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Surgery_Schwartz. Breast Cancer Study Group (IBCSG) 23-01 trial was similar in design to Z0011 but enrolled only patients with micrometastases in the SLNs. Patients with SLN micrometastases were randomized to ALND vs. no further sur-gery. Unlike Z0011, the 23-01 trial did not exclude patients treated with mastectomy. Approximately 9% of patients ran-domized to each study arm underwent mastectomy. The inves-tigators published the primary and secondary endpoints of the trial showing no differences in OS or local-regional recurrence between the study arms.254 However, as with the Z0011 trial, some concerns have been raised regarding the 23-01 study. For example, in the statistics on the primary endpoint, local recur-rence included contralateral breast cancer and other tumor types as events. No hypothesis was presented as to why the differ-ence in axillary surgery should impact on either of these events. Including these events therefore reduced the power of the study to show a statistical difference


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Surgery_Schwartz. was presented as to why the differ-ence in axillary surgery should impact on either of these events. Including these events therefore reduced the power of the study to show a statistical difference between treatment arms. There is also concern that the study appears underpowered to show a meaningful difference in overall survival.Most pathology laboratories perform a more detailed anal-ysis of the SLN than is routinely done for axillary nodes recov-ered from a levels I and II dissection. This can include examining thin sections of the node with step sectioning at multiple levels through the paraffin blocks or performing immunohistochemi-cal staining of the SLN for cytokeratin or a combination of these techniques. The results of ACOSOG Z0010 and NSABP B-32 showed no clinically meaningful difference in survival based on detection of occult metastases in the SLNs using immu-nohistochemical staining and do not support the routine use in SLN processing. The type of intraoperative


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Surgery_Schwartz. difference in survival based on detection of occult metastases in the SLNs using immu-nohistochemical staining and do not support the routine use in SLN processing. The type of intraoperative assessment of SLNs also varies for different clinicians and pathology labo-ratories. Some centers prefer to use touch preparation cyto-logic analysis of the SLNs, whereas others use frozen-section analysis, and the sensitivity and specificity of these assays vary considerably. The GeneSearch Breast Lymph Node Assay is a real-time reverse-transcriptase polymerase chain reaction assay that detects breast tumor cell metastasis in lymph nodes through the identification of the gene expression markers mammaglobin and cytokeratin 19. These markers are present in higher lev-els in breast tissue and not in nodal tissue (cell type-specific messenger RNA). The GeneSearch breast lymph node assay generates expression data for genes of interest, which are then evaluated against predetermined criteria to


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Surgery_Schwartz. in nodal tissue (cell type-specific messenger RNA). The GeneSearch breast lymph node assay generates expression data for genes of interest, which are then evaluated against predetermined criteria to provide a qualitative (positive/negative) result. The assay is designed to detect foci that correspond to metastases that are seen with examination by standard hematoxylin and eosin staining and measure >0.2 mm. The GeneSearch assay results have been compared with per-manent-section histologic analysis and frozen-section analy-sis of sentinel nodes in a prospective trial, and the assay was approved by the FDA for the intraoperative assessment of senti-nel nodes.255 When a positive node is identified intraoperatively by touch preparation, frozen-section analysis, or GeneSearch assay, the surgeon can proceed with immediate ALND. With the findings of ACOSOG Z0011 that there is not a survival ben-efit to the use of ALND in selected patients, many surgeons have abandoned the intraoperative


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Surgery_Schwartz. can proceed with immediate ALND. With the findings of ACOSOG Z0011 that there is not a survival ben-efit to the use of ALND in selected patients, many surgeons have abandoned the intraoperative evaluation of SLNs. There are a number of nomograms and predictive models designed to determine which patients with a positive SLN are at risk for har-boring additional positive non-SLNs in the axilla. These tools can be helpful in determining the likelihood of additional disease in the axilla and may be used clinically to counsel patients.256In patients who present with axillary lymphadenopa-thy that is confirmed to be metastatic disease on FNA or core biopsy, SLN dissection is not necessary, and patients can pro-ceed directly to ALND or be considered for preoperative sys-temic therapy (see “Neoadjuvant [Preoperative] Chemotherapy” under “Nonsurgical Breast Cancer Therapies”). Initially there was controversy about the suitability of SLN dissection in women with larger primary tumors (T3) and


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Surgery_Schwartz. [Preoperative] Chemotherapy” under “Nonsurgical Breast Cancer Therapies”). Initially there was controversy about the suitability of SLN dissection in women with larger primary tumors (T3) and those treated with neoadjuvant chemotherapy. The American Society of Clini-cal Oncology has included SLN dissection is its guidelines as appropriate for axillary staging in these patients.257,258 If an SLN cannot be identified, then ALND is generally performed for appropriate staging. However, this is not universally accepted, and there are as yet no randomized studies that have assessed how a patient with a locally advanced cancer at presentation should be treated if SLN dissection reveals no metastases or micrometastases after neoadjuvant therapy.The ASCO guidelines suggest that adjuvant chemo-therapy should be considered for patients with positive lymph nodes, ER-negative disease, HER2-positive disease, Adju-vant! Online mortality greater than 10%, grade 3 node-neg-ative tumors >5 mm,


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Surgery_Schwartz. should be considered for patients with positive lymph nodes, ER-negative disease, HER2-positive disease, Adju-vant! Online mortality greater than 10%, grade 3 node-neg-ative tumors >5 mm, triple-negative tumors, lymphovascular invasion, or estimated distant relapse risk of greater than 15% at 10 years based on the 21 gene recurrence score assay.259 Adjuvant endocrine therapy is considered for women with hormone receptor-positive cancers, and an aromatase inhibi-tor is recommended if the patient is postmenopausal. HER2/neu status is determined for all patients with newly diagnosed invasive breast cancer and when positive, should be used to guide systemic therapy recommendations. The FDA approved trastuzumab in November 2006 for use as part of a treatment regimen containing doxorubicin, cyclophosphamide, and pacli-taxel for treatment of HER2/neu-positive, node-positive breast cancer.181,183 Subsequently, the BCIRG 006 study reported that giving trastuzumab concurrently with docetaxel


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Surgery_Schwartz. and pacli-taxel for treatment of HER2/neu-positive, node-positive breast cancer.181,183 Subsequently, the BCIRG 006 study reported that giving trastuzumab concurrently with docetaxel and carbopla-tin appeared as effective as giving trastuzumab following an anthracycline containing regimen.182,185 In addition to trastu-zumab, pertuzumab has also recently been FDA approved for adjuvant use in patients with HER2 amplified breast cancers with high risk of recurrence.Advanced Local-Regional Breast Cancer (Stage IIIA or IIIB)Women with stage IIIA and IIIB breast cancer have advanced local-regional breast cancer but have no clinically detected distant metastases (Fig. 17-30).260 In an effort to provide opti-mal local-regional disease-free survival as well as distant dis-ease-free survival for these women, surgery is integrated with radiation therapy and chemotherapy (Fig. 17-31). However, it should be noted that these patients have an increased risk of distant metastasis that is often


Surgery_Schwartz

Surgery_Schwartz. for these women, surgery is integrated with radiation therapy and chemotherapy (Fig. 17-31). However, it should be noted that these patients have an increased risk of distant metastasis that is often highlighted by radiological evidence when staging PET or CT and bone scans are per-formed. Thus, the paradigm for small screen detected cancers where cure can be expected in >90% of patients, often by local treatment alone, is not appropriate for patients with locally advanced disease.Preoperative (also known as neoadjuvant) chemotherapy should be considered in the initial management of patients with Brunicardi_Ch17_p0541-p0612.indd 58501/03/19 5:05 PM 586SPECIFIC CONSIDERATIONSPART IIFigure 17-30. Locally advanced breast cancer. A. Mammography of the right breast reveals a large tumor with enlarged axillary lymph nodes. B. Imaging of the left breast is normal. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital,


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Surgery_Schwartz. with enlarged axillary lymph nodes. B. Imaging of the left breast is normal. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)Figure 17-31. Treatment pathways for stage IIIA and stage IIIB breast cancer.locally advanced stage III breast cancer, especially those with estrogen receptor negative tumors. Chemotherapy is used to maximize distant disease-free survival, whereas radiation ther-apy is used to maximize local-regional control and disease-free survival.In selected patients with stage IIIA cancer, preoperative chemotherapy can reduce the size of the primary cancer and permit breast-conserving surgery. Investigators from the MD Anderson Cancer Center reported that low local-regional fail-ure rates could be achieved in selected patients with stage III disease treated with preoperative chemotherapy followed by breast-conserving surgery and radiation.261 The 5-year actuarial ipsilateral breast tumor


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Surgery_Schwartz. be achieved in selected patients with stage III disease treated with preoperative chemotherapy followed by breast-conserving surgery and radiation.261 The 5-year actuarial ipsilateral breast tumor recurrence-free survival rates in this study were 95%. They noted that the ipsilateral breast tumor recurrence rates increased when patients had clinical N2 or N3 disease, >2 cm of residual disease in the breast at surgery, a pattern of multifocal residual disease in the breast at surgery, and lymphovascular space invasion in the primary tumor. This study demonstrated that breast-conserving surgery can be used for appropriately selected patients with locally advanced breast cancer who achieve a good response with preoperative che-motherapy. However, the Oxford overview of all randomized studies of neoadjuvant therapy (vs. adjuvant therapy) reported a hazard ratio of 1.5 (i.e., 50% increase) in local recurrence rates. ABBrunicardi_Ch17_p0541-p0612.indd 58601/03/19 5:05 PM 587THE


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Surgery_Schwartz. studies of neoadjuvant therapy (vs. adjuvant therapy) reported a hazard ratio of 1.5 (i.e., 50% increase) in local recurrence rates. ABBrunicardi_Ch17_p0541-p0612.indd 58601/03/19 5:05 PM 587THE BREASTCHAPTER 17A meta-analysis reported a hazard ratio of 1.3.262 These stud-ies included some patients treated with radiation therapy alone without resection of the primary tumor bed, which results in higher local failure rates. These findings are important in view of the previous findings that the avoidance of recurrence in a conserved breast avoids about one breast cancer death over the next 15 years for every four such recurrences avoided.12 The German Breast Cancer Group recently reported their local recurrence rate in 5535 patients in seven studies. With a median of 46 months (range 1–127) follow-up the local recurrence rates ranged from 7.6% to 19.5% for T1-T4 tumors and from 6.4% to 17.9% for N0-N3 tumors treated with neoadjuvant therapy.238 For patients with stage IIIA disease


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Surgery_Schwartz. follow-up the local recurrence rates ranged from 7.6% to 19.5% for T1-T4 tumors and from 6.4% to 17.9% for N0-N3 tumors treated with neoadjuvant therapy.238 For patients with stage IIIA disease who experience minimal response to chemotherapy and for patients with stage IIIB breast cancer, preoperative chemotherapy can decrease the local-regional cancer burden enough to permit subsequent modified radical mastectomy to establish local-regional con-trol. In both stages IIIA and IIIB disease, surgery is followed by adjuvant radiation therapy. However there is a small percent-age of patients who experience progression of disease during neoadjuvant therapy, and therefore the surgeon should review patients with the oncologist at regular points during the neoad-juvant regimen.For selected clinically indolent, ER-positive, locally advanced tumors, primary endocrine therapy may be considered, especially if the patient has other comorbid conditions. A series of 195 patients with ER-positive,


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Surgery_Schwartz. indolent, ER-positive, locally advanced tumors, primary endocrine therapy may be considered, especially if the patient has other comorbid conditions. A series of 195 patients with ER-positive, locally advanced breast cancer treated by endocrine therapy—median age 69 years, median tumor size 6 cm, median follow-up 61 months—reported a 5-year overall survival of 76%, a breast cancer–specific sur-vival of 86%, and a metastasis-free survival of 77%. The median time to an alternative treatment was 48 months.263 Given that this was a 20-year series, the number of such patients is small but should be considered when the clinician is discussing treat-ment options. Results from the ACOSOG Z1031 trial suggest that neoadjuvant endocrine therapy is a good option for tumor downstaging in patients with strongly ER-positive tumors. The preoperative endocrine prognostic index (PEPI score) can be calculated based on pathologic findings from surgery following neoadjuvant endocrine therapy. This can


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Surgery_Schwartz. strongly ER-positive tumors. The preoperative endocrine prognostic index (PEPI score) can be calculated based on pathologic findings from surgery following neoadjuvant endocrine therapy. This can help guide decision-making regarding the need for systemic chemotherapy in this patient population.264,265Internal Mammary Lymph NodesMetastatic disease to internal mammary lymph nodes may be occult, may be evident on chest radiograph or CT scan, or may present as a painless parasternal mass with or without skin involvement. There is no consensus regarding the need for internal mammary lymph node radiation therapy in women who are at increased risk for occult involvement (cancers involving the medial aspect of the breast, axillary lymph node involve-ment) but who show no signs of internal mammary lymph node involvement. Systemic chemotherapy and radiation therapy are indicated in the treatment of grossly involved internal mammary lymph nodes.Distant Metastases (Stage IV)Treatment for stage IV


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Surgery_Schwartz. lymph node involvement. Systemic chemotherapy and radiation therapy are indicated in the treatment of grossly involved internal mammary lymph nodes.Distant Metastases (Stage IV)Treatment for stage IV breast cancer is not curative but may prolong survival and enhance a woman’s quality of life.266 Endocrine therapies that are associated with minimal toxicity are preferred to cytotoxic chemotherapy in ER-positive disease. Appropriate candidates for initial endocrine therapy include women with hormone receptor-positive cancers who do not have immediately life threatening disease (or “visceral crisis”). This includes not only women with bone or soft tissue metastases but also women with limited visceral metastases. Symptoms per se (e.g., breathlessness) are not in themselves an indication for chemotherapy. For example, breathlessness due to a pleural effusion can be treated with percutaneous drainage, and if the breathlessness is relieved, the patient should be commenced on endocrine


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Surgery_Schwartz. for chemotherapy. For example, breathlessness due to a pleural effusion can be treated with percutaneous drainage, and if the breathlessness is relieved, the patient should be commenced on endocrine therapy; if the breathlessness is due to lymphangitic spread, then chemotherapy would be the treatment of choice. The same approach should be taken to other symptoms such as pain. Systemic chemotherapy is indicated for women with hormone receptor-negative cancers, “visceral crisis,” and hormone-refractory metastases. Women with stage IV breast cancer may develop anatomically localized problems that will benefit from individualized surgical or radiation treatment, such as brain metastases, pleural effusion, pericardial effusion, biliary obstruction, ureteral obstruction, impending or existing pathologic fracture of a long bone, spinal cord compression, and painful bone or soft tissue metastases. Bisphosphonates or anti-RANKL (receptor activator of nuclear factor kappa-B ligand) agent,


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Surgery_Schwartz. pathologic fracture of a long bone, spinal cord compression, and painful bone or soft tissue metastases. Bisphosphonates or anti-RANKL (receptor activator of nuclear factor kappa-B ligand) agent, denosumab, which may be given in addition to chemo-therapy or endocrine therapy, should be considered in women with bone metastases. Whether to perform surgical resection of the local-regional disease in women with stage IV breast cancer has been debated after several reports have suggested that women who undergo resection of the primary tumor have improved survival over those who do not. Khan and associates used the National Cancer Data Base to identify patterns of treat-ment in women with metastatic breast cancer and found that those who had surgical resection with negative margins had a better prognosis than those women who did not have surgical therapy.267 Gnerlich et al reported similar findings using the SEER database, and there have been several reports subsequent to this study from


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Surgery_Schwartz. prognosis than those women who did not have surgical therapy.267 Gnerlich et al reported similar findings using the SEER database, and there have been several reports subsequent to this study from single institutions that have confirmed these findings.268 Some have suggested that the finding of improved survival is due to selection bias and that local therapy should be reserved for palliation of symptoms. A randomized trial through ECOG (E2108) was designed to address this question.269 The surgical management of patients with stage IV disease should be addressed by obtaining multidisciplinary input and by con-sidering the treatment goals of each individual patient and the patient’s treating physicians.Local-Regional RecurrenceWomen with local-regional recurrence of breast cancer may be separated into two groups: those who have had mastec-tomy and those who have had lumpectomy. Women treated previously with mastectomy undergo surgical resection of the local-regional recurrence and


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Surgery_Schwartz. separated into two groups: those who have had mastec-tomy and those who have had lumpectomy. Women treated previously with mastectomy undergo surgical resection of the local-regional recurrence and appropriate reconstruction. Chemotherapy and antiestrogen therapy are considered, and adjuvant radiation therapy is given if the chest wall has not pre-viously received radiation therapy or if the radiation oncologist feels that given the time from previous treatment there is scope for further radiation therapy, particularly if this is palliative. Women treated previously with a breast-conservation procedure undergo a mastectomy and appropriate reconstruction. Chemo-therapy and antiestrogen therapy are considered depending of the hormone receptor status and HER2 status of the tumor.Breast Cancer PrognosisSurvival rates for women diagnosed with breast cancer in the United States can be obtained from the SEER Program of the Brunicardi_Ch17_p0541-p0612.indd 58701/03/19 5:05 PM 588SPECIFIC


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Surgery_Schwartz. PrognosisSurvival rates for women diagnosed with breast cancer in the United States can be obtained from the SEER Program of the Brunicardi_Ch17_p0541-p0612.indd 58701/03/19 5:05 PM 588SPECIFIC CONSIDERATIONSPART IIABFigure 17-32. Lesion to be targeted for excisional biopsy. A. Craniocaudal view of the left breast demonstrating 2 lesions (arrows) to be targeted for needle localization and excision. B. Oblique view demonstrating target lesions. (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)National Cancer Institute. Data have been collected since 1973 and are updated at regular intervals. The overall 5-year rela-tive survival for breast cancer patients from the time period of 2003 to 2009 from 18 SEER geographic areas was 89.2%.270 The 5-year relative survival by race was reported to be 90.4% for white women and 78.7% for black women. The 5-year sur-vival rate for patients with localized disease


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Surgery_Schwartz. geographic areas was 89.2%.270 The 5-year relative survival by race was reported to be 90.4% for white women and 78.7% for black women. The 5-year sur-vival rate for patients with localized disease (61% of patients) is 98.6%; for patients with regional disease (32% of patients), 84.4%; and for patients with distant metastatic disease (5% of patients), 24.3%. Breast cancer survival has significantly increased over the past two decades due to improvements in screening and local and systemic therapies. Data from the American College of Surgeons National Cancer Data Base can also be accessed; this data reports survival based on stage of disease at presentation using the AJCC staging system.SURGICAL TECHNIQUES IN BREAST CANCER THERAPYExcisional Biopsy With Needle LocalizationExcisional biopsy implies complete removal of a breast lesion with a margin of normal-appearing breast tissue. In the past, surgeons would obtain prior consent from the patient, allow-ing mastectomy if the initial


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Surgery_Schwartz. implies complete removal of a breast lesion with a margin of normal-appearing breast tissue. In the past, surgeons would obtain prior consent from the patient, allow-ing mastectomy if the initial biopsy results confirmed cancer. Today it is important to consider the options for local therapy (lumpectomy vs. mastectomy with or without reconstruction) and the need for nodal assessment with SLN dissection. Needle-core biopsy is the preferred diagnostic method, and excisional biopsy should be reserved for those cases in which the needle biopsy results are discordant with the imaging findings or clini-cal examination (Fig. 17-32). In general, circumareolar incisions can be used to access lesions that are subareolar or within a short distance of the nipple-areolar complex. Elsewhere in the breast, incisions can be placed along the lines of tension in the skin that are generally concentric with the nipple-areola complex. In the lower half of the breast, the use of radial incisions typically


Surgery_Schwartz

Surgery_Schwartz. incisions can be placed along the lines of tension in the skin that are generally concentric with the nipple-areola complex. In the lower half of the breast, the use of radial incisions typically provides the best outcome. When the tumor is quite distant from the central breast, the biopsy incision can be excised separately from the primary mastectomy incision, should a mastectomy be required. Radial incisions in the upper half of the breast are not recommended because of possible scar contracture resulting in displacement of the ipsilateral nipple-areola complex. Similarly, curvilinear incisions in the lower half of the breast may displace the nipple-areolar complex downward.After excision of a suspicious breast lesion, the specimen should be X-rayed to confirm that the lesion has been excised with appropriate margins. The biopsy tissue specimen is ori-entated for the pathologist using sutures, clips, or dyes. Addi-tional margins (superior, inferior, medial, lateral, superficial, and


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Surgery_Schwartz. with appropriate margins. The biopsy tissue specimen is ori-entated for the pathologist using sutures, clips, or dyes. Addi-tional margins (superior, inferior, medial, lateral, superficial, and deep) may be taken from the surgical bed if the specimen X-ray shows the lesion is close to one or more margins. Some surgeons also take additional shavings from the margins as one approach to confirm complete excision of the suspicious lesion. Electrocautery or absorbable ligatures are used to achieve wound hemostasis. Cosmesis may be facilitated by approxima-tion of the surgical defect using 3-0 absorbable sutures. A run-ning subcuticular closure of the skin using 4-0 or 5-0 absorbable monofilament sutures is performed. Wound drainage is usually not required.Excisional biopsy with needle or seed localization requires a preoperative visit to the mammography suite for placement of a localization wire or a radioactive or magnetic seed that can be detected intraoperatively with a handheld probe.


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Surgery_Schwartz. localization requires a preoperative visit to the mammography suite for placement of a localization wire or a radioactive or magnetic seed that can be detected intraoperatively with a handheld probe. The lesion can also be targeted by sonography in the imaging suite or in the operating room. The lesion to be excised is accurately localized by mammography, and the tip of a thin wire hook or a seed is positioned close to the lesion (Fig. 17-33). Using the wire hook as a guide, or detection of the seed with a handheld probe, the surgeon subsequently excises the suspicious breast lesion while removing a margin of normal-appearing breast tissue. Before the patient leaves the operating room, specimen radiography is performed to confirm complete excision of the suspicious lesion (Fig. 17-34).Brunicardi_Ch17_p0541-p0612.indd 58801/03/19 5:05 PM 589THE BREASTCHAPTER 17Figure 17-33. Wire localization procedure. Mammographic images of hookwire in place targeting lesions for excision in the


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Surgery_Schwartz. 58801/03/19 5:05 PM 589THE BREASTCHAPTER 17Figure 17-33. Wire localization procedure. Mammographic images of hookwire in place targeting lesions for excision in the left breast (A) and the right breast (B). (Used with permission from Dr. Anne Turnbull, Consultant Radiologist/Director of Breast Screen-ing, Royal Derby Hospital, Derby, UK.)Figure 17-34. Specimen mammography. Specimen mam-mograms demonstrating excision of targeted (A) density, (B) calcifications, and (C) spiculated mass seen on preoperative imaging. (Used with permission from Dr. Anne Turnbull, Con-sultant Radiologist/Director of Breast Screening, Royal Derby Hospital, Derby, UK.)ABCABBrunicardi_Ch17_p0541-p0612.indd 58901/03/19 5:05 PM 590SPECIFIC CONSIDERATIONSPART IISentinel Lymph Node DissectionSentinel lymph node (SLN) dissection is primarily used to assess the regional lymph nodes in women with early breast cancers who are clinically node-negative by physical examina-tion and imaging studies.271-279 This


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Surgery_Schwartz. (SLN) dissection is primarily used to assess the regional lymph nodes in women with early breast cancers who are clinically node-negative by physical examina-tion and imaging studies.271-279 This method also is accurate in women with larger tumors (T3 N0), but nearly 75% of these women will prove to have axillary lymph node metastases on histologic examination, and wherever possible it is better to identify them preoperatively as this will allow a definitive procedure for known axillary disease. SLN dissection has also been reported to be accurate for staging of the axilla after chemotherapy in women with clinically node-negative dis-ease at initial presentation.280,281 Tan et al in a review and meta-analysis of 449 cases of SLN biopsy in clinically lymph node-negative disease reported a sensitivity of 93%, giving a false negative rate of 7% with a negative predictive value of 94% and an overall accuracy of 95%.282 Clinical situations where SLN dissection is not recommended include


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Surgery_Schwartz. a sensitivity of 93%, giving a false negative rate of 7% with a negative predictive value of 94% and an overall accuracy of 95%.282 Clinical situations where SLN dissection is not recommended include patients with inflammatory breast cancers, those with biopsy proven metasta-sis, DCIS without mastectomy, or prior axillary surgery. Although limited data are available, SLN dissection appears to be safe in pregnancy when performed with radioisotope alone.Evidence from large prospective studies suggests that the combination of intraoperative gamma probe detection of radioactive colloid and intraoperative visualization of blue dye (isosulfan blue dye or methylene blue) is more accurate for identification of SLNs than the use of either agent alone. Some surgeons use preoperative lymphoscintigraphy, although it is not required for identification of the SLNs. On the day before surgery, or the day of surgery, the radioactive colloid is injected either in the breast parenchyma around the


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Surgery_Schwartz. although it is not required for identification of the SLNs. On the day before surgery, or the day of surgery, the radioactive colloid is injected either in the breast parenchyma around the primary tumor or prior biopsy site, into the subareolar region, or subdermally in proximity to the primary tumor site. With a 25-gauge needle, 0.5 mCi of 0.2-μm technetium 99m–labeled sulfur colloid is injected for same-day surgery, or a higher dose of 2.5 mCi of technetium-labeled sulfur colloid is administered when the isotope is to be injected on the day before surgery. Subdermal injections are given in proximity to the cancer site or in the subareolar location. Later, in the operating room, 3 to 5 mL of blue dye is injected either in the breast parenchyma or in the subareolar location. It is not recommended that the blue dye be used in a subdermal injection because this can result in tattoo-ing of the skin (isosulfan blue dye) or skin necrosis (methylene blue). For nonpalpable cancers, the


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Surgery_Schwartz. recommended that the blue dye be used in a subdermal injection because this can result in tattoo-ing of the skin (isosulfan blue dye) or skin necrosis (methylene blue). For nonpalpable cancers, the injection of the technetium-labeled sulfur colloid solution can be guided by ultrasound or by mammographic guidance. In women who have undergone previous excisional biopsy, the injections are made in the breast parenchyma around the biopsy cavity but not into the cavity itself. Women are told preoperatively that the isosulfan blue dye injection will cause a change in the color of their urine and that there is a very small risk of allergic reaction to the dye (1 in 10,000). Anaphylactic reactions have been documented, and some groups administer a regimen of antihistamine, steroids, and a histamine H-2 receptor antagonist preoperatively as a prophylactic regimen to prevent allergic reactions. The use of radioactive colloid is safe, and radiation exposure is very low. Sentinel node dissection


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Surgery_Schwartz. H-2 receptor antagonist preoperatively as a prophylactic regimen to prevent allergic reactions. The use of radioactive colloid is safe, and radiation exposure is very low. Sentinel node dissection can be performed in pregnancy with the radioactive colloid without the use of blue dye.A hand-held gamma counter is used to transcutaneously identify the location of the SLN. This can help to guide place-ment of the incision. A 3to 4-cm incision is made in line with that used for an axillary dissection, which is a curved transverse 9incision in the lower axilla just below the hairline. After dis-secting through the subcutaneous tissue, the surgeon dissects through the axillary fascia, being mindful to identify blue lym-phatic channels. Following these channels can lead directly to the SLN and limit the amount of dissection through the axillary tissues. The gamma probe is used to facilitate the dissection and to pinpoint the location of the SLN. As the dissection continues, the signal from


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Surgery_Schwartz. limit the amount of dissection through the axillary tissues. The gamma probe is used to facilitate the dissection and to pinpoint the location of the SLN. As the dissection continues, the signal from the probe increases in intensity as the SLN is approached. The SLN also is identified by visualization of blue dye in the afferent lymph vessel and in the lymph node itself. Before the SLN is removed, a 10-second in vivo radioactivity count is obtained. After removal of the SLN, a 10-second ex vivo radioactive count is obtained, and the node is then sent to the pathology laboratory for either permanentor frozen-section analysis. The lowest false-negative rates for SLN dissection have been obtained when all blue lymph nodes and all lymph nodes with counts >10% of the 10-second ex vivo count of the SLN are harvested (“10% rule”). Based on this, the gamma counter is used before closing the axillary wound to measure residual radioactivity in the surgical bed. A search is made for additional


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Surgery_Schwartz. the SLN are harvested (“10% rule”). Based on this, the gamma counter is used before closing the axillary wound to measure residual radioactivity in the surgical bed. A search is made for additional SLNs if the counts remain high. This procedure is repeated until residual radioactivity in the surgical bed is less than 10% of the 10-second ex vivo count of the most radioac-tive SLN and all blue nodes have been removed. Studies have demonstrated that 98% of all positive SLNs will be recovered with the removal of four SLNs; therefore, it is not necessary to remove greater than four SLNs for accurate staging of the axilla.Results from the NSABP B-32 trial showed that the false-negative rate for SLN dissection is influenced by tumor loca-tion, type of diagnostic biopsy, and number of SLNs removed at surgery.243 The authors reported that tumors located in the lateral breast were more likely to have a false-negative SLN. This may be explained by difficulty in discriminating the hot spot in


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Surgery_Schwartz. at surgery.243 The authors reported that tumors located in the lateral breast were more likely to have a false-negative SLN. This may be explained by difficulty in discriminating the hot spot in the axilla when the radioisotope has been injected at the primary tumor site in the lateral breast. Those patients who had undergone an excisional biopsy before the SLN procedure were significantly more likely to have a false-negative SLN. This report further confirms that surgeons should use needle biopsy for diagnosis whenever possible and reserve excisional biopsy for the rare situations in which needle biopsy findings are non-diagnostic or discordant. Finally, removal of a larger number of SLNs at surgery appears to reduce the false-negative rate. In B-32, the false-negative rate was reduced from 17.7% to 10% when two SLNs were recovered and to 6.9% when three SLNs were removed. Yi and associates reported that the number of SLNs that need to be removed for accurate staging is influenced by


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Surgery_Schwartz. 17.7% to 10% when two SLNs were recovered and to 6.9% when three SLNs were removed. Yi and associates reported that the number of SLNs that need to be removed for accurate staging is influenced by individual patient and primary tumor factors.283In the B-32 trial, SLNs were identified outside the levels I and II axillary nodes in 1.4% of cases. This was significantly influenced by the site of radioisotope injection. When a subareo-lar or periareolar injection site was used, there were no instances of SLNs identified outside the level I or II axilla, compared with a rate of 20% when a peritumoral injection was used. This sup-ports the overall concept that the SLN is the first site of drain-age from the lymphatic vessels of the primary tumor. Although many patients will have similar drainage patterns from injec-tions given at the primary tumor site and at the subareolar plexus, some patients will have extra-axillary drainage, either alone or in combination with axillary node drainage,


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Surgery_Schwartz. patterns from injec-tions given at the primary tumor site and at the subareolar plexus, some patients will have extra-axillary drainage, either alone or in combination with axillary node drainage, and this is best assessed with a peritumoral injection of the radioiso-tope. Kong et al reported that internal mammary node drain-age on preoperative lymphoscintigraphy was associated with Brunicardi_Ch17_p0541-p0612.indd 59001/03/19 5:05 PM 591THE BREASTCHAPTER 17worse distant disease-free survival in early-stage breast cancer patients.284Breast ConservationBreast conservation involves resection of the primary breast cancer with a margin of normal-appearing breast tissue, adju-vant radiation therapy, and assessment of regional lymph node status.285,286 Resection of the primary breast cancer is alterna-tively called segmental mastectomy, lumpectomy, partial mas-tectomy, wide local excision, and tylectomy. For many women with stage I or II breast cancer, breast-conserving therapy (BCT) is


Surgery_Schwartz

Surgery_Schwartz. is alterna-tively called segmental mastectomy, lumpectomy, partial mas-tectomy, wide local excision, and tylectomy. For many women with stage I or II breast cancer, breast-conserving therapy (BCT) is preferable to total mastectomy because BCT produces survival rates equivalent to those after total mastectomy while preserv-ing the breast.287 Six prospective randomized trials have shown that overall and disease-free survival rates are similar with BCT and mastectomy; however, three of the studies showed higher local-regional failure rates in patients undergoing BCT. In two of these studies, there were no clear criteria for histologically negative margins.285-287 Data from the EBCTCG meta-analysis revealed that the addition of radiation reduces recurrence by half and improves survival at year 15 by about a sixth.288 When all of this information is taken together, BCT is considered to be oncologically equivalent to mastectomy.In addition to being equivalent to mastectomy in terms of


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Surgery_Schwartz. year 15 by about a sixth.288 When all of this information is taken together, BCT is considered to be oncologically equivalent to mastectomy.In addition to being equivalent to mastectomy in terms of oncologic safety, BCT appears to offer advantages over mas-tectomy with regard to quality of life and aesthetic outcomes. BCT allows for preservation of breast shape and skin as well as preservation of sensation, and it provides an overall psychologic advantage associated with breast preservation.Breast conservation surgery is currently the standard treat-ment for women with stage 0, I, or II invasive breast cancer. Women with DCIS require only resection of the primary cancer and adjuvant radiation therapy without assessment of regional lymph nodes. When a lumpectomy is performed, a curvilinear incision lying concentric to the nipple-areola complex is made in the skin overlying the breast cancer when the tumor is in the upper aspect of the breast. Radial incisions are preferred when the


Surgery_Schwartz

Surgery_Schwartz. incision lying concentric to the nipple-areola complex is made in the skin overlying the breast cancer when the tumor is in the upper aspect of the breast. Radial incisions are preferred when the tumor is in the lower aspect of the breast. Skin excision is not necessary unless there is direct involvement of the overlying skin by the primary tumor. The breast cancer is removed with an envelope of normal-appearing breast tissue that is adequate to achieve a cancer-free margin. Significant controversy has existed on the appropriate margin width for BCT.260 However, recently the SSO and ASTRO developed a consensus statement, supported by data from a systematic review data, encouraging “no tumor on ink” to be the standard definition of a negative margin for invasive stages I and II breast cancer in patients who undergo breast conserving surgery with whole-breast irradiation. The meta-analysis found that increasing the margin width does not affect local recurrence rates as long as the inked


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Surgery_Schwartz. in patients who undergo breast conserving surgery with whole-breast irradiation. The meta-analysis found that increasing the margin width does not affect local recurrence rates as long as the inked or transected margin is microscopically negative.289-292 Specimen X-ray should routinely be performed to confirm the lesion has been excised. Specimen orientation is performed by the surgeon. Additional margins from the surgical bed are taken as needed to provide a histologically negative margin. Requests for determination of ER, PR, and HER2 status are conveyed to the pathologist.It is the surgeon’s responsibility to ensure complete removal of cancer in the breast. Ensuring surgical margins that are free of breast cancer will minimize the chances of local recurrence and will enhance cure rates. If negative margins are not obtainable with reexcision, mastectomy is required. SLN is performed before removal of the primary breast tumor. When indicated, intraoperative assessment of the sentinel


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Surgery_Schwartz. If negative margins are not obtainable with reexcision, mastectomy is required. SLN is performed before removal of the primary breast tumor. When indicated, intraoperative assessment of the sentinel node can proceed while the segmental mastectomy is being performed.The use of oncoplastic surgery can be entertained at the time of segmental mastectomy or at a later time to improve the overall aesthetic outcome. The use of oncoplastic techniques range from a simple reshaping of breast tissue to local tissue rearrangement to the use of pedicled flaps or breast reduction techniques. The overall goal is to achieve the best possible aes-thetic result. In determining which patients are candidates for oncoplastic breast surgery, several factors should be considered, including the extent of the resection of breast tissue necessary to achieve negative margins, the location of the primary tumor within the breast, and the size of the patient’s breast and body habitus. Oncoplastic techniques are of


Surgery_Schwartz

Surgery_Schwartz. of breast tissue necessary to achieve negative margins, the location of the primary tumor within the breast, and the size of the patient’s breast and body habitus. Oncoplastic techniques are of prime consideration when (a) a significant area of breast skin will need to be resected with the specimen to achieve negative margins; (b) a large vol-ume of breast parenchyma will be resected resulting in a signifi-cant defect; (c) the tumor is located between the nipple and the inframammary fold, an area often associated with unfavorable cosmetic outcomes; or (d) excision of the tumor and closure of the breast may result in malpositioning of the nipple.Mastectomy and Axillary DissectionA skin-sparing mastectomy removes all breast tissue, the nipple-areola complex, and scars from any prior biopsy pro-cedures.293,294 There is a recurrence rate of less than 6% to 8%, comparable to the long-term recurrence rates reported with stan-dard mastectomy, when skin-sparing mastectomy is used for patients


Surgery_Schwartz

Surgery_Schwartz. There is a recurrence rate of less than 6% to 8%, comparable to the long-term recurrence rates reported with stan-dard mastectomy, when skin-sparing mastectomy is used for patients with Tis to T3 cancers. A total (simple) mastectomy without skin sparing removes all breast tissue, the nipple-areola complex, and skin. An extended simple mastectomy removes all breast tissue, the nipple-areola complex, skin, and the level I axillary lymph nodes. A modified radical (“Patey”) mastectomy removes all breast tissue, the nipple-areola complex, skin, and the levels I, II, and III axillary lymph nodes; the pectoralis minor that was divided and removed by Patey may be simply divided, giving improved access to level III nodes, and then left in situ, or occasionally the axillary clearance can be performed with-out dividing pectoralis minor. The Halsted radical mastectomy removes all breast tissue and skin, the nipple-areola complex, the pectoralis major and pectoralis minor muscles, and the levels


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Surgery_Schwartz. with-out dividing pectoralis minor. The Halsted radical mastectomy removes all breast tissue and skin, the nipple-areola complex, the pectoralis major and pectoralis minor muscles, and the levels I, II, and III axillary lymph nodes. The use of systemic che-motherapy and hormonal therapy as well as adjuvant radiation therapy for breast cancer have nearly eliminated the need for the radical mastectomy.Nipple-areolar sparing mastectomy has been popularized over the last decade especially for risk-reducing mastectomy in high risk women. For those patients with a cancer diagno-sis, many consider the following factors for eligibility: tumor located more than 2 to 3 cm from the border of the areola, smaller breast size, minimal ptosis, no prior breast surgeries with periareolar incisions, body mass index less than 40 kg/m2, no active tobacco use, no prior breast irradiation, and no evi-dence of collagen vascular disease.For a variety of biologic, economic, and psychosocial rea-sons, some


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Surgery_Schwartz. mass index less than 40 kg/m2, no active tobacco use, no prior breast irradiation, and no evi-dence of collagen vascular disease.For a variety of biologic, economic, and psychosocial rea-sons, some women desire mastectomy rather than breast con-servation. Women who are less concerned about cosmesis may view mastectomy as the most expeditious and desirable thera-peutic option because it avoids the cost and inconvenience of radiation therapy. Some women whose primary breast cancers cannot be excised with a reasonable cosmetic result or those who have extensive microcalcifications are best treated with Brunicardi_Ch17_p0541-p0612.indd 59101/03/19 5:05 PM 592SPECIFIC CONSIDERATIONSPART IImastectomy. Similarly, women with large cancers that occupy the subareolar and central portions of the breast and women with multicentric primary cancers also undergo mastectomy.Modified Radical MastectomyA modified radical mastectomy preserves the pectoralis major muscle with removal of levels I, II,


Surgery_Schwartz

Surgery_Schwartz. breast and women with multicentric primary cancers also undergo mastectomy.Modified Radical MastectomyA modified radical mastectomy preserves the pectoralis major muscle with removal of levels I, II, and III (apical) axillary lymph nodes.293 The operation was first described by David Patey, a surgeon at St Bartholomew’s Hospital London, who reported a series of cases where he had removed the pectoralis minor muscle allowing complete dissection of the level III axil-lary lymph nodes while preserving the pectoralis major and the lateral pectoral nerve. A modified radical mastectomy permits preservation of the medial (anterior thoracic) pectoral nerve, which courses in the lateral neurovascular bundle of the axilla and usually penetrates the pectoralis minor to supply the lateral border of the pectoralis major. Anatomic boundaries of the mod-ified radical mastectomy are the anterior margin of the latissi-mus dorsi muscle laterally, the midline of the sternum medially, the subclavius


Surgery_Schwartz

Surgery_Schwartz. of the pectoralis major. Anatomic boundaries of the mod-ified radical mastectomy are the anterior margin of the latissi-mus dorsi muscle laterally, the midline of the sternum medially, the subclavius muscle superiorly, and the caudal extension of the breast 2 to 3 cm inferior to the inframammary fold inferiorly. Skin-flap thickness varies with body habitus but ideally is 7 to 8 mm inclusive of skin and telasubcutanea (Fig. 17-35). Once the skin flaps are fully developed, the fascia of the pectoralis major muscle and the overlying breast tissue are elevated off the underlying musculature, which allows for the complete removal of the breast (Fig. 17-36).Subsequently, an axillary lymph node dissection is per-formed. The most lateral extent of the axillary vein is identified, and the areolar tissue of the lateral axillary space is elevated as the vein is cleared on its anterior and inferior surfaces. The areo-lar tissues at the junction of the axillary vein and the anterior edge of the


Surgery_Schwartz

Surgery_Schwartz. tissue of the lateral axillary space is elevated as the vein is cleared on its anterior and inferior surfaces. The areo-lar tissues at the junction of the axillary vein and the anterior edge of the latissimus dorsi muscle, which include the lateral and subscapular lymph node groups (level I), are cleared. Care is taken to preserve the thoracodorsal neurovascular bundle. The dissection then continues medially with clearance of the central axillary lymph node group (level II). The long thoracic nerve of Bell is identified and preserved as it travels in the investing fascia of the serratus anterior muscle. Every effort is made to preserve this nerve because permanent disability with a winged scapula and shoulder weakness will follow denervation of the serratus anterior muscle. Patey divided the pectoralis minor and removed it to allow access right up to the apex of the axilla. The pectoralis minor muscle is usually divided at the tendinous portion near its insertion onto the coracoid


Surgery_Schwartz

Surgery_Schwartz. the pectoralis minor and removed it to allow access right up to the apex of the axilla. The pectoralis minor muscle is usually divided at the tendinous portion near its insertion onto the coracoid process (Fig. 17-37 inset), which allows dissection of the axillary vein medially to the costoclavicular (Halsted’s) ligament. Finally, the breast and axillary contents are removed from the surgical bed and are sent for pathologic assessment. In his modified radical mastectomy, Patey removed the pectoralis minor muscle. Many surgeons now divide only the tendon of the pectoralis minor muscle at its insertion onto the coracoid process while leaving the rest of the muscle intact, which still provides good access to the apex of the axilla.Figure 17-35. Modified radical mastectomy: eleva-tion of skin flaps. Skin flaps are 7 to 8 mm in thick-ness, inclusive of the skin and telasubcutanea. (Visual Art: © 2013. The University of Texas MD Anderson Cancer Center.)Figure 17-36. Modified radical


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Surgery_Schwartz. of skin flaps. Skin flaps are 7 to 8 mm in thick-ness, inclusive of the skin and telasubcutanea. (Visual Art: © 2013. The University of Texas MD Anderson Cancer Center.)Figure 17-36. Modified radical mastectomy after resection of breast tissue. The pectoralis major muscle is cleared of its fascia as the overlying breast is elevated. The latissimus dorsi muscle is the lateral boundary of the dissection. (Visual Art: © 2013. The University of Texas MD Anderson Cancer Center.)Brunicardi_Ch17_p0541-p0612.indd 59201/03/19 5:05 PM 593THE BREASTCHAPTER 17Seromas beneath the skin flaps or in the axilla represent the most frequent complication of mastectomy and axillary lymph node dissection, reportedly occurring in as many as 30% of cases. The use of closed-system suction drainage reduces the incidence of this complication. Catheters are retained in the wound until drainage diminishes to <30 mL per day. Wound infections occur infrequently after a mastectomy, and the majority are a result


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Surgery_Schwartz. incidence of this complication. Catheters are retained in the wound until drainage diminishes to <30 mL per day. Wound infections occur infrequently after a mastectomy, and the majority are a result of skin-flap necrosis. Cultures of speci-mens taken from the infected wound for aerobic and anaerobic organisms, debridement, and antibiotic therapy are effective management. Moderate or severe hemorrhage in the postop-erative period is rare and is best managed with early wound exploration for control of hemorrhage and reestablishment of closed-system suction drainage. The incidence of functionally significant lymphedema after a modified radical mastectomy is approximately 20% but can be as high as 50% to 60% when postoperative radiation is employed. Extensive axillary lymph node dissection, the delivery of radiation therapy, the presence of pathologic lymph nodes, and obesity are predisposing factors. Patients should be referred to physical therapy at the earliest signs of lymphedema to


Surgery_Schwartz

Surgery_Schwartz. the delivery of radiation therapy, the presence of pathologic lymph nodes, and obesity are predisposing factors. Patients should be referred to physical therapy at the earliest signs of lymphedema to prevent progression to the later stages. The use of individually fitted compressive sleeves and complex decongestive therapy may be necessary.Reconstruction of the Breast and Chest WallThe goals of reconstructive surgery after a mastectomy for breast cancer are wound closure and breast reconstruction, which is either immediate or delayed.295 In most cases, wound closure after mastectomy is accomplished with simple approximation of the wound edges. However, if a more radical removal of skin and subcutaneous tissue is necessary, a pedicled myocutane-ous flap from the latissimus dorsi muscle is generally the best approach for wound coverage. A skin graft provides functional coverage that will tolerate adjuvant radiation therapy; however, this is not preferred because poor graft adherence may


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Surgery_Schwartz. the best approach for wound coverage. A skin graft provides functional coverage that will tolerate adjuvant radiation therapy; however, this is not preferred because poor graft adherence may delay delivery of radiation therapy. Breast reconstruction after risk-reducing mastectomy or after mastectomy for early-stage breast cancer may be performed at the same time as the mastectomy. This allows for a skin-sparing mastectomy to be performed, which offers the best overall cosmetic outcomes. Reconstruc-tion can proceed with an expander/implant reconstruction or with autologous tissue such as a pedicled myocutaneous flap or a free flap using microvascular techniques. In patients with locally advanced breast cancer, reconstruction is often delayed until after completion of adjuvant radiation therapy to ensure that local-regional control of disease is obtained. The expected use of postmastectomy radiotherapy should also be considered as a reason for delayed reconstruction as radiotherapy to a


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Surgery_Schwartz. to ensure that local-regional control of disease is obtained. The expected use of postmastectomy radiotherapy should also be considered as a reason for delayed reconstruction as radiotherapy to a reconstructed breast has been reported to result in inferior cos-metic outcomes. Consideration can be made for placement of a tissue expander to allow for skin-sparing, but this should be discussed with the radiation oncologist and other members of the treatment team. If chest wall coverage is needed to replace a large skin or soft tissue defect, many different types of myo-cutaneous flaps are employed, but the latissimus dorsi and the rectus abdominis myocutaneous flaps are most frequently used. The latissimus dorsi myocutaneous flap consists of a skin paddle based on the underlying latissimus dorsi muscle, which Figure 17-37. Modified radical mastectomy (Patey): axillary lymph node dissection. The dissection proceeds from lateral to medial, with complete visualization of the anterior and


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Surgery_Schwartz. dorsi muscle, which Figure 17-37. Modified radical mastectomy (Patey): axillary lymph node dissection. The dissection proceeds from lateral to medial, with complete visualization of the anterior and inferior aspects of the axillary vein. Loose areolar tissue at the junction of the axillary vein and the anterior margin of the latissimus dorsi muscle is swept inferomedially inclusive of the lateral (axillary) lymph node group (level I). Care is taken to preserve the thoracodorsal artery, vein, and nerve in the deep axillary space. The lateral lymph node group is resected in continuity with the subscapular lymph node group (level I) and the external mammary lymph node group (level I). Dissection anterior to the axillary vein allows removal of the central lymph node group (level II) and the apical (subclavicular) lymph node group (level III). The superomedial limit of this dissection is the clavipectoral fascia (Halsted’s ligament). Inset depicts division of the insertion of the


Surgery_Schwartz

Surgery_Schwartz. and the apical (subclavicular) lymph node group (level III). The superomedial limit of this dissection is the clavipectoral fascia (Halsted’s ligament). Inset depicts division of the insertion of the pectoralis minor muscle at the coracoid process. The surgeon’s finger shields the underlying brachial plexus. (Reproduced with permission from Bland KI, Copeland EMI: The Breast: Comprehensive Management of Benign and Malignant Diseases, 4th ed. Philadelphia, PA: Elsevier/Saunders; 2009.)Brunicardi_Ch17_p0541-p0612.indd 59301/03/19 5:05 PM 594SPECIFIC CONSIDERATIONSPART IIis supplied by the thoracodorsal artery with contributions from the posterior intercostal arteries. A transverse rectus abdominis myocutaneous (TRAM) flap consists of a skin paddle based on the underlying rectus abdominis muscle, which is supplied by vessels from the deep inferior epigastric artery. The free TRAM flap uses microvascular anastomoses to establish blood supply to the flap. When the bony chest wall is


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Surgery_Schwartz. muscle, which is supplied by vessels from the deep inferior epigastric artery. The free TRAM flap uses microvascular anastomoses to establish blood supply to the flap. When the bony chest wall is involved with cancer, resection of a portion of the bony chest wall is indicated. If only one or two ribs are resected and soft tissue coverage is pro-vided, reconstruction of the bony defect is usually not necessary because scar tissue will stabilize the chest wall. If more than two ribs are sacrificed, it is advisable to stabilize the chest wall with prosthetic material, which is then covered with soft tissue by using a latissimus dorsi or TRAM flap.NONSURGICAL BREAST CANCER THERAPIESRadiation TherapyRadiation therapy is used for all stages of breast cancer depending on whether the patient is undergoing BCT or mas-tectomy.296-302 Adjuvant radiation for patients with DCIS and early-stage breast cancer have been described previously in this chapter. Those women treated with mastectomy who


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Surgery_Schwartz. undergoing BCT or mas-tectomy.296-302 Adjuvant radiation for patients with DCIS and early-stage breast cancer have been described previously in this chapter. Those women treated with mastectomy who have cancer at the surgical margins are at sufficiently high risk for local recurrence to warrant the use of adjuvant radiation therapy to the chest wall postoperatively. Women with metastatic disease involving four or more axillary lymph nodes and premeno-pausal women with metastatic disease involving one to three lymph nodes also are at increased risk for recurrence and are candidates for the use of chest wall and supraclavicular lymph node radiation therapy. In advanced local-regional breast can-cer (stage IIIA or IIIB), women are at high risk for recurrent disease after surgical therapy, and adjuvant radiation therapy is used to reduce the risk of recurrence. Current recommenda-tions for stages IIIA and IIIB breast cancer are (a) adjuvant radiation therapy to the breast and


Surgery_Schwartz

Surgery_Schwartz. therapy, and adjuvant radiation therapy is used to reduce the risk of recurrence. Current recommenda-tions for stages IIIA and IIIB breast cancer are (a) adjuvant radiation therapy to the breast and supraclavicular lymph nodes after neoadjuvant chemotherapy and segmental mastectomy with or without axillary lymph node dissection, (b) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after neoadjuvant chemotherapy and mastectomy with or without axillary lymph node dissection, and (c) adjuvant radiation therapy to the chest wall and supraclavicular lymph nodes after segmental mastectomy or mastectomy with axillary lymph node dissection and adjuvant chemotherapy. Data from the EBCTCG has shown improvements in local-regional con-trol and survival in patients treated with mastectomy and post-mastectomy radiation therapy for one to three positive axillary lymph nodes.303 This data is based on clinical trials from the era of axillary lymph node dissection for


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Surgery_Schwartz. with mastectomy and post-mastectomy radiation therapy for one to three positive axillary lymph nodes.303 This data is based on clinical trials from the era of axillary lymph node dissection for staging prior to the routine use of sentinel lymph node dissection. It is likely that the vol-ume of disease in the earlier trials was greater overall than what is currently seen in patients who have small volume metastases detected at sentinel node dissection. It is important to include all multidisciplinary team members (medical oncology, plastic surgery, radiation oncology, and surgical oncology) regarding the risks and benefits of postmastectomy radiation therapy in patients with one to three positive nodes.The use of partial breast irradiation (APBI) for patients treated with breast-conserving surgery has also been previously described. APBI can be delivered via brachytherapy, external beam radiation therapy using 3D conformal radiation, or inten-sity-modulated radiation therapy. Although


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Surgery_Schwartz. surgery has also been previously described. APBI can be delivered via brachytherapy, external beam radiation therapy using 3D conformal radiation, or inten-sity-modulated radiation therapy. Although initial results are Table 17-14Adjuvant chemotherapy regimens for breast cancerHER-2 NEGATIVEHER-2 POSITIVEPreferred Dose dense AC → Paclitaxel every 2 weeksDose dense AC → Paclitaxel weeklyTC (T = docetaxel)Other RegimensCMFAC → Docetaxel every 3 weeksAC → Paclitaxel weeklyTAC (T = docetaxel)AC → T + trastuzumab +/pertuzumab (T = paclitaxel)TCH (docetaxel, carboplatin, trastuzumab +/pertuzumab)Other RegimensAC → T + trastuzumab +/pertuzumab (T = docetaxel)Docetaxel + cyclophosphamide + trastuzumabFEC → Docetaxel + trastuzumab + pertuzumabFEC → Paclitaxel + trastuzumab + pertuzumabPaclitaxel + trastuzumabPaclitaxel + trastuzumab + pertuzumab → FECDocetaxel + trastuzumab + pertuzumab → FECA = Adriamycin (doxorubicin); C = cyclophosphamide; E = epirubicin; F = 5-fluorouracil; M =


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Surgery_Schwartz. + trastuzumabPaclitaxel + trastuzumab + pertuzumab → FECDocetaxel + trastuzumab + pertuzumab → FECA = Adriamycin (doxorubicin); C = cyclophosphamide; E = epirubicin; F = 5-fluorouracil; M = methotrexate; T = Taxane (docetaxel or paclitaxel); → = followed by.Data from NCCN Practice Guidelines in Oncology. Fort Washington, PA: National Comprehensive Cancer Network, 2006.promising in highly selected low-risk populations, use of APBI should be based on current guidelines or offered in the setting of a prospective trial.304Chemotherapy AdjuvantChemotherapy. The Early Breast Cancer Trialists’ Collabora-tive Group overview analysis of adjuvant chemotherapy demon-strated reductions in the odds of recurrence and death in women ≤70 years of age with stage I, IIA, or IIB breast cancer.123,305-309 For those ≥70 years of age, the lack of definitive clinical trial data regarding adjuvant chemotherapy prevented definitive rec-ommendations. Adjuvant chemotherapy is of minimal benefit to women with


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Surgery_Schwartz. For those ≥70 years of age, the lack of definitive clinical trial data regarding adjuvant chemotherapy prevented definitive rec-ommendations. Adjuvant chemotherapy is of minimal benefit to women with negative nodes and cancers ≤0.5 cm in size and is not recommended. Women with negative nodes and cancers 0.6 to 1.0 cm are divided into those with a low risk of recurrence and those with unfavorable prognostic features that portend a higher risk of recurrence and a need for adjuvant chemotherapy. Adverse prognostic factors include blood vessel or lymph ves-sel invasion, high nuclear grade, high histologic grade, HER2/neu overexpression, and negative hormone receptor status. American Society of Clinical Oncology guidelines suggest that adjuvant chemotherapy should be considered for patients with positive lymph nodes, HER2-positive disease, Adjuvant! Online mortality greater than 10%, grade 3 lymph node negative tumors >5 mm, triple-negative tumors, lympho-vascular invasion, or estimated


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Surgery_Schwartz. with positive lymph nodes, HER2-positive disease, Adjuvant! Online mortality greater than 10%, grade 3 lymph node negative tumors >5 mm, triple-negative tumors, lympho-vascular invasion, or estimated distant relapse risk of greater than 15% at 10 years based on 21 gene recurrence score.259 Adjuvant chemotherapy is recommended by the NCCN guidelines for women with these unfavorable prognostic features. Table 17-14 lists the frequently used chemotherapy regimens for breast cancer.For women with hormone receptor-negative cancers that are >1 cm in size, adjuvant chemotherapy is appropriate. Brunicardi_Ch17_p0541-p0612.indd 59401/03/19 5:05 PM 595THE BREASTCHAPTER 17However, women with node-negative hormone receptor–positive cancers and T1 tumors are candidates for antiestrogen therapy with or without chemotherapy. Assessment of overall risk using known prognostic factors or additional testing such as the 21-gene recurrence score assay can help to guide deci-sion making regarding


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Surgery_Schwartz. with or without chemotherapy. Assessment of overall risk using known prognostic factors or additional testing such as the 21-gene recurrence score assay can help to guide deci-sion making regarding chemotherapy in patients with node-negative, ER-positive breast cancer. For special-type cancers (tubular, mucinous, medullary, etc), which are usually strongly estrogen receptor positive, adjuvant antiestrogen therapy should be advised for cancers >1 cm. For women with node-positive tumors or with a special-type cancer that is >3 cm, the use of chemotherapy is appropriate; those with hormone receptor-positive tumors should receive antiestrogen therapy.For stage IIIA breast cancer, preoperative chemotherapy with an anthracycline and taxane-containing regimen followed by either a modified radical mastectomy or segmental mastec-tomy with axillary dissection followed by adjuvant radiation therapy should be considered, especially for estrogen receptor negative disease. While the same regimen


Surgery_Schwartz

Surgery_Schwartz. mastectomy or segmental mastec-tomy with axillary dissection followed by adjuvant radiation therapy should be considered, especially for estrogen receptor negative disease. While the same regimen may be considered for estrogen receptor positive disease, it is known that these tumors respond less well to chemotherapy with <10% pCR rate overall and <3% pCR rate for lobular cancers. Other options such as neoadjuvant endocrine therapy followed by local-regional treatment or in some cases primary endocrine therapy may be considered depending on other tumor characteristics and the patient’s comorbid conditions and preference.Neoadjuvant (Preoperative) Chemotherapy. In the early 1970s, the National Cancer Institute in Milan, Italy, initiated two prospective randomized multimodality clinical trials for women with T3 or T4 breast cancer.310 The best results were achieved when surgery was interposed between chemotherapy courses, with 82% local-regional control and 25% having a 5-year


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Surgery_Schwartz. trials for women with T3 or T4 breast cancer.310 The best results were achieved when surgery was interposed between chemotherapy courses, with 82% local-regional control and 25% having a 5-year dis-ease-free survival. The NSABP B-18 trial evaluated the role of neoadjuvant chemotherapy in women with operable stages II and III breast cancer.206 Women entered into this study were randomly assigned to receive either surgery followed by che-motherapy or neoadjuvant chemotherapy followed by surgery. There was no difference in the 5-year disease-free survival rates for the two groups, but after neoadjuvant chemotherapy there was an increase in the number of lumpectomies performed and a decreased incidence of node positivity. It was suggested that neoadjuvant chemotherapy be considered for the initial manage-ment of breast cancers judged too large for initial lumpectomy.Several prospective clinical trials have evaluated the neo-adjuvant approach, and two meta-analyses have been performed,


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Surgery_Schwartz. initial manage-ment of breast cancers judged too large for initial lumpectomy.Several prospective clinical trials have evaluated the neo-adjuvant approach, and two meta-analyses have been performed, each showing that neoadjuvant vs. adjuvant chemotherapy are equivalent in terms of OS.262,311 These analyses also evaluated local-regional recurrence (LRR) and found that there was an increase in LRR rates for patients receiving neoadjuvant chemo-therapy when radiation therapy was used alone without surgery after completion of chemotherapy. Mittendorf and colleagues evaluated a contemporary series of almost 3000 patients treated with breast conserving surgery and radiation therapy who received either neoadjuvant or adjuvant chemotherapy for breast cancer.312 They found that the risk of LRR was driven by bio-logic factors and disease stage and was not impacted by the timing of chemotherapy delivery. These data high-light the importance of the multidisciplinary management of patients with


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Surgery_Schwartz. driven by bio-logic factors and disease stage and was not impacted by the timing of chemotherapy delivery. These data high-light the importance of the multidisciplinary management of patients with breast cancer in achieving the best outcomes.The use of neoadjuvant chemotherapy offers the oppor-tunity to observe the response of the intact primary tumor 10and any regional nodal metastases to a specific chemotherapy regimen.279 For patients whose tumors remain stable in size or even progress with the initial neoadjuvant chemotherapy regi-men, a new regimen may be considered that uses another class of agents, although there is no randomized data confirming this will improve outcome.After treatment with neoadjuvant chemotherapy, patients are assessed for clinical and pathologic response to the regimen. Patients whose tumors achieve a pathologic complete response to neoadjuvant chemotherapy have been shown to have statisti-cally improved survival outcomes to those of patients whose tumors


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Surgery_Schwartz. regimen. Patients whose tumors achieve a pathologic complete response to neoadjuvant chemotherapy have been shown to have statisti-cally improved survival outcomes to those of patients whose tumors demonstrate only a partial response, remain stable, or progress on treatment. Researchers at MD Anderson Cancer Center have shown that residual cancer burden (RCB)—categorized into four classes, RCB-0 or pathologic complete response, RCB-1, RCB-2, and RCB-3—is predictive of 10-year relapse-free survival with neoadjuvant chemotherapy in triple negative, ER-positive, and HER2-positive tumors.313 Patients who experience progression of disease during neoadjuvant che-motherapy have the poorest survival.314,315 This means that while patients who achieve a pCR will have a better prognosis based on their response to neoadjuvant chemotherapy. Equally other patients will have a poorer prognosis compared to when they started neoadjuvant therapy based on the nonresponse to treat-ment. Consequently,


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Surgery_Schwartz. their response to neoadjuvant chemotherapy. Equally other patients will have a poorer prognosis compared to when they started neoadjuvant therapy based on the nonresponse to treat-ment. Consequently, the FDA has supported the use of the neo-adjuvant platform and pathologic response rates as an endpoint for mechanism of accelerated approval for new agents in high risk early stage breast cancer, though the short-term endpoints (i.e., pCR) have not been shown to correlate with long-term out-comes (i.e., disease free survival and overall survival).Current NCCN recommendations for treatment of oper-able advanced local-regional breast cancer are neoadjuvant chemotherapy with an anthracycline-containing or taxane-containing regimen or both, followed by mastectomy or lumpec-tomy with axillary lymph node dissection if necessary, followed by adjuvant radiation therapy. For patients with HER2-positive breast cancer, trastuzumab and pertuzumab can be combined with chemotherapy in the preoperative


Surgery_Schwartz

Surgery_Schwartz. node dissection if necessary, followed by adjuvant radiation therapy. For patients with HER2-positive breast cancer, trastuzumab and pertuzumab can be combined with chemotherapy in the preoperative setting to increase patho-logic complete response rates. For inoperable stage IIIA and for stage IIIB breast cancer, neoadjuvant chemotherapy is used to decrease the local-regional cancer burden. This may then permit subsequent modified radical or radical mastectomy, which is followed by adjuvant radiation therapy.Nodal Evaluation in Patients Receiving Neoadjuvant Chemotherapy. The management of the axilla after neoadjuvant chemotherapy has not been specifically addressed in randomized trials. Standard practice has been to perform an axillary lymph node dissection after chemotherapy or to perform a sentinel lymph node dissection before chemotherapy for nodal staging before chemotherapy is initiated. A number of small single-institution studies, one multicenter study, and a recent


Surgery_Schwartz

Surgery_Schwartz. to perform a sentinel lymph node dissection before chemotherapy for nodal staging before chemotherapy is initiated. A number of small single-institution studies, one multicenter study, and a recent meta-analysis have explored the use of SLN dissection at the completion of chemo-therapy. The published results from these studies have demon-strated the feasibility of SLN dissection in breast cancer patients after neoadjuvant chemotherapy. A review of 14 studies with 818 patients showed a false negative rate of 11% with an overall accu-racy of 94%.280,281,316 While SLN dissection has been accepted for assessment of the axilla in the clinically node-negative axilla after neoadjuvant chemotherapy, clinicians have been slower to adopt this approach for axillary staging after chemotherapy in patients who started with initial node-positive disease. Several clinical Brunicardi_Ch17_p0541-p0612.indd 59501/03/19 5:05 PM 596SPECIFIC CONSIDERATIONSPART IItrials have been performed to evaluate


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Surgery_Schwartz. who started with initial node-positive disease. Several clinical Brunicardi_Ch17_p0541-p0612.indd 59501/03/19 5:05 PM 596SPECIFIC CONSIDERATIONSPART IItrials have been performed to evaluate the accuracy of SLN dis-section in patients with documented axillary metastases at initial presentation, including ACOSOG Z1071, SENTINA, and SN FNAC. ACOSOG Z1071 (Alliance) analyzed women with clini-cal T0-T4, N1-N2, M0 breast cancer who underwent both SLN surgery and axillary lymph node dissection (ALND).317 The pri-mary endpoint was the false-negative rate (FNR) of SLN surgery after chemotherapy with clinically node-positive disease with a prespecified endpoint of 10% considered to be an acceptable rate. However, the FNR was found to be 12.6%, though it was lower when dual-agent mapping technique was used and at least three or more SLNs removed.317 The SENTINA and SN FNAC trials had findings similar to Z1071. The results from Z1071 were further analyzed to determine if a clip was placed in


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Surgery_Schwartz. was used and at least three or more SLNs removed.317 The SENTINA and SN FNAC trials had findings similar to Z1071. The results from Z1071 were further analyzed to determine if a clip was placed in the positive node at initial diagnosis and if the clipped node location at surgery (SLN or ALND) was evaluated. Indeed, this showed that identification of the clipped node during the surgical procedure further decreased the FNR.318 The results from the ACOSOG Z1071 (Alliance) trial, in cases presenting with cN1 disease and at least two SLN resec-tions and clipped node was within the SLN specimen, showed that the FNR was 6.8%.318 Caudle et al at MD Anderson Cancer Center performed a prospective study of patients with biopsy-confirmed nodal metastases with a clip placed in the biopsy-proven lymph node, who were treated with neoadjuvant chemotherapy; at the time of surgery these patients underwent SLN dissection with targeting and removal of the clipped node (targeted axillary dis-section


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Surgery_Schwartz. node, who were treated with neoadjuvant chemotherapy; at the time of surgery these patients underwent SLN dissection with targeting and removal of the clipped node (targeted axillary dis-section [TAD]).319 TAD includes SLN surgery and selective local-ization and removal of the clipped node, with the goal to determine if pathologic changes in the clipped node accurately reflect the status of the nodal basin, and proposing that TAD improves the FNR compared to SLN surgery alone.319 In patients undergoing SLN surgery and ALND (n = 118), the FNR was 10.1% (95% CI, 4.2–19.8), and adding evaluation of the clipped node reduced the FNR to 1.4% (95% CI, 0.03–7.3; P = .03). TAD followed by ALND was performed in 85 patients, with an FNR of 2.0% (1 of 50; 95% CI, 0.05–10.7).319 Although the use of dual tracer tech-nique, retrieval of three or more SLNs, and TAD improve axillary staging after neoadjuvant chemotherapy, there is no long-term data about the oncologic safety of omitting ALND in


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Surgery_Schwartz. of dual tracer tech-nique, retrieval of three or more SLNs, and TAD improve axillary staging after neoadjuvant chemotherapy, there is no long-term data about the oncologic safety of omitting ALND in patients who con-vert from cN1 to cN0 disease at this time.Neoadjuvant Endocrine Therapy. While initially used in elderly women who were deemed poor candidates for surgery or cytotoxic chemotherapy, neoadjuvant endocrine therapy is being increasingly evaluated in clinical trials. As clinicians have gained experience with neoadjuvant treatment strategies, it is now clear from examination of predictors of complete pathologic response that ER-positive tumors do not shrink in response to chemotherapy as readily as ER-negative tumors.320 Indeed, the pCR rate in ER-negative tumors is approximately three times that of ER-positive tumors. Fisher et al examined the results of the NSABP B-14 and B-20 trials and found that, as age increased, women obtained less benefit from chemo-therapy. They


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Surgery_Schwartz. three times that of ER-positive tumors. Fisher et al examined the results of the NSABP B-14 and B-20 trials and found that, as age increased, women obtained less benefit from chemo-therapy. They recommended that factors214 including tumor estrogen receptor concentration, nuclear grade, histologic grade, tumor type, and markers of proliferation should be considered in these patients before choosing between the use of chemotherapy and hormonal therapy. If in fact the tumor is estrogen-receptor rich, these patients may benefit more from endocrine therapy in the neoadjuvant setting than they might if they received stan-dard chemotherapy. Neoadjuvant endocrine therapy has been shown to shrink tumors, enabling breast-conserving surgery in women with hormone receptor-positive disease who otherwise would have to be treated with mastectomy, although long-term recurrence rates have not been reported.265 The IMPACT trial evaluated neoadjuvant use of tamoxifen or anastrozole or both in


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Surgery_Schwartz. otherwise would have to be treated with mastectomy, although long-term recurrence rates have not been reported.265 The IMPACT trial evaluated neoadjuvant use of tamoxifen or anastrozole or both in combination in postmenopausal women with ER-positive operable or locally advanced breast cancer.321 While there were no significant differences in objective tumor response among tamoxifen, anastrozole, or a combination of the two, in patients who were initially deemed as mastectomy candidates, only 31% had breast-conserving surgery with tamoxifen, whereas 44% underwent breast-conserving surgery with anastrozole. Invasive lobular cancers in particular have been shown to respond poorly to neoadjuvant chemotherapy and may have better response to neoadjuvant endocrine therapy.322-324 A meta-analysis evaluating the response rate and rate of breast conservation surgery with the use of neoadjuvant endocrine therapy compared to combi-nation chemotherapy was recently reported. This meta-analysis


Surgery_Schwartz

Surgery_Schwartz. evaluating the response rate and rate of breast conservation surgery with the use of neoadjuvant endocrine therapy compared to combi-nation chemotherapy was recently reported. This meta-analysis included nearly 3500 patients across 20 studies.325 Interestingly, aromatase inhibitors had a similar response, and breast conserva-tion rates in comparison with combination chemotherapy albeit with lower toxicity suggest that neoadjuvant endocrine therapy is an appropriate alternative in ER-positive breast cancers. However, the incidence of complete pathological response was low (<10%) with both approaches. Also, aromatase inhibitors were associated with significantly higher response and breast conservation rates compared with tamoxifen. The ALTER-NATE (Alternate Approaches for Clinical Stage II or III Estro-gen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women) trial is currently evaluating neo-adjuvant endocrine therapy with fulvestrant or anastrozole or in


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Surgery_Schwartz. II or III Estro-gen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women) trial is currently evaluating neo-adjuvant endocrine therapy with fulvestrant or anastrozole or in combination.Increasing knowledge of secondary resistance mecha-nisms to endocrine therapy and cross talk between ER and the PI3K/Akt/mTOR pathway have led to the evaluation of PI3K pathway inhibitors in combination with endocrine therapy. Post-menopausal women with ER-positive early breast cancers were treated with letrozole or letrozole in combination with everoli-mus, a mTOR inhibitor, in a randomized, phase 2 clinical trial. Clinical response and antiproliferative response, characterized by reduction in Ki67, was superior in the combination arm, sug-gesting that everolimus can increase efficacy of neoadjuvant letrozole.326 The LORLEI study is evaluating the use of taselisib, a PI3K inhibitor in combination with letrozole compared with letrozole alone. With the approval of CDK 4/6


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Surgery_Schwartz. efficacy of neoadjuvant letrozole.326 The LORLEI study is evaluating the use of taselisib, a PI3K inhibitor in combination with letrozole compared with letrozole alone. With the approval of CDK 4/6 inhibitors in the metastatic setting, clinical trials are evaluating the use of CDK inhibitors in combination with neoadjuvant endocrine therapy. Neoadjuvant anastrozole in combination with palbociclib, a CDK4/6 inhibitor, has been shown to significantly reduce Ki67, suggesting that CDK4/6 inhibition can increase the efficacy of neoadjuvant endocrine therapy.With the use of neoadjuvant chemotherapy or endocrine therapy, observation of the response of the intact tumor and/or nodal metastases to a specific regimen could ultimately help to define which patients will benefit from specific therapies in the adjuvant setting. In adjuvant trials the primary endpoint is typi-cally survival, whereas in neoadjuvant trials the endpoints have more often been clinical or pathologic response rates. There


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Surgery_Schwartz. in the adjuvant setting. In adjuvant trials the primary endpoint is typi-cally survival, whereas in neoadjuvant trials the endpoints have more often been clinical or pathologic response rates. There are a number of clinical trials underway comparing neoadjuvant chemotherapy and endocrine therapy regimens with pretreat-ment and posttreatment biopsy samples obtained from the pri-mary tumors in all of the participants. These samples are being subjected to intensive genomic and proteomic analyses that may Brunicardi_Ch17_p0541-p0612.indd 59601/03/19 5:05 PM 597THE BREASTCHAPTER 17help to define a more personalized or individualized approach to breast cancer treatment in the future.Antiestrogen TherapyTamoxifen. Within the cytosol of breast cancer cells are spe-cific proteins (receptors) that bind and transfer steroid moieties into the cell nucleus to exert specific hormonal effects.308,327-331 The most widely studied hormone receptors are the estrogen receptor and progesterone


Surgery_Schwartz

Surgery_Schwartz. that bind and transfer steroid moieties into the cell nucleus to exert specific hormonal effects.308,327-331 The most widely studied hormone receptors are the estrogen receptor and progesterone receptor. Hormone receptors are detectable in >90% of well-differentiated ductal and lobular invasive cancers. Although the receptor status may remain the same between the primary cancer and metastatic disease in the same patient in the majority of cases, there are instances where the status is changed in the metastatic focus; therefore, biopsy of newly diagnosed metastatic disease should be considered for assessment of hormone receptor and HER2 status.After binding to estrogen receptors in the cytosol, tamoxi-fen blocks the uptake of estrogen by breast tissue. Clini-cal responses to antiestrogen are evident in >60% of women with hormone receptor-positive breast cancers but in <10% of women with hormone receptor-negative breast cancers. A meta-analysis by the Early Breast Cancer Trialists’


Surgery_Schwartz

Surgery_Schwartz. are evident in >60% of women with hormone receptor-positive breast cancers but in <10% of women with hormone receptor-negative breast cancers. A meta-analysis by the Early Breast Cancer Trialists’ Collabora-tive Group showed that adjuvant therapy with tamoxifen for 5 years reduced breast cancer mortality by about a third through the first 15 years of follow-up.14 This mortality benefit contin-ues to be statistically significant in the second and third 5-year periods (i.e., years 5–9 and 10–15) when the patients are no longer receiving endocrine treatment—the so-called carry-over effect. The analysis also showed a 39% reduction in the risk of cancer in the contralateral breast. The antiestrogens do have defined toxicity, including bone pain, hot flashes, nausea, vom-iting, and fluid retention. Thrombotic events occur in <3% of treated women. Cataract surgery is more frequently performed in patients receiving tamoxifen. The Stockholm trial showed that 5 years of tamoxifen was associated


Surgery_Schwartz

Surgery_Schwartz. Thrombotic events occur in <3% of treated women. Cataract surgery is more frequently performed in patients receiving tamoxifen. The Stockholm trial showed that 5 years of tamoxifen was associated with a significant reduction in locoregional recurrences and distant metastasis in postmenopausal women with ER-positive breast cancer.332 However, an increase in endometrial cancers was observed with long-term tamoxifen use. The NSABP B14 trial evaluated 10 years of tamoxifen compared to 5 years.333 However, the study was terminated based on interim analyses indicating no addi-tional benefit from tamoxifen beyond 5 years. The ATLAS trial also evaluated the use of tamoxifen for 5 years vs. 10 years in nearly 13,000 women across the world. This study showed that continuing tamoxifen for 10 years vs. 5 years produced a significant reduction in recurrence and mortality.334 Interestingly, the benefit was not seen in the second 5 years (i.e., years 5–9) while the patients were on treatment, but


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Surgery_Schwartz. 5 years produced a significant reduction in recurrence and mortality.334 Interestingly, the benefit was not seen in the second 5 years (i.e., years 5–9) while the patients were on treatment, but it was seen from years 10 to 15. One reason the NSABP B14 study was led to conclude that 10 years of tamoxifen was not beneficial was that the follow-up time was shorter. Results of the ATLAS study were also corroborated by the aTTom study. Similarly, extended adjuvant therapy with letrozole after 5 years of tamoxifen was shown to improve disease-free survival without improvement in overall survival except in node-positive patients.335Tamoxifen therapy is also considered for women with DCIS that is found to be ER-positive. The goals of such ther-apy are to decrease the risk of an ipsilateral recurrence after breast conservation therapy for DCIS and to decrease the risk of a primary invasive breast cancer or a contralateral breast cancer event. Consequently, tamoxifen is not recommended for


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Surgery_Schwartz. after breast conservation therapy for DCIS and to decrease the risk of a primary invasive breast cancer or a contralateral breast cancer event. Consequently, tamoxifen is not recommended for patients who have had bilateral mastectomies with ER-positive DCIS. With the use of aromatase inhibitors in postmenopausal women, use of adjuvant tamoxifen has increasingly been limited to premenopausal women.Aromatase Inhibitors. In postmenopausal women, aromatase inhibitors are now considered first-line therapy in the adjuvant setting. Currently, three third-generation aromatase inhibitors are approved for clinical use: the reversible nonsteroidal inhibitors anastrozole and letrozole and the irreversible steroidal inhibitor exemestane. While all the aromatase inhibitors have been shown to have similar efficacy with a similar spectrum of adverse effects, the Early Breast Cancer Trialists’ Collaborative Group meta-analyses of 31,920 postmenopausal women with ER-positive early breast cancers


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Surgery_Schwartz. similar efficacy with a similar spectrum of adverse effects, the Early Breast Cancer Trialists’ Collaborative Group meta-analyses of 31,920 postmenopausal women with ER-positive early breast cancers treated with tamoxifen or aroma-tase inhibitors demonstrated that 5 years of aromatase inhibitors reduced the rate of recurrence by 30% and 10-year breast cancer mortality by about 15% compared to 5 years of tamoxifen.336-339 The NSABP B42 study evaluated whether an additional 5 years of letrozole improved disease-free survival in postmenopausal women who have completed 5 years of tamoxifen or an aromatase inhibitor. After a median follow-up of 6.9 years, while extended letrozole significantly improved breast cancer-free interval, no improvement in disease-free survival, the primary endpoint, was observed. Recently, the results of the MA-17R study, designed to assess the efficacy of adjuvant letrozole for 10 years, were reported.340 Similar to NSABP B42, extended letrozole improved


Surgery_Schwartz

Surgery_Schwartz. was observed. Recently, the results of the MA-17R study, designed to assess the efficacy of adjuvant letrozole for 10 years, were reported.340 Similar to NSABP B42, extended letrozole improved disease-free survival without significant improvement in overall survival. Patients who are node-positive, have received adjuvant chemotherapy, with prior receipt of tamoxifen are likely to ben-efit from long-term use of an aromatase inhibitor.The aromatase inhibitors are less likely than tamoxifen to cause endometrial cancer but do lead to changes in bone mineral density that may result in osteoporosis and an increased rate of fractures in postmenopausal women. The risk of osteoporosis can be averted by treatment with bisphosphonates. Joint pains are a side effect that affects a significant number of patients. Node-negative and node-positive breast cancer patients whose tumors express hormone receptors should be considered for endocrine therapy in the adjuvant setting. Women with hormone


Surgery_Schwartz

Surgery_Schwartz. of patients. Node-negative and node-positive breast cancer patients whose tumors express hormone receptors should be considered for endocrine therapy in the adjuvant setting. Women with hormone receptor–positive cancers achieve significant reduction in risk of recurrence of breast cancer and mortality from breast cancer through the use of endocrine therapies.For postmenopausal women with ER-positive, HER2-negative, metastatic breast cancer, available endocrine thera-pies include nonsteroidal aromatase inhibitors (anastrozole and letrozole); steroidal aromatase inhibitors (exemestane); serum ER modulators (tamoxifen or toremifene); ER down-regulators (fulvestrant); progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol). A third generation nonsteroidal aromatase inhibitor or palbo-ciclib, the CDK 4/6 inhibitor, in combination with letrozole may be considered as a treatment option for first-line therapy. Activation of CDK4/CDK6 cell cycle


Surgery_Schwartz

Surgery_Schwartz. aromatase inhibitor or palbo-ciclib, the CDK 4/6 inhibitor, in combination with letrozole may be considered as a treatment option for first-line therapy. Activation of CDK4/CDK6 cell cycle signaling axis has been implicated in mediating endocrine resistance. Consequently, PALOMA-1 evaluated the safety and efficacy of palbociclib in combination with letrozole vs. letrozole alone as first-line treat-ment for patients with ER-positive, HER2-negative advanced breast cancer. Median progression-free survival (PFS) was doubled with the combination compared to letrozole alone (20.2 months vs. 10.2 months for the letrozole).341 Based on this, the FDA approved palbociclib in combination with letrozole for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer as initial treatment. The Brunicardi_Ch17_p0541-p0612.indd 59701/03/19 5:05 PM 598SPECIFIC CONSIDERATIONSPART IIbenefit of palbociclib in combination with letrozole was sub-sequently confirmed in


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Surgery_Schwartz. as initial treatment. The Brunicardi_Ch17_p0541-p0612.indd 59701/03/19 5:05 PM 598SPECIFIC CONSIDERATIONSPART IIbenefit of palbociclib in combination with letrozole was sub-sequently confirmed in a phase 3 trial (PFS 24.8 months vs. 14.5 months for letrozole).342 Two additional CDK4/6 inhibitors, ribociclib and abemaciclib, have been approved for use in com-bination with endocrine therapy for patients with hormone receptor–positive advanced breast cancer.On the other hand, PALOMA-3 compared the combina-tion of palbociclib and fulvestrant to fulvestrant alone in preor postmenopausal ER-positive, HER2-negative metastatic breast cancer patients, whose disease progressed on prior endocrine therapy. Premenopausal women also received the GNRH ago-nist, goserelin. The median PFS was 9.2 months for the combi-nation compared to 3.8 months with fulvestrant alone.343 Thus, fulvestrant with palbociclib is a potential option for women with metastatic breast cancer who have progressed on prior


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Surgery_Schwartz. for the combi-nation compared to 3.8 months with fulvestrant alone.343 Thus, fulvestrant with palbociclib is a potential option for women with metastatic breast cancer who have progressed on prior endo-crine therapy. Additionally, abemaciclib in combination with fulvestrant or as single agent is approved for use in ER-posi-tive advanced breast cancers previously treated with endocrine therapy.In premenopausal women with stage IV ER-positive breast cancer without previous exposure to endocrine therapy, initial treatment with tamoxifen or ovarian suppression/ablation plus aromatase inhibitor with or without CDK4/6 inhibitors are reasonable options.Activation of the PI3K/mammalian target of rapamycin (mTOR) signal transduction pathway has also been implicated in secondary resistance to estrogen targeting. BOLERO-2 eval-uated the use of exemestane in combination with everolimus in postmenopausal women with ER-positive tumors who had progressed or recurred on a nonsteroidal aromatase


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Surgery_Schwartz. estrogen targeting. BOLERO-2 eval-uated the use of exemestane in combination with everolimus in postmenopausal women with ER-positive tumors who had progressed or recurred on a nonsteroidal aromatase inhibitor.344 An improvement in PFS was observed with combination com-pared to exemestane alone (11 vs. 4.1 months) leading to FDA approval. Similar improvement in PFS was observed with a combination of tamoxifen and everolimus.345 However, a phase 3 trial of letrozole in combination with temsirolimus, an mTOR inhibitor, did not show any improvement in PFS in aromatase inhibitor–naive metastatic postmenopausal women.346 Trials evaluating the adjuvant use of mTOR inhibitors and CDK 4/6 inhibitors are currently in progress.Women whose tumors respond to an endocrine therapy with either shrinkage of their breast cancer (objective response) or long-term stabilization of disease (stable disease) are con-sidered to represent “clinical benefit” and should receive addi-tional endocrine therapy at