Andrea Silber

Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women

Purpose: To evaluate the frequency and distribution of BRCA1 and BRCA2 mutations in a cohort of young women with breast cancer and to compare the distribution of mutations as a function of race. Methods: After IRB approved informed consent, 170 white women and 30 African American women with known breast cancer diagnosed at a young age (45 years or less) underwent complete sequencing of the BRCA1 and BRCA2 genes. Each cohort represented approximately 40% of women of the same ethnic background aged 45 years or younger in a breast cancer database. Results: Of the 200 patients tested, 131 (65%) had wild type mutations, 34 (17%) had deleterious mutations, and 35 (18%) had variants of uncertain significance. There were no significant differences between the white and African American cohorts regarding the percentage of deleterious mutations (17% v 17%). However, most African American patients had mutations in BRCA2 (4/5, 80%), while most mutations in the white cohort were in BRCA1 (20/29, 69%). In addition, 46% of the African American women had variants of uncertain significance, compared to only 12% of the white cohort. Conclusions: Young African American women with breast cancer have a similar frequency of deleterious mutations as white women, but have a significantly higher frequency of variants of uncertain significance. Review of these variants revealed that the majority were unlikely to be associated with disease risk or were likely to be polymorphisms. The implications for genetic testing and counselling in young women with breast cancer are discussed.

Preoperative Breast Magnetic Resonance Imaging and Contralateral Breast Cancer Occurrence Among Older Women With Breast Cancer

PURPOSE Preoperative magnetic resonance imaging (MRI) detects occult contralateral breast cancers (CBCs) in women with breast cancer, but the impact of detection on long-term CBC events is unclear. We examined whether MRI use decreases the occurrence of CBCs and the detection of stages II to IV disease among women who develop a CBC. PATIENTS AND METHODS Analyzing the SEER-Medicare database, we assessed overall, synchronous (< 6 months after primary cancer diagnosis), and subsequent (ie, metachronous) stage-specific CBC occurrences in women who were diagnosed with stages I and II breast cancer during 2004-2009 and who were observed through 2011. RESULTS Among 38,971 women with breast cancer, 6,377 (16.4%) received preoperative MRI. After propensity score matching, and compared with women who did not undergo MRI, preoperative MRI use was significantly associated with a higher synchronous CBC detection rate (126.4 v 42.9 per 1,000 person-years, respectively; hazard ratio, 2.85; P < .001) but a lower subsequent CBC detection rate (3.3 v 4.5 per 1,000 person-years, respectively; hazard ratio, 0.68; P = .002). However, the 5-year cumulative incidence of CBC remained significantly higher among women undergoing MRI compared with those not undergoing MRI (7.2% v 4.0%, respectively; P < .001). The analyses of projected CBC events for 10,000 patients who receive MRI indicated that, after a 5-year follow-up, MRI use would detect an additional 192 in situ CBCs (95% CI, 125 to 279) and 120 stage I CBCs (95% CI, 62 to 193) but would not have a significant impact on stages II to IV CBC occurrences (∼ 6; 95% CI, -21 to 47). CONCLUSION An increased synchronous CBC detection rate, attributable to MRI, was not offset by a decrease of subsequent CBC occurrence among older women with early-stage breast cancer, suggesting that preoperative MRI in women with breast cancer may lead to overdiagnosis.

Impacts of Early Guideline-Directed 21-Gene Recurrence Score Testing on Adjuvant Therapy Decision Making

PURPOSE The 21-gene recurrence score (RS) assay is used to help formulate adjuvant chemotherapy recommendations for patients with estrogen receptor-positive, early-stage breast cancer. Most frequently, medical oncologists order RS after surgery. Results take an additional 2 weeks to return, which can delay decision making. We conducted a prospective quality-improvement project to assess the impact of early guideline-directed RS ordering by surgeons before the first visit with a medical oncologist on adjuvant therapy decision making. MATERIALS AND METHODS Surgical oncologists ordered RS testing following National Comprehensive Cancer Network guidelines at time of diagnosis or at time of surgery between July 1, 2015 and December 31, 2015. We measured the testing rate of patients eligible for RS, time to chemotherapy decisions, rates of chemotherapy use, accrual to RS-based clinical trials, cost, and physician acceptance of the policy and compared the results to patients who met eligibility criteria for early guideline-directed testing during the 6 months before the project. RESULTS Ninety patients met eligibility criteria during the testing period. RS was ordered for 91% of patients in the early testing group compared with 76% of historical controls ( P < .001). Median time to chemotherapy decision was significantly shorter in the early testing group (20 days; 95% CI, 17 to 23 days) compared with historical controls (32 days; 95% CI, 29 to 35 days; P < .001). There were no significant differences in time to chemotherapy initiation, chemotherapy use, RS-based trial enrollment, or calculated costs between the groups. CONCLUSION Early guideline-directed RS testing in selected patients is an effective way to shorten time to treatment decisions.

Bidirectional Text Messaging to Monitor Endocrine Therapy Adherence and Patient-Reported Outcomes in Breast Cancer

INTRODUCTION Up to 40% of patients with breast cancer may not adhere to adjuvant endocrine therapy. Therapy-related adverse effects (AEs) are important contributors to nonadherence. We developed a bidirectional text-message application, BETA-Text, that simultaneously tracks adherence, records symptoms, and alerts the clinical team. PATIENTS AND METHODS We piloted our intervention in 100 patients. The intervention consisted of text messages to which patients responded for 3 months: daily, evaluating adherence; weekly, evaluating medication-related AEs; and monthly, regarding barriers to adherence. Concerning responses prompted a telephone call from a clinic nurse. The primary objective was to assess patient acceptance of this intervention using self-reported surveys. To compare participants with the general population at our institution, we assessed 100 consecutively treated patients as historical controls using medical record review. RESULTS We approached 141 consecutive patients, 100 (71%) of whom agreed to participate and 89 of whom completed the intervention. A majority of patients reported that the intervention was easy to use (98%) and helpful in taking their medication (96%). Four patients discontinued therapy before 3 months, and 93% of patients who continued therapy took ≥ 80% of their medication. The frequency of AEs reported by participants via text was higher than that reported in clinical trials: hot flashes (72%), arthralgias (53%), and vaginal symptoms (35%). Approximately 39% of patients reported one or more severe AE that prompted an alert to the provider team to call the patient. CONCLUSION A daily bidirectional text-messaging system can monitor adherence and identify AEs and other barriers to adherence in real time without inconveniencing patients. AEs of endocrine therapy, as detected using this texting approach, are more prevalent than reported in clinical trials.

Mutation based treatment recommendations from next generation sequencing data: a comparison of web tools

Interpretation of complex cancer genome data, generated by tumor target profiling platforms, is key for the success of personalized cancer therapy. How to draw therapeutic conclusions from tumor profiling results is not standardized and may vary among commercial and academically-affiliated recommendation tools. We performed targeted sequencing of 315 genes from 75 metastatic breast cancer biopsies using the FoundationOne assay. Results were run through 4 different web tools including the Drug-Gene Interaction Database (DGidb), My Cancer Genome (MCG), Personalized Cancer Therapy (PCT), and cBioPortal, for drug and clinical trial recommendations. These recommendations were compared amongst each other and to those provided by FoundationOne. The identification of a gene as targetable varied across the different recommendation sources. Only 33% of cases had 4 or more sources recommend the same drug for at least one of the usually several altered genes found in tumor biopsies. These results indicate further development and standardization of broadly applicable software tools that assist in our therapeutic interpretation of genomic data is needed. Existing algorithms for data acquisition, integration and interpretation will likely need to incorporate artificial intelligence tools to improve both content and real-time status.

Associations of preoperative breast magnetic resonance imaging with subsequent mastectomy and breast cancer mortality

PurposeTo examine associations between pre-operative magnetic resonance imaging (MRI) use and clinical outcomes among women undergoing breast-conserving surgery (BCS) with or without radiotherapy for early-stage breast cancer.MethodsWe identified women from the Surveillance, Epidemiology, and End Results-Medicare dataset aged 67–94 diagnosed during 2004–2010 with stage I/II breast cancer who received BCS. We compared subsequent mastectomy and breast cancer mortality with versus without pre-operative MRI, using Cox regression and competing risks models. We further stratified by receipt of radiotherapy for subgroup analyses.ResultsOur sample consisted of 24,379 beneficiaries, 4691 (19.2%) of whom received pre-operative MRI. Adjusted rates of subsequent mastectomy and breast cancer mortality were not significantly different with and without MRI: 3.2 versus 4.1 per 1000 person-years [adjusted hazard ratio (AHR) 0.92; 95% confidence interval (CI) 0.70–1.19] and 5.3 versus 8.7 per 1000 person-years (AHR 0.89; 95% CI 0.73–1.08), respectively. In subgroup analyses, women receiving BCS plus radiotherapy had similar rates of subsequent mastectomy (AHR 1.17; 95% CI 0.84–1.61) and breast cancer mortality (AHR 1.00; 95% CI 0.80–1.24) with versus without MRI. However, among women receiving BCS alone, MRI use was associated with lower risks of subsequent mastectomy (AHR 0.60; 95% CI 0.37–0.98) and breast cancer mortality (AHR 0.57; 95% CI 0.36–0.92).ConclusionsPre-operative MRI was associated with improved outcomes among older women with breast cancer receiving BCS alone, but not among those receiving BCS plus radiotherapy. Further research is needed to identify appropriate settings for which MRI may be helpful.