ACR Appropriateness Criteria® Imaging of the Axilla.

This publication reviews the current evidence supporting the imaging approach of the axilla in various scenarios with broad differential diagnosis ranging from inflammatory to malignant etiologies. Controversies on the management of axillary adenopathy results in disagreement on the appropriate axillary imaging tests. Ultrasound is often the appropriate initial imaging test in several clinical scenarios. Clinical information (such as age, physical examinations, risk factors) and concurrent complete breast evaluation with mammogram, tomosynthesis, or MRI impact the type of initial imaging test for the axilla. Several impactful clinical trials demonstrated that selected patient's population can received sentinel lymph node biopsy instead of axillary lymph node dissection with similar overall survival, and axillary lymph node dissection is a safe alternative as the nodal staging procedure for clinically node negative patients or even for some node positive patients with limited nodal tumor burden. This approach is not universally accepted, which adversely affect the type of imaging tests considered appropriate for axilla. This document is focused on the initial imaging of the axilla in various scenarios, with the understanding that concurrent or subsequent additional tests may also be performed for the breast. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Association of Medicaid Expansion with Post-mastectomy Reconstruction Rates.

BACKGROUND: The Affordable Care Act sought to improve access to health care for low-income individuals. This study aimed to assess whether expansion of Medicaid coverage increased rates of post-mastectomy reconstruction (PMR) for patients who had Medicaid or no insurance. METHODS: A retrospective analysis performed through the National Cancer Database examined women who underwent PMR and were uninsured or had Medicaid, private insurance, or Medicare, and whose race/ethnicity, age, and state expansion status were known. Trends in the use of PMR after passage of Medicaid expansion in 2014 were evaluated. RESULTS: In all states and at all time periods, patients with private insurance were about twice as likely to undergo PMR as patients who had Medicaid or no insurance. In 2016, only 28.7 % of patients with Medicaid or no insurance in nonexpansion states underwent PMR (p < 0.001) compared with 38.5 % of patients in expansion states (p < 0.001). Patients in expansion states also have higher levels of education, higher income, and greater likelihood of living in metropolitan areas. Additionally, patients in all states saw an increase in early-stage disease, with a concomitant reduction in late disease, but this change was greater in expansion states than in non-expansion states. CONCLUSIONS: Expansion states have larger proportions of patients undergoing PMR than non-expansion states. This difference stems from significant differences in income, education, comorbidities, race, and location. Large metropolitan areas have the largest number of patients undergoing PMR, whereas rural areas have the least.

CALGB 40603 (Alliance): Long-Term Outcomes and Genomic Correlates of Response and Survival After Neoadjuvant Chemotherapy With or Without Carboplatin and Bevacizumab in Triple-Negative Breast Cancer.

PURPOSE: CALGB 40603 (NCT00861705), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points. PATIENTS AND METHODS: The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing. RESULTS: Among baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P < .0001) and overall survival (87.9% v 63.4%, P < .0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS. CONCLUSION: Despite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival.

Early Local Therapy for the Primary Site in De Novo Stage IV Breast Cancer: Results of a Randomized Clinical Trial (EA2108).

PURPOSE: Distant metastases are present in 6% or more of patients with newly diagnosed breast cancer. In this context, locoregional therapy for the intact primary tumor has been hypothesized to improve overall survival (OS), but clinical trials have reported conflicting results. METHODS: Women presenting with metastatic breast cancer and an intact primary tumor received systemic therapy for 4-8 months; if no disease progression occurred, they were randomly assigned to locoregional therapy for the primary site (surgery and radiotherapy per standards for nonmetastatic disease) or continuing sysmetic therapy. The primary end point was OS; locoregional control and quality of life were secondary end points. The trial design provided 85% power to detect a 19.3% absolute difference in the 3-year OS rate in randomly assigned patients. The stratified log-rank test and Cox proportional hazards model were used to compare OS between arms. Cumulative incidence of locoregional progression was compared using Gray's test. Quality-of-life assessment used standard instruments. RESULTS: Of 390 participants enrolled, 256 were randomly assigned: 131 to continued systemic therapy and 125 to early locoregional therapy. The 3-year OS was 67.9% without and 68.4% with early locoregional therapy (hazard ratio = 1.11; 90% CI, 0.82 to 1.52; P = .57). The median OS was 53.1 months (95% CI, 47.9 to not estimable) in the systemic therapy arm and 54.9 months (95% CI, 46.7 to not estimable) in the locoregional therapy arm. Locoregional progression was less frequent in those randomly assigned to locoregional therapy (3-year rate: 16.3% v 39.8%; P < .001). Quality-of-life measures were largely similar between arms. CONCLUSION: Early locoregional therapy for the primary site did not improve survival in patients presenting with metastatic breast cancer. Although it was associated with improved locoregional control, this had no overall impact on quality of life.

Exploring the impact of exercise and mind-body prehabilitation interventions on physical and psychological outcomes in women undergoing breast cancer surgery.

PURPOSE: To compare the impact of exercise and mind-body prehabilitation interventions on changes in quality of life and cancer treatment-related symptoms in women with newly diagnosed breast cancer. METHODS: The following describes a secondary analysis of a randomized window of opportunity trial (The Pre-Operative Health and Body Study). Forty-nine women were randomized to participate in either an exercise prehabilitation intervention or a mind-body prehabilitation intervention from the time of enrollment to surgery. Participants (N = 47) completed measures of quality of life, anxiety, depression, and stress at the time of enrollment (T1), post-intervention/surgery (T2), and one-month post-surgery (T3). Changes in outcome measures between groups were compared over time using longitudinal models. RESULTS: Mind-body group participants experienced significant improvements in cognitive functioning in comparison to exercise group participants between T1 and T3 (difference in average change: -9.61, p = 0.04, d = 0.31), otherwise, there were no significant differences between groups. Within group comparisons demonstrated that both groups experienced improvements in anxiety (exercise: average change = -1.18, p = 0.03, d = 0.34; mind-body: average change = -1.69, p = 0.006, d = 0.43) and stress (exercise: average change = -2.33, p = 0.04, d = 0.30; mind-body: average change = -2.59, p = 0.05, d = 0.29), while mind-body group participants experienced improvements in insomnia (average change = -10.03, p = 0.04, d = 0.30) and cognitive functioning (average change = 13.16, p = 0.0003, d = 0.67). CONCLUSIONS: Both prehabilitation interventions impacted cancer treatment-related symptoms. Further work in larger groups of patients is needed to evaluate the efficacy of prehabilitation interventions on quality of life in women with breast cancer. Pre-operative exercise and mind-body interventions may impact physical and/or psychological effects of cancer diagnosis and treatment in women with breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01516190. Registered January 24, 2012.

Matched cohort study of germline BRCA mutation carriers with triple negative breast cancer in brightness.

In the BrighTNess trial, carboplatin added to neoadjuvant chemotherapy (NAC) was associated with increased pathologic complete response (pCR) rates in patients with stage II/III triple-negative breast cancer (TNBC). In this matched cohort study, cases with a germline BRCA1/2 mutation (gBRCA; n = 75) were matched 1:2 with non-gBRCA controls (n = 150) by treatment arm, lymph node status, and age to evaluate pCR rates and association of benefit from platinum/PARP inhibitors with validated RNA expression-based immune, proliferation, and genomic instability scores among gBRCA with the addition of carboplatin ± veliparib to NAC. Among the well-matched cohorts, odds of pCR were not higher in gBRCA cancers who received standard NAC with carboplatin (OR 0.24, 95% CI [0.04-1.24], p = 0.09) or with carboplatin/veliparib (OR 0.44, 95% CI [0.10-1.84], p = 0.26) compared to non-gBRCA cancers. Higher PAM50 proliferation, GeparSixto immune, and CIN70 genomic instability scores were each associated with higher pCR rate in the overall cohort, but not specifically in gBRCA cases. In this study, gBRCA carriers did not have higher odds of pCR than non-gBRCA controls when carboplatin ± veliparib was added to NAC, and showed no significant differences in molecular, immune, chromosomal instability, or proliferation gene expression metrics.

The Impact of COVID-19 on Breast Surgery Fellowships.

Purpose of Review: Across the world, medical training has been affected by the COVID-19 virus and this has changed the way physicians are educated. What is less clear is the effect of the pandemic on breast surgical oncology fellows who were in training during this time. This review discusses the experience of breast surgical oncology fellows during the pandemic and how fellowships adapted to preserve the educational experience and conserve the quality of training. Recent Findings: The challenges and changes experienced by breast surgery fellows during the COVID-19 pandemic have proved to be sudden shifts in not only fellowship training, but future patient care and research opportunities, all while confronting the global impact of a deadly pandemic. While experiences between fellowships varied, the similarities and differences encountered highlight the regional and temporal differences in how fellowships responded to the pandemic. Summary: Breast surgical oncology fellowship is one year long, with every day allocated to ensure the surgeon has a deep understanding of the multidisciplinary approach to this ever-evolving field. As the pandemic spread and affected different regions with varying severity, elective cases were canceled, resources were re-allocated, and uncertainty abounded. At the same time, novel approaches to fellowship training were rapidly implemented. It will take time and additional research to fully understand the long-term consequences for trainees affected during their breast surgery fellowship.

Interim clinical trial analysis of intraoperative mass spectrometry for breast cancer surgery.

Optimal resection of breast tumors requires removing cancer with a rim of normal tissue while preserving uninvolved regions of the breast. Surgical and pathological techniques that permit rapid molecular characterization of tissue could facilitate such resections. Mass spectrometry (MS) is increasingly used in the research setting to detect and classify tumors and has the potential to detect cancer at surgical margins. Here, we describe the ex vivo intraoperative clinical application of MS using a liquid micro-junction surface sample probe (LMJ-SSP) to assess breast cancer margins. In a midpoint analysis of a registered clinical trial, surgical specimens from 21 women with treatment naïve invasive breast cancer were prospectively collected and analyzed at the time of surgery with subsequent histopathological determination. Normal and tumor breast specimens from the lumpectomy resected by the surgeon were smeared onto glass slides for rapid analysis. Lipidomic profiles were acquired from these specimens using LMJ-SSP MS in negative ionization mode within the operating suite and post-surgery analysis of the data revealed five candidate ions separating tumor from healthy tissue in this limited dataset. More data is required before considering the ions as candidate markers. Here, we present an application of ambient MS within the operating room to analyze breast cancer tissue and surgical margins. Lessons learned from these initial promising studies are being used to further evaluate the five candidate biomarkers and to further refine and optimize intraoperative MS as a tool for surgical guidance in breast cancer.

Surgical Management of Hereditary Breast Cancer.

The identification that breast cancer is hereditary was first described in the nineteenth century. With the identification of the BRCA1 and BRCA 2 breast/ovarian cancer susceptibility genes in the mid-1990s and the introduction of genetic testing, significant advancements have been made in tailoring surveillance, guiding decisions on medical or surgical risk reduction and cancer treatments for genetic variant carriers. This review discusses various medical and surgical management options for hereditary breast cancers.

Immunotherapy Treatment for Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has dismal prognosis. Local recurrence rate after standard therapy in the early breast cancer setting can be upwards to 72% in 5 years, and in the metastatic setting, the 5-year overall survival is 12%. Due to the lack of receptor expression, there has been a paucity of targeted therapeutics available, with chemotherapy being the primary option for systemic treatment in both the neoadjuvant and metastatic setting. More recently, immunotherapy has revolutionized the landscape of cancer treatment, particularly immune checkpoint inhibitor (ICI) therapy, with FDA approval in over 20 types of cancer since 2011. Compared to other cancer types, breast cancer has been traditionally thought of as being immunologically cold; however, TNBC has demonstrated the most promise with immunotherapy use, a timely discovery due to its lack of targeted therapy options. In this review, we summarize the trials using checkpoint therapy in early and metastatic TNBC, as well as the development of biomarkers and the importance of immune related adverse events (IRAEs), in this disease process.

Apocrine Breast Cancer: Unique Features of a Predominantly Triple-Negative Breast Cancer.

INTRODUCTION: Invasive apocrine carcinoma is a rare breast cancer that is frequently triple negative. Little is known about the characteristics of its molecular subtypes. We compared the incidence, demographics, and clinicopathologic features of this cancer with non-apocrine carcinomas stratified by molecular subtype. METHODS: Women with invasive apocrine cancer were retrospectively identified from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic and demographic features were compared with non-apocrine carcinomas, both overall using data from 2004 to 2017 and stratified by molecular subtypes using data from 2010 to 2017. The life table method was used to determine the 7-year breast cancer-specific survival. RESULTS: Compared with non-apocrine cancers, apocrine cancers presented at a younger age, with larger, higher-grade tumors that were much more likely to be triple negative (50% vs. 11%) or human epidermal growth factor receptor 2 (HER2)-positive (28% vs. 15%) and less likely to be luminal (22% vs. 74%); however, the 7-year survival was the same at 85%. The characteristics varied dramatically by molecular type. Compared with non-apocrine triple-negative, apocrine triple-negative patients were less likely to be African American and were much older, with smaller, lower-grade tumors and much better survival (86% vs. 74%). In contrast, compared with luminal non-apocrine, apocrine luminal patients had larger, higher-grade tumors and worse survival (79% vs. 89%). CONCLUSIONS: Invasive apocrine carcinomas have more aggressive features than non-apocrine carcinomas but the breast cancer-specific survival is the same. Half of these apocrine tumors are triple negative but these have more favorable features and much better survival than non-apocrine triple-negative cancers.

Cancer Awareness and Stigma in Rural Assam India: Baseline Survey of the Detect Early and Save Her/Him (DESH) Program.

BACKGROUND: India has an estimated incidence of more than one million cancers annually. Breast, oral, and cervical cancers account for over one-third of newly diagnosed cases. With the introduction of pilot cancer screening programs in India, little is known about current sociocultural barriers that may hinder acceptance of screening and treatment. We sought to identify knowledge gaps, misconceptions, and stigmas surrounding cancer diagnosis. PATIENTS AND METHODS: A baseline survey was conducted in Assam, India, as part of the Detect Early and Save Her/Him program, a mobile screening program for breast, oral, and cervical cancer. Data were collected on participants' cancer knowledge, and attitudes towards screening, diagnosis, and treatment. RESULTS: Of the 923 residents who participated, a large majority (92.9%; n = 858) were neither aware of cancer screening availability nor had prior screening. Low-medium awareness was demonstrated regarding the carcinogenic effects of betel nuts (n = 433, 47%). Only one-third of participants recognized oral ulcers and dysphagia as cancer symptoms. Approximately 10% of respondents had misconceptions about cancer etiologies, and 42-57% endorsed statements reflecting a negative stigma towards cancer, including its long-term detrimental effects on personal, occupational, and familial life. However, the majority (68-96%) agreed with statements endorsing positive community support and medical care for cancer patients. CONCLUSIONS: This study identifies actionable targets for intervention in cancer education and awareness within a large rural Indian population. Education to address preventable causes of cancer and to correct misconceptions and stigma is a critical component in ensuring the successful implementation of cancer screening programs.

Optimal Management for Residual Disease Following Neoadjuvant Systemic Therapy.

OPINION STATEMENT: Treatment sequencing in early-stage breast cancer has significantly evolved in recent years, particularly in the triple negative (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive subsets. Instead of surgery first followed by chemotherapy, several clinical trials showed benefits to administering systemic chemotherapy (and HER2-targeted therapies) prior to surgery. These benefits include more accurate prognostic estimates based on the extent of residual cancer that can also guide adjuvant treatment, and frequent tumor downstaging that can lead to smaller surgeries in patients with large tumors at diagnosis. Patients with extensive invasive residual cancer after neoadjuvant therapy are at high risk for disease recurrence, and two pivotal clinical trials, CREATE-X and KATHERINE, demonstrated improved recurrence free survival with adjuvant capecitabine and ado-trastuzumab-emtansine (T-DM1) in TNBC and HER2-positive residual cancers, respectively. Patients who achieve pathologic complete response (pCR) have excellent long-term disease-free survival regardless of what chemotherapy regimen induced this favorable response. This allows escalation or de-escalation of adjuvant therapy: patients who achieved pCR could be spared further chemotherapy, while those with residual cancer could receive additional chemotherapy postoperatively. Ongoing clinical trials are testing this strategy (CompassHER2-pCR: NCT04266249). pCR also provides an opportunity to assess de-escalation of locoregional therapies. Currently, for patients with residual disease in the lymph nodes (ypN+), radiation therapy entails coverage of the undissected axilla, and may include supra/infraclavicular/internal mammary nodes in addition to the whole breast or chest wall, depending on the type of surgery. Ongoing trials are testing the safety of omitting post-mastectomy breast and post-lumpectomy nodal irradiation (NCT01872975) as well as omitting axillary lymph node dissection (NCT01901094) in the setting of pCR. Additionally, evolving technologies such as minimal residual disease (MRD) monitoring in the blood during follow-up may allow early intervention with "second-line systemic adjuvant therapy" for patients with molecular relapse which might prevent impending clinical relapse.

Factors Associated with Nodal Pathologic Complete Response Among Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: Results of CALGB 40601 (HER2+) and 40603 (Triple-Negative) (Alliance).

BACKGROUND: De-escalation of axillary surgery after neoadjuvant chemotherapy (NAC) requires careful patient selection. We seek to determine predictors of nodal pathologic complete response (ypN0) among patients treated on CALGB 40601 or 40603, which tested NAC regimens in HER2+ and triple-negative breast cancer (TNBC), respectively. PATIENTS AND METHODS: A total of 760 patients with stage II-III HER2+ or TNBC were analyzed. Those who had axillary surgery before NAC (N = 122), or who had missing pretreatment clinical nodal status (cN) (N = 58) or ypN status (N = 41) were excluded. The proportion of patients with ypN0 disease was estimated for those with and without breast pathologic complete response (pCR) according to pretreatment nodal status. RESULTS: In 539 patients, the overall ypN0 rate was 76.3% (411/539) to 93.2% (245/263) in patients with breast pCR and 60.1% (166/276) with residual breast disease (RD) (P < 0.0001). For patients who were cN0 pretreatment, the ypN0 rate was 88.8% (214/241), 96.3% (104/108) with breast pCR, and 82.7% (110/133) with RD. For patients who were cN1, 66.2% (157/237) converted to ypN0, 91.7% (111/121) with breast pCR and 39.7% (46/116) with RD. For patients who were cN2/3, 65.6% (40/61) converted to ypN0, 88.2% (30/34) with breast pCR and 37.0% (10/27) with RD. On multivariable analysis, only pretreatment clinical nodal status and breast pCR/RD were associated with ypN0 status (both P < 0.0001). CONCLUSIONS: Breast pCR and pretreatment nodal status are predictive of ypN0 axillary nodal involvement, with < 5% residual nodal disease among cN0 patients who experience breast pCR. These findings support the incorporation of axillary surgery de-escalation strategies into NAC trials.

Association of Immunophenotype With Pathologic Complete Response to Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Secondary Analysis of the BrighTNess Phase 3 Randomized Clinical Trial.

IMPORTANCE: Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood. OBJECTIVE: To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression-based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019. INTERVENTIONS: Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib. MAIN OUTCOMES AND MEASURES: Association of gene expression-based molecular subtype (PAM50 and TNBC subtypes) with pCR. RESULTS: Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P < .001) and immune (hazard ratio, 0.62; 95% CI, 0.49-0.79; P < .001) signatures were independently associated with pCR. Tumors above the median for proliferation and immune signatures had the highest pCR rate (84 of 125; 67%), while those below the median for both signatures had the lowest pCR rate (42 of 125; 34%). Exploratory gene expression immune analyses suggested that tumors with higher inferred CD8+ T-cell infiltration may receive greater benefit with addition of carboplatin. CONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized clinical trial, triple-negative breast cancer subtyping revealed high pCR rates in basal-like and immunomodulatory subsets. Analysis of biological processes related to basal-like and immunomodulatory phenotypes identified tumor cell proliferation and immune scores as independent factors associated with achieving pCR; the benefit of carboplatin on pCR was seen across all molecular subtypes. Further validation of immunophenotype with existing biomarkers may help to escalate or de-escalate therapy for patients with TNBC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02032277.