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.

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.

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.

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.).

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.

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.

Contralateral Prophylactic Mastectomy: Challenging Considerations for the Surgeon.

The use of both bilateral prophylactic mastectomy and contralateral prophylactic mastectomy (CPM) has increased significantly during the last decade. Various risk models have been developed to identify patients at increased risk for breast cancer. The indications for bilateral prophylactic mastectomy for patients without a diagnosis of breast cancer include high risk from mutation in BRCA or other breast cancer predisposition gene, very strong family history with no identifiable mutation, and high risk based on breast histology. Additionally, the use of CPM has more than doubled in the last decade, and this increase is noted among all stages of breast cancer, even in patients with ductal carcinoma in situ (stage 0). The risk of contralateral breast cancer often is overestimated by both patients and physicians. Nevertheless, specific risk factors are associated with an increased risk of contralateral breast cancer, including BRCA or other genetic mutation, young age at diagnosis, lobular histology, family history, and prior chest wall irradiation. Although CPM reduces the incidence of contralateral breast cancer, the effect on disease-free survival and, more importantly, overall survival is questionable and underscored by the fact that the reason most patients choose CPM is to achieve "peace of mind." Newer and effective reconstructive options have made the procedure more attractive. This panel addresses the indications and rationale for bilateral prophylactic mastectomy and CPM, the decision-making process by patients, and ethical considerations. Changes in the physician-patient relationship during the past few decades have altered the approach, and ethical considerations are paramount in addressing these issues.

Breast cancer prevention.

Breast cancer is the most common cancer in women with 232,670 new cases estimated in the USA for 2014. Approaches for reducing breast cancer risk include lifestyle modification, chemoprevention, and prophylactic surgery. Lifestyle modification has a variety of health benefits with few associated risks and is appropriate for all women regardless of breast cancer risk. Chemoprevention options have expanded rapidly, but most are directed at estrogen receptor positive breast cancer and uptake is low. Prophylactic surgery introduces significant additional risks of its own and is generally reserved for the highest risk women.

The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience.

PURPOSE: The advent of next-generation sequencing for cancer susceptibility genes holds promise for clinical genetics application, but the practical issues surrounding integration of this testing into the clinical setting have not been well addressed. This article describes the clinical experience of genetic counselors in an academic and community setting with next-generation sequencing cancer panels. METHODS: Between April 2012 and January 2013, 60 next-generation sequencing panels were ordered. A retrospective review was conducted to determine the indication for ordering the results of the tests and the patient management based on the results. RESULTS: Ten tests were canceled due to out-of-pocket costs or previously identified mutations. Among the 50 tests, 5 (10%) showed a positive result. Moreover, 15 of the 50 (30%) panels detected variant(s) of uncertain significance or variant(s) suspected benign. CONCLUSION: We propose clinical guidelines for identifying high-risk patients who should be offered this testing. Our data support the National Comprehensive Cancer Network recommendations that next-generation sequencing be ordered as a second-tier test for high-risk individuals with cancer by trained cancer genetics providers. Literature review and expert knowledge should be used to create management plans for the identification of both positive and variants of uncertain significance results. Providers should be aware of limitations regarding reimbursement for testing and recommended management strategies.

Commentary on the Canadian National Breast Screening study.

In the setting of the 25-year follow-up of the Canadian National Breast Screening Study, the Society of Surgical Oncology continues to endorse mammographic screening for women beginning at 40 years of age, while acknowledging that mammography has both risks and benefits. Further investigation is warranted to develop better screening methods and to determine optimal screening schedules for women based on their risk of future breast cancer and their imaging characteristics.

The clinical consequences of hemizygosity across 2 MB of 10q23 are restricted to Cowden syndrome.

Cowden syndrome is caused by germline mutations in PTEN and clinically characterized by hamartomas, macrocephaly, classic dermatologic stigmata, and an estimated 85 % lifetime risk of female breast cancer. A young woman with macrocephaly, tricholemmomas, AV malformations, and mammary papillomatosis was found to be hemizygous for PTEN in her germline DNA. Using MLPA, comparative genomic hybridization, and DNA sequencing, we identified a 2-Mb deletion in chromosome 10 spanning 344-kb centromeric and 1.7-Mb telomeric of PTEN. Her father who has a clinical history including macrocephaly, Hashimoto's thyroiditis, colonic polyposis, acral keratoses, and goiter was also found to have the same deletion. In benign breast tissue from the hemizygous female, PTEN protein expression was significantly reduced in luminal and stromal cells but present in the myoepithelium. Compared with a typical papilloma of the breast which had intense cytoplasmic PTEN staining, the majority of the patient's papilloma had significantly decreased PTEN expression while some cells had mislocalized perinuclear PTEN expression. In addition to PTEN, 22 other protein-coding genes were deleted including two predicted haploinsufficient genes and five additional genes that have previously been associated with hereditary predispositions to certain diseases. However, because all significant clinical features of the proband and her father are common to patients with genetic alterations in PTEN, the other 22 hemizygous protein-coding genes appear to be haplosufficient.

Evaluation of a hydrogel based breast biopsy marker (HydroMARK®) as an alternative to wire and radioactive seed localization for non-palpable breast lesions.

BACKGROUND AND OBJECTIVES: HydroMARK® is a newly available biopsy marker for image-guided needle biopsies of non-palpable breast lesions. Objective was to determine if the marker could be utilized independently for lesion localization using intra-operative ultrasound alone. METHODS: A single institution retrospective review identified patients who underwent surgical excision of breast lesions after placement of the HydroMARK®. Endpoints included intra-operative visualization of the marker, successful excision of the lesion, and presence of the marker on specimen radiograph. RESULTS: The study included 31 lesions in 25 patients. Twenty-nine (93.6%) HydroMARKSs® were adequately visualized by intra-operative ultrasound. Intra-operative ultrasound without pre-operative placement of a localizing device was successful for localization in six cases (19.4%). Intra-operative difficulties were encountered in 16 of 31 (51.6%) procedures. This included either extrusion of the marker when the biopsy tract was transected in 14 (45.2%) cases or migration of the marker prior to the procedure in two (6.4%) cases. The marker was visualized on specimen radiograph in 15 (48.4%) cases. CONCLUSIONS: While intraoperative sonographic visibility was excellent, a large number of excisions were associated with extrusion of the marker. Modifications are needed to improve acceptability of this marker for intra-operative localization independent of pre-operative wire or seed localization.

ETV6-NTRK3--Trk-ing the primary event in human secretory breast cancer.

In this issue of Cancer Cell, propose a single chromosomal translocation as the cause of a particularly troubling form of breast cancer, secretory carcinoma. They challenge widely held beliefs concerning breast carcinogenesis as well as beliefs concerning the absolute association of specific fusion genes with specific tumor types. Their data highlight the role of Trk signaling in breast cancer and also suggest a target for drug development.

New insights into the prevention and treatment of familial breast cancer.

Individuals who inherit a deleterious mutation in BRCA1 or BRCA2 are at very high risk for breast cancer but there are several strategies available for successfully managing this risk. Breast cancers that develop in the context of germline BRCA gene mutation present challenges for management but also opportunities. DNA damaging agents, like cisplatin, and the new class of drugs called PARP inhibitors exploit the underlying defect in DNA damage repair to great effect.