytological malignant cells within the lobules is termed lobular neoplasia (LCIS). Nearly 30% of patients who have had adequate local excision, or incidentally discovered LCIS, or just a biopsy a needle biopsy of a suspicious area develop a subsequent breast cancer (usually infiltrating ductal carcinoma) over the next 15–20 years. Ipsilateral and contralateral cancers are equally common. Therefore, LCIS may be considered a premalignant condition with associated elevated risk of subsequent breast cancer, rather than a form of malignancy itself, and aggressive local management seems unreasonable. Management options include careful observation with routine mammography or chemoprevention with either a SERM or an AI (for postmenopausal women) for 5 years as well as concurrent and subsequent annual mammography and semiannual physical examinations. A third option, although no more effective and associated with substantial cosmetic, and perhaps emotional, morbidity is bilateral prophylactic mastectomy.
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TREATMENT Breast Cancer BIOLOGICAL CONSIDERATIONS
One of the most important advances in our understanding of breast cancer has been the appreciation that it can be classified by gene expression patterns into a series of subtypes.
Luminal: Luminal breast cancers are almost always positive for ER and negative for HER2 amplification. They are divided into two groups:
Luminal A: Luminal A tumors have the highest levels of ER expression as well as of downstream ER-dependent genes, such as PgR. They are almost universally negative or low in HER2, and they have low proliferative thrust. They are usually low grade, are most likely to respond to endocrine therapy, and have a favorable prognosis. They appear to be less responsive to chemotherapy.
Luminal B: Luminal B breast cancers are also of luminal epithelial origin, but with a gene expression pattern distinct from luminal A. They tend to be PgR negative and have evidence of higher proliferative activity. They also tend to express HER2, but not to the level of the so-called “HER2 amplified” cancers. Their grade is more often higher than luminal A cancers. Prognosis is somewhat worse. They may be more sensitive to chemotherapy.
HER2 amplified: These tumors have amplification of the HER2 gene on chromosome 17q and frequently exhibit coamplification and overexpression of other genes adjacent to HER2. Historically the clinical prognosis of such tumors was poor. However, with the advent of trastuzumab and other targeted therapies, the clinical outcome of HER2 positive patients is markedly improved compared to 20 or more years ago.
Basal: These ER/PgR–negative and HER2-negative tumors (so-called triple negative) are characterized by markers of basal/myoepithelial cells. They tend to be high grade, and express cytokeratins 5/6 and 17 as well as vimentin, p63, CD10, α-smooth muscle actin, and epidermal growth factor receptor (EGFR). Patients with BRCA1 mutations also fall within this molecular subtype. They also have stem cell characteristics.
Normal breast-like: These tumors have a gene expression profile reminiscent of nonmalignant “normal” breast epithelium. Prognosis is similar to the luminal B group. This subtype is somewhat controversial and may represent contamination of the sample by normal mammary epithelium.
Claudin-low: These cancers are often triple negative but they have low expression of cell-cell junction proteins including E-cadherin. They are frequently associated with lymphocytic infiltration.
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GENERAL TREATMENT CONSIDERATIONS
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Treatment of breast cancer depends on whether the patient does or does not have evidence of distant (meaning outside the breast, chest wall, and regional lymph nodes) metastases, as detected by scintigraphic or radiologic imaging and biopsy. For patients with no evidence of detectable distant metastases, the goal of therapy is cure, or at least substantial survival prolongation, and is divided into primary and systemic considerations. Primary therapies consist of surgical and radiation treatments directed toward the breast and locoregional lymph nodes. These approaches are designed to excise and eliminate the cancer and sterilize unaffected breast tissue as appropriate. Adjuvant systemic treatments, consisting of antiestrogen (or endocrine), anti-HER2, and/or chemotherapies, are given to treat micrometastases that may have already escaped to distant sites but are not yet detectable.
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All treatments for breast cancer are based on prognostic and predictive factors. Prognostic factors provide an indication of how likely a cancer will recur, either locally or in distant organs, in the future if a patient is not treated with the respective treatments. Predictive factors are used to determine if a given treatment is likely to work or not, assuming the patient’s prognosis justifies treatment (or further treatment assuming the patient has been treated in some manner already).
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Prognostic features guide both whether and what type of primary and adjuvant systemic treatments should be pursued. Anatomic prognostic features include visual and physical examination findings of locally advanced breast cancer (T4 lesions: skin erythema [“inflammatory”] or edema [“peau d’orange”], nodules, or ulceration or tumor fixation to the chest wall). In patients without any of these findings, the most important prognostic features are tumor size and lymph node status (TN in the staging system). As discussed below, biologic features, such as histologic tumor grade as well as ER, PgR, and HER2, are also prognostic. Over the last decade, several multiparameter tests based on gene expression have been developed to determine prognosis in patients who have node-negative, ER-positive, and HER2-negative disease.
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Predictive features are usually used to guide systemic therapies. These include ER for endocrine treatments and HER2 for anti-HER2 therapies, such as trastuzumab. There are no established predictive factors to predict response to radiation treatment. The issue of chemoresistance in luminal A cancers is under large-scale investigations.
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EARLY-STAGE BREAST CANCER
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Prior to 1980, the Halsted radical mastectomy, in which the breast, chest wall muscles, and complete axillary nodal contents were removed, was the standard treatment of choice for women with newly diagnosed breast cancer. In the 1980s, prospective randomized trials demonstrated that recurrence and survival rates were the same with the less disfiguring modified radical mastectomy, in which the chest wall muscles were preserved and only a sampling of axillary lymph nodes were removed.
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In the same decade, breast-conserving treatments, consisting of the removal of the primary tumor by some form of surgical excision (designated as lumpectomy, quadrantectomy, or partial mastectomy), were shown to result in equal, if not slightly superior, to that associated with mastectomy. Several of these trials also demonstrated that the in-breast recurrence rate was quite high in the absence of breast radiation, while it was reduced substantially if radiation was provided. Therefore, for women undergoing breast conservation, postlumpectomy radiation is usually indicated, although it may be less necessary and withheld in older women with ER-positive, node-negative breast cancer, since their risk of subsequent in-breast recurrence is quite low with surgery and endocrine therapy only. When lumpectomy with negative tumor margins is achieved and radiation is delivered appropriately, breast conservation is associated with a recurrence rate in the breast of ≤5%.
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Not all patients are candidates for breast-conserving therapy. Contraindications include large tumor to breast ratio, inability to achieve clear margins with adequate cosmesis after extensive surgery, multifocal cancers, extensive four-quadrant DCIS, and inability to receive radiation. The latter issue arises in women with dermal autoimmune disease (such as lupus erythematosus), prior radiation to the site, and/or lack of available radiation treatment facilities. Further, although not contraindicated, breast-conserving therapy may be less cosmetically acceptable than mastectomy with reconstruction if the nipple-areolar complex is involved with cancer and must be sacrificed. This is a personal choice, and some women prefer mastectomy, especially those with high genetic risks for second breast cancers.
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For patients who do undergo mastectomy, postoperative chest wall and regional nodal radiation is also associated with an improvement in survival if they have a high risk of local-regional recurrence, such as tumors ≥5 cm, four or more positive axillary lymph nodes, or postoperative positive margins. Postmastectomy radiation is not indicated in women with cancers <2 cm, negative lymph nodes, and negative margins. It is considered for women who fall into the areas between these (2–5 cm, one to three positive nodes, or close margins), and is usually recommended if a patient has one to three involved axillary lymph nodes.
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At present, nearly one-third of women in the United States are managed by lumpectomy, and recent data suggest that the fraction of women treated with breast-conserving therapy is decreasing. It appears that many women still undergo mastectomy who could safely avoid this procedure and probably would if appropriately counseled.
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Axillary node sampling or dissection is unnecessary in many cases. Sentinel lymph node mapping and biopsy (SLNB) is generally the standard of care for women with localized breast cancer and clinically negative axilla. If SLNB is negative, more extensive axillary surgery is not required, avoiding much of the risk of lymphedema following more extensive axillary dissections. Even in the presence of sentinel lymph node involvement, further axillary surgery may not be required for selected patients, such as older women and those with ER-positive cancers.
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The survival of patients who have recurrence in the breast after proper treatment (adequate surgery and radiation if indicated) is somewhat worse than that of women who do not, but it is not worse than those who suffer local-regional recurrence after mastectomy. Thus, local-regional recurrence is a negative prognostic variable for long-term survival but not the cause of distant metastasis. Most patients should consult with a radiation oncologist before making a final decision concerning local therapy. However, a multimodality clinic in which the surgeon, radiation oncologist, medical oncologist, and other caregivers cooperate to evaluate the patient and develop a treatment plan is usually considered a major advantage by patients.
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Adjuvant Systemic Therapies
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The concept of adjuvant systemic therapy is based on the observation that cancer is a condition of genetic instability, and with increasing generations of cellular replication, genetic abnormalities accumulate. Although these occur randomly, and therefore may lead to sensitivity or resistance to therapies, the latter is of greater concern. Thus, as a consequence of accumulation of mutations to resistance, almost all patients with metastatic breast cancer are destined to die with, if not of their cancer.
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However, treatment with the same therapies administered earlier, in the setting of micrometastatic disease only, has been repeatedly shown to be more effective than waiting until symptomatic, documented metastases occur. Put simply, the use of systemic therapy as an adjuvant to local management of breast cancer substantially improves survival. More than half of the women who would otherwise die of metastatic breast cancer remain disease-free and experience considerable survival advantaged when treated with the appropriate adjuvant systemic regimen. These data have grown more and more impressive with longer follow-up and more effective regimens.
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As noted, prognostic factors help define who most likely needs, or perhaps more importantly does not need, adjuvant systemic therapy. The most important prognostic variables are provided by tumor staging: tumor size (T), lymph node status (N) and detectable distant metastases (M) (Table 75-1). Histologic classification of the tumor has also been used as a prognostic factor. Tumors with a poor nuclear grade have a higher risk of recurrence than tumors with a good nuclear grade. Semiquantitative measures such as the Elston score improve the reproducibility of this measurement. Importantly, there is no need to perform imaging for distant metastases in a patient with no signs or symptoms of widespread disease and who has a T3 or less tumor and fewer than four involved axillary lymph nodes.
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Adjuvant systemic therapy may not be needed at all for patients with very small (<1 cm) tumors and negative lymph nodes. However, there is no patient with invasive breast cancer who does not have some risk of subsequent distant metastases, and therefore who might not benefit at all. This consideration raises two issues: (1) the differences in odds of benefit and odds of toxicities of the various types of therapies and (2) the judgment between the patient and her caregiver regarding the calculated absolute benefit-risk ratio for specific types of adjuvant systemic treatments.
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There are three types of adjuvant systemic therapies: (1) chemotherapy; (2) endocrine; and (3) anti-HER2 therapies. The decision whether to apply each of these depends on prognostic and predictive features as well as the combined judgment of the patient and caregiver. For example, a patient might be much more likely to accept endocrine therapy for a very small potential benefit than she would accept chemotherapy for the same calculated advantage, since the former is much less often associated with either life-taking, life-threatening, or permanently life-changing toxicities than the latter. Thus, one has to consider prognostic and predictive factors for each type of therapy, separately.
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The greatest controversy concerns the recommendation for adjuvant chemotherapy, since there is no good predictive factor for this class of treatments, and the decision must be made on prognosis alone. Large overview analyses suggest that chemotherapy reduces the risk of recurrence over the 10 years subsequent to primary diagnosis by approximately one-third. For patients with positive lymph nodes and/or features that render the cancer T4, the risk of distant recurrence (and thus not being cured) over that decade is 50% or higher. Therefore, a one-third reduction of at least 50% means that 15–20%, or more, women will be cured who would not have been in the absence of adjuvant chemotherapy. The life-taking, life-threatening, or permanently life-changing toxicities of adjuvant chemotherapy are ~1–2%, and therefore almost all medical oncologists would recommend adjuvant chemotherapy in this setting.
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In contrast, there is rarely justification for adjuvant chemotherapy in most women with tumors <1 cm in size whose axillary lymph nodes are negative. However, this decision is very much weighed by the expression of ER and HER2. For example, the risk of recurrence of such a patient whose tumor is negative for ER, PgR, and HER2 (so-called triple-negative breast cancer) over the succeeding 10 years without any adjuvant is ~15%. If chemotherapy reduces this risk by approximately one-third or more, which is what large overview analyses suggest, then 5%, or perhaps even higher, of patients will be cured who would otherwise be destined to die of their disease. Likewise, a patient with ER and PgR-negative, but HER2-positive, disease has a slightly worse prognosis (risk of recurrence over 10 years is ~20%), and will benefit not only from the adjuvant chemotherapy but from anti-HER2 therapy as well, so that her potential absolute benefit is even higher. Many, but not all, clinicians would recommend adjuvant chemotherapy for such patients.
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On the other hand, patients with ER-positive disease have a better prognosis than those with ER-negative breast cancer, and adjuvant endocrine therapy will further reduce the odds of recurrence by approximately one-half. Therefore, the same patient in the example above (<1 cm, node negative) but who has an ER-positive and HER2-negative cancer has a lower initial risk of recurrence (~10% over 10 years). Given the relatively low life-taking, life-threatening, or permanently life-changing toxicities, she is very likely to accept adjuvant endocrine therapy, further lowering her estimated risk of recurrence to ~5%. If chemotherapy reduces this risk by approximately one-third, no more than 1–2% of patients will benefit. This potential benefit is approximately the same as the number of patients who will suffer life-taking, life-threatening, or permanently life-changing toxicities. Thus, in this case, most clinicians would recommend adjuvant endocrine, but not chemotherapy.
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These examples represent extremes. In the screening era, up to 30% of newly diagnosed patients have T2-3, node-negative, ER-positive cancers. These patients have an intermediate risk between the two extremes, and the calculated absolute benefit of adjuvant chemotherapy is ~3–5%. It is unclear if this small but real benefit is sufficient to justify adjuvant chemotherapy. Detection of breast cancer cells either in the circulation or bone marrow is associated with an increased relapse rate. However, the finding of bone marrow micrometastases only portends a slightly worse prognosis, especially in node negative patients, and bone marrow biopsies are not recommended in patients with early stage disease.
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The most exciting development in this area is the use of gene expression arrays to analyze patterns of tumor gene expression, especially for node-negative, ER-positive cancers. Several groups have independently defined gene sets that reliably predict disease-free and overall survival far more accurately than any single prognostic variable. The Oncotype DX® Recurrence Score (RS) analysis of 21 genes was the first such assay to be adopted. A number of retrospective and more recently prospective studies have documented its utility in identifying patients with node-negative, ER-positive breast cancer whose prognosis, assuming adequate adjuvant endocrine therapy, is so good that they can forego adjuvant chemotherapy. Basically, the 30–50% of patients with ER positive, node negative, but low RS, appear to have luminal A breast cancers, and they do not need chemotherapy, whereas those with high RS appear to have luminal B cancers and the benefits of adjuvant chemotherapy clearly outweigh the risks. For those with intermediate RS, the answer is still unclear and has been the focus of now completed, but as yet unreported, prospective trials.
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More recently, other assays, including the Prosigna,® EndoPredict,® and Breast Cancer Index® have also been shown to have clinical utility in this setting. Only one of these tests should be ordered for a single patient, since they do not always give the same results and there are no data to determine which, in the case of discordance, might be “correct.” Also, the use of such standardized risk assessment tools such as Adjuvant! Online (www.adjuvantonline.com) is very helpful. These tools are highly recommended in otherwise ambiguous circumstances.
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Several measures of tumor growth rate correlate with early relapse, but their use is problematic due to analytical variability. Of these, assessment using immunochemical assays for the proliferation marker, Ki67, is the most widespread. However, there is substantial lab-to-lab variability and disagreement regarding optimal cut points. At present, in standard practice outside of a highly skilled laboratory, use of Ki67 is not recommended to make clinical decisions.
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Molecular changes in the tumor are also useful. Tumors that overexpress erbB2 (HER2/neu) have a worse prognosis, but expression of this gene for prognosis is most important in patients with ER-positive, node-negative disease. Indeed, patients with HER2-positive breast cancer are so likely to have a high RS that it is not recommended that the Oncotype DX,® or for that matter any of the other multiparameter assays, be ordered. HER2 should be performed on every breast cancer biopsy, however, because of its predictive role for anti-HER2 therapies.
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Predictive Factors to Choose Adjuvant Systemic Therapy
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The decision to recommend AST is also based on predictive factors; those that provide a prediction of the likelihood that a given class, or even specific drug within a class, will have activity or not. The two important predictive factors, which should be ordered in all breast cancer biopsies (primary or metastatic), are ER and HER2.
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There is no detectable benefit in patients with ER-poor, or -negative, cancers, whereas adjuvant endocrine therapy reduces the risk of recurrence by one-half or more in patients with ER-rich cancers. ER is most commonly measured by counting the percent of positive cells within the cancer after immunohistochemical (IHC) staining. Endocrine therapy is recommended for any patient with ≥10% positive cells, whereas it is not for those whose cancers only have 0–1% staining. The evidence supporting benefit in 1–9% cases is weak, but given the potential benefit and relatively low toxicities of endocrine therapy, it is recommended for patients in this circumstance, with a low threshold for discontinuation if side effects are intolerable.
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HER2 is the target for anti-HER2 therapies. Adjuvant trastuzumab therapy reduces the risk of distant recurrence by one-third or more, with associated substantial risk of dying of breast cancer. Most, if not all, of the large adjuvant trastuzumab trials have been performed in patients with HER2-”positive” breast cancer. HER2 status is determined using either IHC staining for protein overexpression, or fluorescent in situ hybridization (FISH) for gene amplification. IHC staining of 3+ (on a scale of 0–3+) is considered positive, whereas 0–1+ is considered negative. For cases with 2+ staining, reflex FISH analysis is recommended. FISH can either be used as the initial evaluation, or for additional evaluation in IHC 2+ cases. FISH results are considered positive if the ratio of HER2 to centromere signal on chromosome 17 is ≥2.0. There is no reason to do FISH if IHC is 3+ or 0–1+, nor is there reason to order IHC testing if FISH is ≥2.0. If note, preclinical studies and retrospective analyses of a few selected cases from the prospective randomized trials have suggested that perhaps trastuzumab might be effective in cases with IHC 1–2+ results. A large prospective randomized clinical trial addressing this issue is completed but not yet reported.
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There are no reliable predictive factors for chemotherapy, in general or for specific types of chemotherapies. It has been hypothesized that chemotherapy may be more active in ER-negative and/or HER2-positive cancers. More recently, this issue has evolved to imply that luminal B cancers may be more chemosensitive, whereas luminal A cancers are perceived to be relatively chemoresistant. At present, none of the tests for intrinsic subtype should be used to determine whether to give chemotherapy or not, based on prediction of resistance in patients with poor prognosis, such as those with T4 or node-positive disease. Attempts to identify reliable predictive factors for individual classes of chemotherapeutic agents (such as anthracyclines, alkylating agents, or taxanes) have been unsuccessful. The platin salts (carbo-, cisplatin) may have higher activity in patients with triple-negative breast cancer and perhaps in patients with HER2-positive disease.
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If chemotherapy is indicated, it should include multiple agents, either in combination or as sequential single agents. If indicated, anti-HER2 therapy should include at least 1 year of trastuzumab, and preliminary data have supported addition of pertuzumab for at least three months. Endocrine therapy should be administered to patients with ER-positive breast cancer following completion of chemotherapy and administered for at least 5 years, and probably longer.
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There are two proven endocrine therapy strategies: the SERM, tamoxifen, or estrogen ablation. In addition to being effective in preventing new cancers and reducing the risk of local-regional recurrences in patients with DCIS, tamoxifen reduces the risk of distant recurrence and death due to invasive breast cancer by ~40% over the decade following diagnosis. It is equally effective in pre- and postmenopausal women, although it may be slightly less effective in very young (<40 years) patients. Because tamoxifen is a SERM, it has mixed ER antagonism (in the breast and brain) and agonism (in the bone, liver, and uterus). Therefore, it is active against breast cancer in the prevention, adjuvant, and metastatic settings, but frequently causes hot flashes. The agonistic effect results in reduction of osteopenia/osteoporosis, especially in postmenopausal women, but it increases thrombosis and endometrial cancers due to this effect in the liver and uterus, respectively.
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Estrogen depletion can be achieved surgically in premenopausal women by oophorectomy or ovarian suppression with a gonadotropin-releasing hormone super-agonist (GnRH agonist), such as goserelin, that results in tachyphylaxis of the pituitary. However, women with nonfunctioning ovaries, whether induced or by natural menopause, still produce small amounts of estrogen. Estrogen production in these women occurs by adrenal synthesis of estrogen precursors (testosterone, dehydroepiandrosterone [DHEA]) that are converted to estradiol and estrone by aromatase activity in peripheral fat and possible cancer cells. In postmenopausal women, circulating estrogen can be reduced to nearly imperceptible levels with the use of oral AIs. There are three such agents available (anastrozole, letrozole, and exemestane). Although there is no perceptible difference in activity or toxicity among the three AIs, they are all slightly more effective than tamoxifen.
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It is recommended that all postmenopausal women with ER-positive breast cancer be treated for at least 3–5 years with an AI, unless there is a contraindication. The most common concern is the presence of severe osteoporosis, since this is the most frequent life-taking or life-threatening toxicity of the AIs. Likewise, ~15–20% of patients cannot tolerate the AIs due to musculoskeletal symptoms mimicking osteoarthritis and arthralgias. For both these groups of women, tamoxifen is a reasonable therapy, again assuming no contraindications exist. The most important of these is a past history of thrombosis, or high risk of cerebrovascular disease.
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For premenopausal women, the decision of optimal endocrine therapy depends on prognosis and patient choice. Complete estrogen depletion is slightly more effective than tamoxifen alone, but it may also be associated with more bothersome side effects, such as hot flashes, vaginal dryness, and sexual dysfunction. Recent studies have suggested that complete estrogen depletion, consisting of either oophorectomy or chemical suppression of gonadotropins coupled with an AI, is indicated for women with worse prognosis, in particular node positivity. For those with more favorable prognosis, tamoxifen alone may be preferable. The AIs should not be administered to women with functioning, or dormant, ovaries, since the negative hypothalamic-pituitary feedback can result in a rebound hyperestrogenic production effect.
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The duration of adjuvant endocrine treatment is unclear. Until recently, the standard recommendation was at least 5 years of therapy. Several studies have now demonstrated that although 5 years of adjuvant endocrine treatment clearly reduces the risk of recurrence during that time and for a few years after discontinuation, the annual risk of distant recurrence during the subsequent 15 years is 0.5–3%, depending on the initial T and N status. Further, so-called extended adjuvant endocrine therapy with either tamoxifen or an AI, for at least years 6–10, continues to reduce this late risk of relapse. The decision of whether to continue adjuvant endocrine therapy or not after 5 years must therefore take into consideration initial risk (T, N, grade), current side effects and potential cumulative toxicities, and the patient’s perception of the relative and absolute benefits and risks.
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If adjuvant chemotherapy is indicated, as discussed above, one must consider the optimal regimen. Several studies, and a combined overview analysis, have demonstrated that multiple-agent chemotherapy is more effective than single agent. However, at least two studies have shown that sequential single-agent chemotherapy is as effective, and may be slightly less toxic, than simultaneous combination chemotherapy although it requires longer total duration to deliver. Administration of four to six cycles of chemotherapy appears to be optimal; one cycle is less effective than six, but more than six have generally increased toxicity without further efficacy.
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Several chemotherapeutic agents have activity in the adjuvant setting. These include alkylating agents, (principally cyclophosphamide), anthracyclines (doxorubicin, epirubicin), antimetabolites (5-fluoruracil [5FU], capecitabine, methotrexate), and the taxanes (paclitaxel, docetaxel). Within classes, randomized trials have failed to demonstrate superiority of one agent versus another (e.g., doxorubicin vs epirubicin, or paclitaxel vs docetaxel). Dose escalation above an optimal dose is not more effective. The advantage of more frequent scheduling for most individual agents is unclear, but weekly or every other week paclitaxel is superior to every 3-week infusion, while, enigmatically, the opposite is true for its cousin, docetaxel. However, one benefit of a “dose dense” regimen (e.g., every 2 weeks with cytokine support vs every 3 weeks) is earlier completion of therapy.
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These agents are usually combined within a single regimen. The oldest of these is cyclophosphamide, methotrexate, and 5FU (CMF) Addition of an anthracycline, or substitution of an anthracycline for the antimetabolite, improves outcomes slightly, albeit with slightly increased risk of heart failure and secondary leukemia. Addition of a taxane to an anthracycline-based regimen further reduces the chances of distant recurrence and death, albeit only modestly. Recent studies have suggested that addition of an anthracycline to a taxane-based regimen is also modestly more effective than a taxane plus cyclophosphamide alone.
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Which regimen is appropriate for a patient must be individualized based on prognosis, comorbid conditions, and the perspective of the patient. For example, the modest relative improvement of giving an anthracycline, cyclophosphamide, and a taxane (AC-T) may not transfer to a sufficiently large absolute improvement in survival in a patient with a relative small (T2) tumor and negative nodes, whereas that same relative reduction in death may translate to a sufficiently large absolute benefit in a patient with a worse prognosis. Therefore, the former patient might best be served with a taxane/cyclophosphamide (TC) regimen alone, while the latter might wish to accept the added risk of congestive heart failure and leukemia associated with the anthracyclines.
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Neoadjuvant treatment involves the administration of adjuvant systemic therapy, most commonly chemotherapy, before definitive surgery and radiation therapy. The objective partial and complete response rates of patients with breast cancer to neoadjuvant chemotherapy exceed 75%. Thus, many patients will be “downstaged” by neoadjuvant chemotherapy. In this circumstance, patients with locally advanced, inoperable cancers may become candidates for surgery, and a small fraction of patients who are not considered eligible for breast-conserving surgery may become so due to shrinkage of their cancer. However, overall survival has not been improved using this approach as compared with the same drugs given postoperatively.
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Patients who achieve a pathologic complete remission after neoadjuvant chemotherapy have a substantially improved survival compared to those who do not. It is unknown if this observation implies that the latter group did not benefit, or just had a worse initial prognosis, yet still gained some benefit. Although it is appealing to consider treating patients who have not had a pathologic complete response with even more chemotherapy, no studies have demonstrated that doing so improves overall survival. It is possible that these patients have chemoresistant disease, and therefore more chemotherapy will not be of value. However, it is essential that all patients, regardless of response to neoadjuvant chemotherapy, receive adjuvant endocrine therapy if they have an ER-positive breast cancer and adjuvant anti-HER2 therapy if their cancer is HER2 positive.
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The neoadjuvant setting also provides an appealing opportunity for the evaluation of new agents. For example, a second HER2-targeting antibody, pertuzumab, has been shown to provide increased rates of pathologic complete response when combined with trastuzumab in the neoadjuvant setting. However, this approach is controversial; it is not clear that demonstration of higher response rates in the neoadjuvant setting will translate into better overall survival. For example, neoadjuvant trials demonstrated that combination trastuzumab and lapatinib resulted in higher pathologic complete responses than trastuzumab alone, yet a classically performed adjuvant trial failed to demonstrate improved survival for this regimen.
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Chemotherapy is associated with nausea, vomiting, and alopecia in ~100% of patients, although the former two are well controlled with modern antiemetics. More importantly, chemotherapy causes neutropenia and fever, with a risk of infection of ~1%. The neutropenia can be prevented in most patients with appropriate use of the growth factor filgrastim. Secondary myelodysplasia and leukemia occur in ~0.5–1% of patients treated with anthracyclines as well as with high cumulative doses of cyclophosphamide, usually occurring within 2–5 years of treatment. The anthracyclines cause cumulative dose-related congestive heart failure, which occurs in ~1% of patients treated with standard four to five cycles at 60 mg/m2. Peripheral neuropathy is the major dose-limiting and life-changing toxicity of the taxanes. Neuropathy occurs during treatment in ~15–20% of patients, and permanent, chronic neuropathy persists in 3–5%.
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The emergence of therapies directed toward HER2 has been one of the great success stories of all oncology. Several trials have demonstrated that the humanized monoclonal antibody, trastuzumab, decreases both risk of recurrence and mortality in early-stage breast cancer. While trastuzumab administered after chemotherapy is effective, the accumulated evidence suggests that it is optimally delivered concurrently with chemotherapy, particularly in association with a taxane. However, concurrent treatment with an anthracycline is generally avoided, since the main toxicity of trastuzumab is cardiac dysfunction, which appears more often when the agent is delivered simultaneously with doxorubicin. Therefore, if an anthracycline is to be used, it is most commonly given prior to administration of trastuzumab—for example as AC for four cycles followed by a taxane plus trastuzumab. In patients with reasonably favorable prognosis (T1 or 2, node negative), single-agent paclitaxel plus trastuzumab appears to be an adequate regimen.
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Twelve months of trastuzumab therapy is optimal. Randomized trials have demonstrated no additional benefit beyond 12 months, whereas 6 months has been shown to be inferior to 12. Trastuzumab is administered intravenously weekly or every 3 weeks.
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Other, anti-HER2 treatments that are effective in the metastatic setting are appealing candidates for adjuvant therapies. As noted, neoadjuvant studies have demonstrated that chemotherapy with the combination of trastuzumab and pertuzumab results in higher pathologic complete responses than trastuzumab alone. The U.S. Food and Drug Administration (FDA) has granted this combination with accelerated approval, but final approval for the combination is pending more clinically meaningful results (disease-free, overall survival) from now-completed, classic adjuvant trials. Although lapatinib did not add to trastuzumab therapy and single-agent adjuvant lapatinib is inferior to single agent trastuzumab, another anti-HER2 tyrosine kinase inhibitor, neratinib, is superior to no anti-HER2 therapy. Neratinib has not been compared to trastuzumab, either as a single agent or in combination. Ado-trastuzumab emtansine, an antibody-drug conjugate, has activity in the metastatic setting even in patients who have progressed on trastuzumab and is now being tested in the adjuvant setting.
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Skeletal Strengthening Agents
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Bone-strengthening agents that are commonly used to treat osteoporosis appear to have some, but limited, activity in preventing recurrent breast cancer, particularly in postmenopausal women. In an overview analysis of all trials addressing bisphosphonate therapy, improvement in overall survival was not significantly associated with any specific bisphosphonate class, treatment schedule, ER status, nodal status, tumor grade, or concomitant chemotherapy. No differences were seen in nonbreast cancer mortality. Bone fractures were reduced (relative risk [RR] 0.85, 95% confidence interval [CI] 0.75–0.97; 2 p = 0.02). At present, there is no clear consensus regarding routine use of bisphosphonates as an adjuvant therapy, although patients with advancing osteopenia or confirmed osteoporosis should be treated accordingly.
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Novel Adjuvant Systemic Agents
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Other exciting adjuvant strategies are being tested, such as poly–ADP ribose polymerase (PARP) inhibitors in patients with known germline BRCA1 or BRCA2 mutations or those with triple-negative cancers that share similar defects in DNA repair in their etiology. The remarkable results of immune checkpoint inhibitors in other cancers have led to studies of this approach in both metastatic and post-neoadjuvant chemotherapy settings but are still considered highly investigational.
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Recommendations for adjuvant therapy are found in Table 75-2.
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STAGE III BREAST CANCER
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Between 10 and 25% of patients present with so-called locally advanced, or stage III, breast cancer at diagnosis. Many of these cancers are technically operable, whereas others, particularly cancers with chest wall involvement, inflammatory breast cancers, or cancers with large matted axillary lymph nodes, cannot be managed with surgery initially. As noted, neoadjuvant compared may be no more effective than postsurgical adjuvant chemotherapy in prolonging survival, but the advantages of downstaging and therefore facilitating local therapy are accepted. Radiotherapy either to the chest wall after mastectomy or to the breast after tumor excision is almost always recommended, as is regional lymph node treatment. Adjuvant anti-HER2 and endocrine therapies are also used, as appropriate. These patients should be managed in multimodality clinics to coordinate surgery, radiation therapy, and systemic chemo-, endocrine, and anti-HER2 therapies, as indicated. Such approaches produce long-term disease-free survival in ~30–50% of patients.
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BREAST CANCER SURVIVORSHIP ISSUES
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The odds of surviving breast cancer have increased dramatically over the last 35 years due to a combination of early detection and more effective therapies. Although detection bias improves case fatality rates, age-adjusted mortality rates (mortality/100,000 women in society/year) have declined by >30%. Therefore, while ~40,000 American women will die of metastatic breast cancer in 2016, >60,000 would have suffered breast cancer mortality without these advances. Thus, all clinicians, not just oncologists, need to be aware of survivorship issues in patients with previously diagnosed and treated breast cancer.
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No special follow-up procedures, such as serial circulating tumor biomarkers or systemic radiographic/scintigraphic imaging, are indicated in an asymptomatic patient with no physical findings of recurrence. Although randomized trials have demonstrated slightly higher incidence of detection of metastases with lead times of 3–12 months by screening asymptomatic patients compared to no special follow-up, there is no evidence of improved overall survival. If anything, one of these studies suggested a worse quality of life due to higher anxiety levels associated with the testing, and toxicities associated with earlier treatment in patients who were otherwise doing well at that time. These recommendations are summarized in Table 75-3.
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It is important to carefully assess and evaluate new symptoms, considering whether they might be due to the cancer, the treatment, or an unassociated condition. Judgment needs to be used to decide if blood tests or imaging are required, in order to avoid missing a lesion for which appropriate treatment would improve the patient’s quality of life but to diminish overtesting, with associated inconvenience, anxieties, false positives, and cost. Serial echocardiography should be performed every 3 months for patients on adjuvant trastuzumab, but not after it is discontinued.
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Likewise, there is no role for serial monitoring for long-term, life-threatening toxicities associated with chemotherapy, such as myelodysplastic syndromes or congestive heart failure, since these are quite uncommon and likely to cause obvious symptoms requiring proper evaluation if they occur.
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For patients on endocrine therapy, quality-of-life issues may be critical, including hot flashes, sexual difficulties, musculoskeletal complaints, and risk of osteoporosis. Although estrogen therapy, given orally, transdermally, or transvaginally, effectively reduces these side effects, it should not be given to these patients, since it may counteract the efficacy of the endocrine therapy. Nonhormonal treatments, such as selected antidepressants for hot flashes and musculo-skeletal symptoms, and counseling and water-based lubricants for sexual issues can be quite helpful. It is important to screen bone density in patients on an AI more frequently than is recommended for the average postmenopausal woman, since total estrogen depletion results in enhanced risk of osteoporosis and fracture. All women should be counseled to take daily calcium and vitamin D replacement, and if osteoporosis is present or osteopenia is worsening, bone strengthening agents should be administered.
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THERAPY OF METASTATIC DISEASE
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About 15–20% of patients treated for localized breast cancer develop metastatic disease in the subsequent decade after diagnosis. Soft tissue, bony, and visceral (lung and liver) metastases all account for approximately one-third of sites of initial relapses. However, by the time of death, most patients will have bony involvement. Recurrences can appear at any time after primary therapy, but at least half occur >5 years after initial therapy. This observation is particularly true in patients with ER-positive disease, for whom the risk of distant recurrence remains constant for as long as 20 years and is the basis for recommendation of extended adjuvant endocrine therapy. It is now clear that a variety of host factors can influence recurrence rates, including depression and central obesity, and these diseases should be managed as aggressively as possible.
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For patients with no prior history of metastases, a biopsy of suspicious physical or radiographic lesions should be performed, both for confirmation that the lesion does, indeed, represent recurrent cancer and to reevaluate ER and HER2, which can differ between the primary and metastatic lesions in up to 15% of cases. One should not assume that an apparent abnormality is a breast cancer metastasis. Many benign conditions, such as tuberculosis, gallstones, sarcoidosis, or other nonmalignant diseases, can mimic a recurrent breast cancer and are of course treated much differently.
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Although treatable, metastatic disease is rarely if ever cured. The median survival for all patients diagnosed with metastatic breast cancer is <3 years, but with remarkable variability depending on intrinsic subtype and effective treatments. Patients with triple-negative metastatic breast cancer have the shortest expected survival, while those with ER-positive disease can expect to live the longest. HER2 positivity was initially found to be a very poor prognostic factor in metastatic breast cancer, but the availability of several effective treatments has improved the expected survival rates to at least those of ER-positive patients, if not better.
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In the absence of cure, the overall goal of treatment of metastatic disease is palliation, or, put simply, to “keep the patient feeling as well as she can for as long as she can.” A secondary goal is improved survival. It is important to point out that survival has not been improved by advocating more aggressive, or toxic, therapies, such as high-dose or combination chemotherapy, but rather by more selective and biologically based therapy, such as use of endocrine or anti-HER2 therapies in patients with ER- or HER2-positive breast cancers, respectively. Generally, a new treatment is continued until either progression or unacceptable toxicities are evident. These are both evaluated by serial history and physical examinations and periodic serologic evaluation for hematologic or hepatic abnormalities, as well as circulating tumor biomarker tests (assays for MUC1, such as CA15-3 or CA27.29, and for carcinoembryonic antigen or occasionally CA125). If all these evaluations fail to suggest progression, it is unlikely that imaging will contribute. However, if one or more of these suggest progression, whole-body imaging with either a PET/CT or a scintigraphic bone scan and dedicated CT are indicated. Brain imaging is not recommended unless the patient has some sort of central nervous system (CNS) symptom or finding.
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The choice of therapy requires consideration of local therapy needs, specifically surgical approaches to particularly worrisome long-bone lytic lesions or isolated CNS metastases. New back pain in patients with breast cancer should be explored aggressively on an emergent basis; to wait for neurologic symptoms is a potentially catastrophic error. Metastatic involvement of endocrine organs can occasionally cause profound dysfunction, including adrenal insufficiency and hypopituitarism. Similarly, obstruction of the biliary tree or other impaired organ function may be better managed with a local therapy than with a systemic approach. Radiation as an adjunct to or instead of surgery is an important consideration for particularly symptomatic disease in long or vertebral bones, local-regional recurrences, and CNS metastases. In many cases, systemic therapy can be withheld while the patient is managed with appropriate local therapy.
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There is no evidence that aggressive local treatment, such as excision; radiation; radiofrequency ablation; or cryotherapy of metastases to the lung, liver, or other distant sites, improves survival. Although appealing, these strategies are associated with increased toxicity and cost and should be reserved for palliation.
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Selection of the systemic therapy strategy depends on the overall medical condition of the patient, the hormone receptor and HER2 status of the tumor, and clinical judgment. Because therapy of systemic disease is palliative, the potential toxicities of therapies should be balanced against expected response rates. Several variables influence the response to systemic therapy. For example, the presence of ER and PgR is a strong indication for endocrine therapy, even for patients with limited visceral (lung/liver) disease. On the other hand, patients with short disease-free intervals or rapidly progressive visceral disease (liver and lung) with end-organ dysfunction, such as lymphangitic pulmonary disease, are unlikely to respond to endocrine therapy.
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Many patients with bone-only or bone-dominant disease have a relatively indolent course. Because the goal of therapy is to maintain well-being for as long as possible, emphasis should be placed on avoiding the most hazardous complications of metastatic disease, including pathologic fracture of the axial skeleton and spinal cord compression. Under such circumstances, systemic chemotherapy has a modest effect, whereas radiation therapy may be effective for long periods. Other systemic treatments, such as strontium-89, may provide a palliative benefit without inducing objective responses. Patients with bone involvement should receive concurrent bone strengthening agents, such as bisphosphonates or the humanized monoclonal anti-RANK ligand antibody, denosumab.
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Many patients are inappropriately treated with toxic regimens into their last days of life. Often, oncologists are unwilling to have the difficult conversations that are required with patients nearing the end of life, and not uncommonly, patients and families can pressure physicians into treatments with very little survival value. Palliative care consultation and realistic assessment of treatment expectations need to be reviewed with patients and families. We urge consideration of palliative care consultations for patients who have received at least two lines of therapy for metastatic disease.
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ER-positive breast cancer will respond to endocrine therapy ~30–70% of the time. Potential endocrine therapies are summarized in Table 75-4. As in the adjuvant setting, one can choose among the SERM, tamoxifen, the AIs (anastrozole, letrozole, exemestane), or other strategies. Among the latter, the selective estrogen receptor downregulator (SERD), fulvestrant, has substantial activity. Early clinical studies with this drug were unexciting, but more recent studies have proven a very steep dose-response curve, and at higher levels (500 mg/month), it is as or more active than either tamoxifen or the AIs. Additive endocrine therapies, including treatment with progestins, and androgens, and enigmatically, pharmacologic doses of estrogens, are all active, but they may be associated with unacceptable side effects in many women. The mechanism of action of these latter therapies is unknown. Cases in which tumors shrink in response to tamoxifen withdrawal (as well as withdrawal of pharmacologic doses of estrogens) have been reported, but with the advent of so many other therapies for metastatic disease, this strategy is rarely used in modern oncology.
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The sequence of endocrine therapy is variable. Patients who respond to one endocrine therapy have at least a 50% chance of responding to a second endocrine therapy. It is not uncommon for patients to respond to two or three sequential endocrine therapies. In most postmenopausal patients, the initial endocrine therapy should be an AI rather than tamoxifen. As noted, AIs are not used in premenopausal women because their hypothalamus can respond to estrogen deprivation by producing gonadotropins that promote estrogen synthesis. Tamoxifen and fulvestrant are usually used in sequence after AI therapy. Combination endocrine therapies increase the chances of response initially, but they do not appear to increase the ultimate time to chemotherapy use or overall survival. Combinations of chemotherapy with endocrine therapy are not useful, as summarized in Table 75-4.
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At least two different targeted agents have been shown to enhance outcomes of patients with ER-positive metastatic breast cancer when combined with endocrine therapy. Addition of an inhibitor of the mammalian target of rapamycin (mTOR), everolimus, to the hormonal treatment can lead to AIs, tamoxifen, or fulvestrant improves time to progression, and this agent is now being explored as front-line therapy and in the adjuvant setting. Likewise, inhibitors of cyclin D kinase 4/6 (CDK4/6) (palbociclib, ribociclib, abemaciclib) have also been shown to substantially improve progression-free survival when combined either with an AI or fulvestrant. These agents are also being tested in the adjuvant setting. Data regarding overall survival benefits from the mTOR or CDK4/6 inhibitors are still pending, but addition of one or the other in combination with ET for women with ER-positive metastatic breast cancer is becoming the standard of care. These should not be given simultaneously but rather in sequence as appropriate, as summarized in Table 75-5.
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Unlike many other epithelial malignancies, breast cancer responds to multiple chemotherapeutic agents, including anthracyclines, alkylating agents, taxanes, and antimetabolites. Multiple combinations of these agents have been found to improve response rates somewhat, but they have had little effect on duration of response or survival. Unless patients have rapidly progressive visceral (lung, liver) metastases with end-organ dysfunction, single-agent chemotherapy, used in sequence as one drug fails going on the next, is preferable. Given the significant toxicity of most drugs, the use of a single effective agent will minimize toxicity by sparing the patient exposure to drugs that would be of little value. No method to select the drugs most efficacious for a given patient has been demonstrated to be useful.
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Most oncologists use either capecitabine or an anthracycline or a taxane for first-line chemotherapy, either in a patient with ER-positive disease that is refractory to endocrine therapy or for a patient with ER-negative breast cancer. Within these general classes, it is not clear that one particular agent (such as doxorubicin vs epirubicin or paclitaxel vs docetaxel) is preferable, and the choice has to be balanced with individual needs. Objective responses in previously treated patients may also be seen with gemcitabine, vinorelbine, and oral etoposide, as well as a new class of agents, epothilones. Platinum-based agents have become far more widely used in both the adjuvant and advanced disease settings for some breast cancers, particularly those of the “triple-negative” subtype.
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Treatment of patients with anti-HER2 metastatic breast cancer is one of the great success stories in the last 30 years of oncology. Initial use of a trastuzumab, either alone or with chemotherapy, was shown to improve response rate and survival for women with HER2-positive disease. Indeed, anecdotal reports of a few patients with remarkably sustained complete responses suggest that, on occasion, a few may be cured. Chronologically, the tyrosine kinase, lapatinib, was subsequently shown to be effective when added to chemotherapy after patients progressed on prior trastuzumab. Further, both continuation of trastuzumab after progression, in combination with the next chemotherapeutic regimen and combination of trastuzumab and lapatinib in patients who had progressed on trastuzumab are both superior to discontinuing the trastuzumab.
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For patients who have become refractory to trastuzumab–based therapy, and more recently even in the upfront setting, other therapies have remarkably high activity. A novel antibody drug conjugate (ADC) that links trastuzumab to a cytotoxic agent, ado-trastuzumab emtansine, is active even in patients who have progressed on trastuzumab. More recently, the combination of chemotherapy and trastuzumab and pertuzumab has been shown to result in prolonged overall survival compared to trastuzumab alone. These recommendations are summarized in Table 75-6.
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Bevacizumab is an agent that targets the vascular endothelial growth factor (VEGF). Bevacizumab with paclitaxel or other chemotherapeutic agents modestly increases the response rate and response duration to paclitaxel, but without improvement in overall survival and with occasional major toxicities. After initial excitement and FDA approval, its use has been mostly abandoned in breast cancer. As in the metastatic setting, trials are ongoing testing the value of PARP (poly-ADP ribose polymerase) inhibitors in patients with known germline BRCA1/2 mutations or cancers that have BRCA-like biologies. The excitement over immune check-point inhibitors has spread to metastatic breast cancer, especially of the triple-negative subtype, but at present there are no agents approved for it.
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Breast cancer is ~1/150th as frequent in men as in women; ~2000 men developed breast cancer annually in the United States. Risk factors include inherited, deleterious SNPs in BRCA2, as well as Klinefelter’s syndrome. Men with Klinefelter’s syndrome have two or more copies of the X chromosome and have lower levels of and higher levels of estrogen. Other conditions of hyperestrogenism, such as in hepatic failure, are also associated with higher risk of male breast cancers. However, the vast majority of men who present with breast cancer have none of these conditions.
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Breast cancer usually presents in men as a unilateral lump in the breast and is frequently not diagnosed promptly. Given the small amount of soft tissue and the unexpected nature of the problem, locally advanced presentations are somewhat more common. Although gynecomastia may initially be unilateral or asymmetric, any unilateral mass in a man aged >40 years should receive a careful workup including biopsy. On the other hand, bilateral symmetric breast development rarely represents breast cancer and is almost invariably due to endocrine disease or a drug effect. It should be kept in mind, nevertheless, that the risk of cancer is much greater in men with gynecomastia; in such men, gross asymmetry of the breasts should arouse suspicion of cancer.
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Approximately 90% of male breast cancers contain ERs, and it behaves similarly to that in a postmenopausal woman. When matched to female breast cancer by age and stage, its overall prognosis is identical. Male breast cancer is best managed by mastectomy and axillary lymph node dissection or SLNB, although some men prefer breast-conserving therapy. Patients with locally advanced disease or positive nodes should also be treated with irradiation, and ~60% of cases with metastatic disease respond to endocrine therapy. Tamoxifen is usually the agent of choice, and it is unknown if the AIs are effective in men. No randomized studies have evaluated adjuvant therapy for male breast cancer. Two historic experiences suggest that the disease responds well to adjuvant systemic therapy, and, if not medically contraindicated, the same criteria for the use of adjuvant therapy in women should be applied to men.
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The sites of relapse and spectrum of response to chemotherapeutic drugs are virtually identical for breast cancers in either sex.