Underutilization of Needle Biopsy Before Breast Surgery: A Measure of Low-Value Care.

BACKGROUND: Breast core needle biopsy (CNB) can obviate the need for breast surgery in patients with an unknown breast lesion; however, variation in compliance with this guideline may represent a disparity in health care and a surrogate measure of unnecessary surgery. We evaluated variation in breast CNB rates prior to initial breast cancer surgery. METHODS: We performed a retrospective analysis using Medicare claims from 2015 to 2017 to evaluate the proportion of patients who received a CNB within 6 months prior to initial breast cancer surgery. Outlier practice pattern was defined as a preoperative CNB rate ≤ 70%. Logistic regression was used to evaluate surgeon characteristics associated with outlier practice pattern. RESULTS: We identified 108,935 female patients who underwent initial breast cancer surgery performed by 3229 surgeons from July 2015 to June 2017. The mean CNB rate was 86.7%. A total of 7.7% of surgeons had a CNB performed prior to initial breast surgery ≤ 70% of the time, and 2.0% had a CNB performed ≤ 50% of the time. Outlier breast surgeons were associated with practicing in a micropolitan area (odds ratio [OR] 1.88, 95% confidence interval [CI] 1.29-2.73), in the South (OR 1.84, 95% CI 1.20-2.84) or West region (OR 1.78, 95% CI 1.11-2.86), > 20 years in practice (OR 1.52, 95% CI 1.09-2.11), and low breast cancer surgery volume (< 30 cases in the study period; OR 4.03, 95% CI 2.75-5.90). CONCLUSIONS: Marked variation exists in whether a breast core biopsy is performed prior to initial breast surgery, which may represent unnecessary surgery on individual patients. Providing surgeon-specific feedback on guideline compliance may reduce unwarranted variation.

Association of Event-Free and Distant Recurrence-Free Survival With Individual-Level Pathologic Complete Response in Neoadjuvant Treatment of Stages 2 and 3 Breast Cancer: Three-Year Follow-up Analysis for the I-SPY2 Adaptively Randomized Clinical Trial.

Importance: Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial. Objective: To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents. Design, Setting, and Participants: Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019. Interventions: Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide. Main Outcomes and Measures: Pathologic complete response and 3-year EFS and DRFS. Results: Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS. Conclusions and Relevance: The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.

Management of the clinically positive axilla.

Axillary dissection has been the standard of care for any patient with clinically positive lymph nodes at initial breast cancer presentation. However, modern neo-adjuvant therapies can convert positive nodes to negative nodes, especially in the setting of HER2-positive disease. Accurate axillary staging can be achieved after neo-adjuvant therapy in initially node-positive patients using dual tracer lymphatic mapping, removal of three or more lymph nodes, and confirmation of excision of the previously biopsied and clipped lymph node. Currently accruing clinical trials are designed to determine which patients can safely avoid axillary dissection and/or axillary radiation.

Survival and Disease Recurrence Rates among Breast Cancer Patients following Mastectomy with or without Breast Reconstruction.

BACKGROUND: Concerns have been expressed about the oncologic safety of breast reconstruction following mastectomy for breast cancer. This study aimed to evaluate the association of breast reconstruction with breast cancer recurrence, and 5-year survival among breast cancer patients. METHODS: The authors analyzed data from The Johns Hopkins Hospital comprehensive cancer registry, comparing mastectomy-only to postmastectomy breast reconstruction in breast cancer patients to evaluate differences in breast cancer recurrence and 5-year survival. Kaplan-Meier curves were used to compare unadjusted estimates of survival or disease recurrence. Data were modeled through Cox proportional hazards regression, using as outcomes time to death from any cause or time to cancer recurrence. RESULTS: The authors analyzed data on 1517 women who underwent mastectomy for breast cancer at The Johns Hopkins hospital between 2003 and 2015. Of these, 504 (33.2 percent) underwent mastectomy only and 1013 (66.8 percent) underwent mastectomy plus immediate breast reconstruction. Women were followed up for a median of 5.1 years after diagnosis. There were 132 deaths and 100 breast cancer recurrences. A comparison of Kaplan-Meier survival estimates demonstrated a survival benefit among patients undergoing mastectomy plus reconstruction. After adjusting for various clinical and socioeconomic variables, there was still an overall survival benefit associated with breast reconstruction which, however, was not statistically significant (hazard ratio, 0.78; 95 percent CI, 0.53 to 1.13). Patients who underwent reconstruction had a similar rate of recurrence compared to mastectomy-only patients (hazard ratio, 1.08; 95 percent CI, 0.69 to 1.69). CONCLUSION: This study suggests that breast reconstruction does not have a negative impact on either overall survival or breast cancer recurrence rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Consensus Guidelines on Genetic` Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons.

BACKGROUND: The purpose of this consensus guideline is to outline recommendations for genetic testing that medical professionals can use to assess hereditary risk for breast cancer. METHODS: Literature review included large datasets, basic and clinical science publications, and recent updated national guidelines. Genetic testing to assess hereditary risk of cancer is a complex, broad, and dynamic area of medical research. The dominant focus of this guideline is limited in scope to breast cancer. RESULTS: There is a lack of consensus among experts regarding which genes among many should be tested in different clinical scenarios. There is also variation in the degree of consensus regarding the understanding of risk and appropriate clinical management of mutations in many genes. CONCLUSIONS: Genetic testing should be made available to all patients with a personal history of breast cancer. Recent data are reviewed that support genetic testing being offered to each patient with breast cancer (newly diagnosed or with a personal history). If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and family history. For patients with newly diagnosed breast cancer, identification of a mutation may impact local treatment recommendations. Patients who had genetic testing previously may benefit from updated testing. Genetic testing should be made available to patients without a history of breast cancer who meet National Comprehensive Cancer Network guidelines. Finally, variants of uncertain significance are not clinically actionable and these patients should be managed based on their individual risk factors.

Germline Genetic Testing: What the Breast Surgeon Needs to Know.

PURPOSE: The American Society of Breast Surgeons (ASBrS) sought to provide educational guidelines for breast surgeons on how to incorporate genetic information and genomics into their practice. METHODS: A comprehensive nonsystematic review was performed of selected peer-reviewed literature. The Genetics Working Group of the ASBrS convened to develop guideline recommendations. RESULTS: Clinical and educational guidelines were prepared to outline the essential knowledge for breast surgeons to perform germline genetic testing and to incorporate the findings into their practice, which have been approved by the ASBrS Board of Directors. RECOMMENDATIONS: Thousands of women in the USA would potentially benefit from genetic testing for BRCA1, BRCA2, and other breast cancer genes that markedly increase their risk of developing breast cancer. As genetic testing is now becoming more widely available, women should be made aware of these tests and consider testing. Breast surgeons are well positioned to help facilitate this process. The areas where surgeons need to be knowledgeable include: (1) identification of patients for initial breast cancer-related genetic testing, (2) identification of patients who tested negative in the past but now need updated testing, (3) initial cancer genetic testing, (4) retesting of patients who need their genetic testing updated, (5) cancer genetic test interpretation, posttest counseling and management, (6) management of variants of uncertain significance, (7) cascade genetic testing, (8) interpretation of genetic tests other than clinical cancer panels and the counseling and management required, and (9) interpretation of somatic genetic tests and the counseling and management required.

Change in health-related quality of life in older women after diagnosis of a small breast cancer.

BACKGROUND: Screening mammography reduces breast cancer mortality at the cost of frequent false-positive results that lead to unnecessary medical procedures, and the treatment of indolent breast cancers that would never threaten life or health. Earlier diagnosis generally permits less disruptive treatment, but it is possible that even the diagnosis of a very small breast cancer could significantly adversely impact health-related quality of life (HRQOL) in older women. METHODS: The authors compared changes in HRQOL measured by either the Medical Outcomes Study 36-Item Short Form (SF-36) or the Veterans Rand 12-item Health Survey (VR-12) between 198 women diagnosed with in situ or invasive breast cancer measuring ≤1 cm and 36,814 matched controls using the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registry linked with the Medicare Health Outcomes Survey. RESULTS: The mean age of the cases and controls was 75 years. The SF-36/VR-12 physical component score 12 was found to decrease by 1.6 points between the baseline and follow-up surveys for the controls compared with 3.2 points for women diagnosed with small breast cancers (P = .016). A 2-point decline is recognized as the minimally significant difference for this measure. On multivariable analysis, diagnosis of a small breast cancer was found to be one of the strongest predictors of a significant decrease in both the physical and mental domains of HRQOL (P = .012 and P = .023, respectively). CONCLUSIONS: Receiving the diagnosis of even a very small breast cancer significantly impacts the physical and mental domains of HRQOL in older women. This finding can inform discussions regarding the relative benefits and costs of screening mammography in older women.

Surgeon Re-Excision Rates after Breast-Conserving Surgery: A Measure of Low-Value Care.

BACKGROUND: To better understand re-excision practice patterns after breast-conserving therapy (BCT), we evaluated variation in surgeon-specific re-excision rates and associated factors. STUDY DESIGN: We performed a retrospective analysis using Medicare claims from 2012 to 2018 to identify patients undergoing BCT and subsequent breast resection procedures within 12 months. We compared rates before and after the 2014 "no tumor on ink" consensus guideline. A hierarchical logistic regression model was also used to evaluate patient and physician characteristics associated with re-excision. RESULTS: We identified 291,065 female Medicare beneficiaries who underwent an initial BCT procedure, of which 19.0% had a re-excision. The overall re-excision rate was 22.1% in the pre-guideline period and 17.2% in the post-guideline period. For the 5,337 physicians that performed more than 10 initial BCT procedures during the study period, their physician-level re-excision rate ranged from 0% to 91.7% (median 18.2%). In total, 17.5% of the physicians had a re-excision rate greater than the expert consensus cutoff of 30%. The percentage of outlier physicians decreased from 22.2% in 2012 to 8.8% in 2017. High surgeon volume of BCT was associated with a lower re-excision odds (≥51 cases vs ≤20 cases: adjusted odds ratio 0.78; 95% CI 0.74 to 0.82; 21 to 50 cases vs ≤20 cases: adjusted odds ratio 0.92; 95% CI 0.88 to 0.96). Patient factors associated with decreased odds of re-excision were age older than 75 years and Northeast region of the US (adjusted odds ratio 0.93; 95% CI 0.89 to 0.98). CONCLUSIONS: Marked variation exists in surgeon re-excision rates among patients undergoing BCT, which might represent unnecessary operations for patients and a financial burden to the healthcare system. Formalizing a re-excision frequency metric could have implications for quality improvement and data-driven surgeon feedback aimed at reducing unwarranted variation.

The Use of Tumescent Technique in Mastectomy and Related Complications: A Meta-Analysis.

BACKGROUND: Postoperative skin necrosis in surgical patients is costly to hospitals and health care providers. Tumescent dissection technique is commonly used in mastectomy and immediate breast reconstruction, as it helps reduce blood loss; however, it may increase the risk of mastectomy skin flap necrosis. In this context, the authors have conducted a systematic review of the literature to perform a meta-analysis of the relationship between tumescent technique in mastectomy with or without breast reconstruction and complication rates. METHODS: The authors screened the PubMed (1966 to 2016), Scopus (2004 to 2016), Embase (1966 to 2016), and Web of Science (1964 to 2016) databases for relevant articles through March 30, 2017. The authors included studies on the use of tumescent technique in the context of mastectomy with or without immediate breast reconstruction. The primary outcome the authors evaluated was the rate of skin flap necrosis; the secondary outcomes were the rates of breast hematomas and infections. Because of the heterogeneity of the studies, the authors performed a meta-analysis using the random effects model. RESULTS: After screening, the authors evaluated five studies including 3982 mastectomies. Mastectomies performed under the preoperative application of tumescent solution had statistically higher rates of skin flap necrosis overall (p = 0.03) and major (p < 0.01) and minor skin necrosis (p = 0.03). However, the rates of hematoma and infection were not correlated with the use of tumescent technique. CONCLUSIONS: The authors' systematic review of the literature provides a better understanding of the consequences of the application of tumescent technique in mastectomy. The authors' findings suggest that tumescent technique may increase the risk of skin necrosis in mastectomy with or without breast reconstruction.

Invasive Breast Cancer Preferably and Predominantly Occurs at the Interface Between Fibroglandular and Adipose Tissue.

BACKGROUND: Increasing evidence suggests adipocyte involvement in malignant breast tumor invasive front or margin. The aim of this study was to evaluate the location of invasive breast tumors in relation to fibroglandular and adipose tissue by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). PATIENTS AND METHODS: Pretreatment breast DCE-MRI images of 294 patients with biopsy-proven invasive breast cancer from 2008 to 2014 were studied. Invasive breast tumors were visualized as enhanced lesions in the postcontrast subtraction images. Positive identification of biopsy-confirmed invasive breast tumors on DCE-MRI images was achieved by correlation of findings from breast MRI and pathology reports. Tumor location in relation to fibroglandular and adipose tissue was investigated using precontrast T1-weighted MRI images. RESULTS: Of 294 patients, 291 had DCE-MRI discernable invasive breast tumors located at the interface between fibroglandular and adipose tissues, regardless of the tumor size, type, receptor status, or breast composition. CONCLUSION: Invasive breast cancer preferably and predominantly occurs adjacent to breast adipose tissue.

Society of Surgical Oncology Breast Disease Working Group Statement on Prophylactic (Risk-Reducing) Mastectomy.

Over the past several years, there has been an increasing rate of bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM) surgeries. Since publication of the 2007 SSO position statement on the use of risk-reducing mastectomy, there have been significant advances in the understanding of breast cancer biology and treatment. The purpose of this manuscript is to review the current literature as a resource to facilitate a shared and informed decision-making process regarding the use of risk-reducing mastectomy.

A comparison of trends in operative approach and postoperative outcomes for colorectal cancer surgery.

BACKGROUND: Data-assessing trends and perioperative outcomes relative to surgical approach for colorectal cancer (CRC) surgery are lacking. We report national trends of CRC surgery and compare postoperative outcomes by surgical approach. METHODS: A total of 261,886 patients undergoing surgery for CRC were identified using the Nationwide Inpatient Sample from 2009 to 2012. Trends in surgical approach were assessed using the Cochrane-Armitage test of trends. Multivariable logistic and linear regression analyses were performed to compare length of stay (LOS), postoperative complications, and cost by surgical approach. RESULTS: At the time of surgery, 57.5% underwent an open procedure, whereas 42.4% underwent either a laparoscopic (39.9%) or robotic (2.5%) colorectal surgery. The use of minimally invasive surgery increased over time (2009 versus 2012: 37.3% versus 46.8%; P < 0.001). Postoperative morbidity was 15.9% and was higher after open surgery (open versus laparoscopic versus robotic: 18.4% versus 12.4% versus 13.3%; P < 0.001). Patients who underwent a minimally invasive surgery had shorter LOS (laparoscopic: OR, 0.55, 95% CI, 0.52-0.58; robotic: OR, 0.58; 95% CI, 0.49-0.69; both P < 0.001). Robotic surgery was consistently associated with the highest mean costs followed by laparoscopic and open surgery (P < 0.001). CONCLUSIONS: Patients undergoing minimally invasive colorectal surgery had a lower postoperative morbidity and shorter LOS compared with patients undergoing open colorectal surgery.

Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study.

Purpose Epigenetic alterations measured in blood may help guide breast cancer treatment. The multisite prospective study TBCRC 005 was conducted to examine the ability of a novel panel of cell-free DNA methylation markers to predict survival outcomes in metastatic breast cancer (MBC) using a new quantitative multiplex assay (cMethDNA). Patients and Methods Ten genes were tested in duplicate serum samples from 141 women at baseline, at week 4, and at first restaging. A cumulative methylation index (CMI) was generated on the basis of six of the 10 genes tested. Methylation cut points were selected to maximize the log-rank statistic, and cross-validation was used to obtain unbiased point estimates. Logistic regression or Cox proportional hazard models were used to test associations between the CMI and progression-free survival (PFS), overall survival (OS), and disease status at first restaging. The added value of the CMI in predicting survival outcomes was evaluated and compared with circulating tumor cells (CellSearch). Results Median PFS and OS were significantly shorter in women with a high CMI (PFS, 2.1 months; OS, 12.3 months) versus a low CMI (PFS, 5.8 months; OS, 21.7 months). In multivariable models, among women with MBC, a high versus low CMI at week 4 was independently associated with worse PFS (hazard ratio, 1.79; 95% CI, 1.23 to 2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21 to 2.54; P = .003). An increase in the CMI from baseline to week 4 was associated with worse PFS ( P < .001) and progressive disease at first restaging ( P < .001). Week 4 CMI was a strong predictor of PFS, even in the presence of circulating tumor cells ( P = .004). Conclusion Methylation of this gene panel is a strong predictor of survival outcomes in MBC and may have clinical usefulness in risk stratification and disease monitoring.

Adaptive Randomization of Neratinib in Early Breast Cancer.

BACKGROUND: The heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for high-risk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery). METHODS: We used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature. RESULTS: Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%. CONCLUSIONS: Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor-negative breast cancer. (Funded by QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer.

BACKGROUND: The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS: In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS: With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. CONCLUSIONS: The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

New Insights into the Surgical Management of Breast Cancer.

William Halstead is considered by many as the father of modern breast surgery. He popularized the notion that breast cancer progresses in an orderly fashion and that appropriately timed radical surgery can interrupt this progression to save lives. This view dominated for nearly 100 years and still persists to one extent or another in the minds of physicians and patients alike. Rapid advances in breast cancer biology have highlighted the heterogeneity of breast cancer and paradigm-shifting clinical trials have successfully challenged prevailing wisdom to effect a seed change in breast cancer surgery. Advances in radiation and systemic therapies permit more limited surgery for most patients. Recurrence rates of all kinds are on the decline; yet, paradoxically, use of bilateral mastectomy is increasing.