Adherence to Recommended Risk Management among Unaffected Women with a BRCA Mutation

Identifying unaffected women with a BRCA mutation can have a significant individual and population health impact on morbidity and mortality if these women adhere to guidelines for managing cancer risk. But, little is known about whether such women are adherent to current guidelines. We conducted telephone surveys of 97 unaffected BRCA mutation carriers who had genetic counseling at least one year prior to the survey to assess adherence to current guidelines, factors associated with adherence, and common reasons for performing and not performing recommended risk management. More than half of participants reported being adherent with current risk management recommendations for breast cancer (69%, n=67), ovarian cancer (82%, n=74) and both cancers (66%, n=64). Older age (OR=10.53, p=0.001), white race (OR=8.93, p=0.019), higher breast cancer genetics knowledge (OR=1.67, p=0.030), higher cancer-specific distress (OR=1.07, p=0.002) and higher physical functioning (OR=1.09, p=0.009) were significantly associated with adherence to recommended risk management for both cancers. Responses to open-ended questions about reasons for performing and not performing risk management behaviors indicated that participants recognized the clinical utility of these behaviors. Younger individuals and those with lower physical functioning may require targeted interventions to improve adherence, perhaps in the setting of long-term follow-up at a multi-disciplinary hereditary cancer clinic

Improved Surgical Outcomes for Breast Cancer Patients Receiving Neoadjuvant Aromatase Inhibitor Therapy: Results from a Multicenter Phase II Trial

Background: Neoadjuvant aromatase inhibitor therapy has been reported to improve surgical outcomes for postmenopausal women with clinical stage II or III hormone receptor-positive breast cancer. A multicenter phase II clinical trial was conducted to investigate the value of this approach for US surgical practice. Study Design: One hundred fifteen postmenopausal women with >2 cm, estrogen receptor (ER) or progesterone receptor (PgR)-positive breast cancer were enrolled in a trial of 16 to 24 weeks of letrozole 2.5 mg daily before operation. Results: One hundred six patients were eligible for primary analysis, 96 underwent operations, 7 received chemotherapy after progressive disease, and 3 did not undergo an operation. Baseline surgical status was marginal for breast-conserving surgery (BCS) in 48 (45%), 47 were definitely ineligible for BCS (44%), and 11 were inoperable by standard mastectomy (10%). Overall Response Evaluation Criteria In Solid Tumors clinical response rate in the breast was 62%, with 12% experiencing progressive disease. Fifty percent underwent BCS, including 30 of 46 (65%) patients who were initially marginal for BCS and 15 of 39 (38%) patients who were initially ineligible for BCS. All 11 inoperable patients successfully underwent operations, including 3 (27%) who had BCS. Nineteen percent of patients undergoing mastectomy had a pathologic T1 tumor, suggesting that some highly responsive tumors were overtreated surgically. Conclusions: Neoadjuvant aromatase inhibitor improves operability and facilitates BCS, but there was considerable variability in responsiveness. Better techniques to predict response, determine residual tumor burden before operation, and greater willingness to attempt BCS in responsive patients could additionally improve the rate of successful BCS

Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer

A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor ‘drivers’ (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-015-3476-2) contains supplementary material, which is available to authorized users

Cancer Yield of Mammography, MR, and US in High-Risk Women: Prospective Multi-Institution Breast Cancer Screening Study

PURPOSE: To prospectively determine cancer yield, callback and biopsy rates, and positive predictive value (PPV) of mammography, magnetic resonance (MR) imaging, and ultrasonography (US) in women at high risk for breast cancer. MATERIALS AND METHODS: The study was approved by the institutional review board and was HIPAA compliant, and informed consent was obtained. We conducted a prospective pilot study of screening mammography, MR, and US in asymptomatic women 25 years of age or older who were genetically at high risk, defined as BRCA1/BRCA2 carriers or with at least a 20% probability of carrying a BRCA1/BRCA2 mutation. All imaging modalities were performed within 90 days of each other. Data were analyzed by using exact confidence intervals (CIs) and the McNemar test. RESULTS: A total of 195 women were enrolled in this study over a 6-month period, and 171 completed all study examinations (mammography, US, and MR). Average age of the 171 participants was 46 years +/- 10.2 (standard deviation). Sixteen biopsies were performed and six cancers were detected, for an overall 3.5% cancer yield. MR enabled detection of all six cancers; mammography, two; and US, one. The diagnostic yields for each test were 3.5% for MR, 0.6% for US, and 1.2% for mammography. MR, US, and mammography findings prompted biopsy in 8.2%, 2.3%, and 2.3% of patients, respectively. None of the pairwise comparisons were statistically significant. The PPV of biopsies performed as a result of MR was 43%. CONCLUSION: Screening MR imaging had a higher biopsy rate but helped detect more cancers than either mammography or US. US had the highest false-negative rate compared with mammography and MR, enabling detection of only one in six cancers in high-risk women

An Integrated Approach to the Prediction of Chemotherapeutic Response in Patients with Breast Cancer

BACKGROUND: A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective. METHODS AND RESULTS: Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide) chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%). When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06). Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8%) of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04), representing a viable alternative therapy. CONCLUSIONS: Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding microRNA and mRNA expression profiles. Importantly, we also present evidence to support the concept that analysis of molecular variables can present a rational strategy to identifying alternative therapeutic opportunities

Femara® and the future: tailoring treatment and combination therapies with Femara

Long-term estrogen deprivation treatment for breast cancer can, in some patients, lead to the activation of alternate cellular pathways, resulting in the re-emergence of the disease. This is a distressing scenario for oncologists and patients, but recent intensive molecular and biochemical studies are beginning to unravel these pathways, revealing opportunities for new targeted treatments. Far from making present therapies redundant, these new discoveries open the door to novel combination therapies that promise to provide enhanced efficacy or overcome treatment resistance. Letrozole, one of the most potent aromatase inhibitors, is the ideal candidate for combination therapy; indeed, it is one of the most intensively studied aromatase inhibitors in the evolving combinatorial setting. Complementary to the use of combination therapy is the development of molecular tools to identify patients who will benefit the most from these new treatments. Microarray gene profiling studies, designed to detect letrozole-responsive targets, are currently under way to understand how the use of the drug can be tailored more efficiently to specific patient needs