Rate of BRCA mutation in patients tested under NCCN genetic testing criteria.

BACKGROUND: BRCA genetic testing is recommended by the National Comprehensive Cancer Network (NCCN) in breast cancer patients who meet specific criteria. Limited data are available on the likelihood of detecting a mutation when these guidelines are followed. METHODS: A retrospective chart review examined patients with breast cancer who underwent BRCA testing based on NCCN guidelines. RESULTS: Twelve (6.0%) of the 199 patients had a deleterious BRCA mutation. Family history of BRCA mutations (50%, p = 0.019), age ≤45 at diagnosis (9.7%, p = 0.034) and meeting ≥3 NCCN criteria (13.3%, p = 0.03) yielded the highest rates of BRCA mutation. Having a family history of BRCA mutation and age ≤45 were associated with increased rate of BRCA mutation on multivariate analysis (OR 14.3, CI 1.2-166.3; OR 11.6, CI 1.2-108.6). CONCLUSION: Select NCCN criteria are associated with higher rates of BRCA mutations. Waiting for genetic testing results to guide surgical management may be warranted in this subset of patients.

Updates on the role of receptor activator of nuclear factor κB/receptor activator of nuclear factor κB ligand/osteoprotegerin pathway in breast cancer risk and treatment.

PURPOSE OF REVIEW: Treatment with bisphosphonates and denosumab is the standard of care in bone metastatic disease. In addition, the adjuvant therapy of denosumab or bisphosphonates is very effective to prevent loss of bone mineral density, for example in osteoporosis. However, it is still unclear if this therapy has an influence on preventing cancer. RECENT FINDINGS: Since the identification of novel genes in the 1980s, it took about 30 years until denosumab, as a fully human mAb against receptor activator of nuclear factor (NF)-κB ligand (RANKL), could be introduced to clinical practice. The discovery of the receptor activator of NF-κB/RANKL/osteoprotegerin pathway in the 1990s is an example of how modern databases of genes were utilized to discover new pathways relevant to a variety of diseases. The essential role of this pathway for the function, differentiation and survival of osteoclasts, and the influence on the bone microenvironment helped to understand the vicious circle of bone resorption and destruction in many skeletal diseases. SUMMARY: In the following review, we discuss the important role of rational targeting concerning receptor activator of NF-κB/RANKL/osteoprotegerin and the bisphosphonate therapy and provide an update for the related treatment of patients suffering from breast cancer and further implications for clinical practice and research using denosumab as a potential chemoprevention in BRCA1-related breast cancer.

Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities.

OBJECTIVE: To estimate the incidence of genetic counseling referral for ovarian cancer patients who are at substantial risk for a BRCA1 or BRCA2 mutation. METHODS: An analysis was performed of new ovarian cancer patients who were seen at a comprehensive cancer center from January 1, 1999, through December 31, 2007. Patients at substantial (more than 20-25%) risk for a BRCA1 or BRCA2 mutation were identified and records reviewed for referral to genetic counseling. Time to referral was estimated using the Kaplan-Meier method. RESULTS: A total of 3,765 epithelial ovarian cancer patients were seen during the 9-year period. On average, 23.8% of patients met substantial-risk criteria for BRCA mutations. In 1999, only 12% of patients at substantial-risk were referred. Referral improved over time with 48% referred in 2007 (P<.001). Newly diagnosed patients were more often referred for genetic counseling than new patients with recurrent disease or those seen as second opinions. African-American women meeting substantial-risk criteria were less likely to be referred than were white or Hispanic women (P=.009). CONCLUSION: Although dictated family history was accurate, interpretation of risk for BRCA1 or BRCA2 mutations and subsequent referral to genetic counseling was poor. Although there was significant improvement over time, 50% of substantial-risk patients still were missed. Systematic efforts to identify those ovarian cancer patients at substantial risk for a BRCA1 or BRCA2 are necessary.

Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan.

There is no tailored therapy yet for human basal-like mammary carcinomas. However, BRCA1 dysfunction is frequently present in these malignancies, compromising homology-directed DNA repair. This defect may serve as the tumor's Achilles heel and make the tumor hypersensitive to DNA breaks. We have evaluated this putative synthetic lethality in a genetically engineered mouse model for BRCA1-associated breast cancer, using the topoisomerase I (Top1) poison topotecan as monotherapy and in combination with poly(ADP-ribose) polymerase inhibition by olaparib. All 20 tumors tested were topotecan sensitive, but response heterogeneity was substantial. Although topotecan increased mouse survival, all tumors eventually acquired resistance. As mechanisms of in vivo resistance, we identified overexpression of Abcg2/Bcrp and markedly reduced protein levels of the drug target Top1 (without altered mRNA levels). Tumor-specific genetic ablation of Abcg2 significantly increased overall survival of topotecan-treated animals (P < 0.001), confirming the in vivo relevance of ABCG2 for topotecan resistance in a novel approach. Despite the lack of ABCG2, a putative tumor-initiating cell marker, none of the 11 Abcg2(-/-);Brca1(-/-);p53(-/-) tumors were eradicated, not even by the combination topotecan-olaparib. We find that olaparib substantially increases topotecan toxicity in this model, and we suggest that this might also happen in humans.

[Hereditary breast and ovarian cancer: primary and secondary prevention for BRCA1 and BRCA2 mutation carriers]. / Cáncer de mama y ovario hereditario: prevención primaria y secundaria en mujeres portadoras de mutación en los genes BRCA1 y BRCA2.

Ten years after the identification of the breast and ovarian cancer predisposition genes, BRCA1 and BRCA2, an emerging literature has explored the efficacy of strategies for primary as well as secondary prevention of breast and ovarian cancer in BRCA1 and BRCA2 mutations carriers. The integration of magnetic resonance imaging for breast cancer screening in BRCA carriers has achieved a higher sensibility of the screening, and an early detection of breast cancer. However, we don't have yet enough level of evidence that magnetic resonance imaging could reduce mortality in BRCA carriers. Because of the limitations of screening for ovarian cancer, bilateral prophylactic salpingo-oophorectomy has been established as one of the most effective strategies to prevent ovarian cancer in BRCA1 and BRCA2 mutation carriers. This strategy also has a favorable effect on the reduction of risk of breast cancer if is performed before the age of 50. The management of this patients must be individualized and multidisciplinary.

Soya phytonutrients act on a panel of genes implicated with BRCA1 and BRCA2 oncosuppressors in human breast cell lines.

Breast cancer is the most common cancer in women and a significant cause of death. Mutations of the oncosuppressor genes BRCA1 and BRCA2 are associated with a hereditary risk of breast cancer, and dysregulation of their expression has been observed in sporadic cases. Soya isoflavones have been shown to inhibit breast cancer in studies in vitro, but associations between the consumption of isoflavone-containing foods and breast cancer risk have varied in epidemiological studies. Soya is a unique source of the phytoestrogens daidzein (4',7-dihydroxyisoflavone) and genistein (4',5,7-trihydroxyisoflavone), two molecules that are able to inhibit the proliferation of human breast cancer cells in vitro. The aim of the present study was to determine the effects of genistein (5 microg/ml) and daidzein (20 microg/ml) on transcription in three human breast cell lines (one dystrophic, MCF10a, and two malignant, MCF-7 and MDA-MB-231) after 72 h treatment. The different genes involved in the BRCA1 and BRCA2 pathways (GADD45A, BARD1, JUN, BAX, RB1, ERalpha, ERbeta, BAP1, TNFalpha, p53, p21Waf1/Cip1, p300, RAD51, pS2, Ki-67) were quantified by real-time quantitative RT-PCR, using the TaqMan method and an ABI Prism 7700 Sequence Detector (Applied Biosystems). We observed that, in response to treatment, many of these genes were overexpressed in the breast cancer cell lines (MCF-7 and MDA-MB-231) but not in the dystrophic cell line (MCF10a).