Women with adverse mutations in the BRCA1 or BRCA2 gene are at an increased lifetime risk of ovarian cancer, and these mutations also increase vulnerability to cancers of the fallopian tube and peritoneum. Risk levels were examined in a prospective study based on data from an international registry comprising 32 centers in Canada, the United States, Europe, and Israel. The 1828 women identified as carrying a BRCA1 or BRCA2 mutation were followed up for a mean of 3.5 years. Participants had a mean age at entry of 47 years. Approximately three-fourths of the women carried a BRCA1 mutation and about one-fourth, a BRCA2 mutation; eight individuals carried both. Nearly one-third of women in the study (30.4%) had undergone bilateral salpingo-oophorectomy before entering the study, and another 38.5% had an oophorectomy during follow-up. Fifty incident cancers were discovered during follow-up. Thirty-two of these cancers developed in women with intact ovaries. Eleven cancers were identified at the time of prophylactic oophorectomy, and 7 others after this procedure. The cumulative incidence of peritoneal cancer was estimated at 4.3% two decades after oophorectomy. The overall adjusted reduction in cancer risk associated with bilateral oophorectomy was 80%, with a multivariate hazard ratio of 0.2 and a 95% confidence interval of 0.07-0.58 (Fig. 1). The risk of ovarian, tubal, and primary peritoneal cancers in women with intact ovaries was highest for those 60-70 years of age who carried the BRCA1 mutation. Based on estimated incidence rates for women having both ovaries intact, the estimated penetrance of ovarian cancer was 62% up to age 75 years for carriers of the BRCA1 mutation, and 18% up to age 75 for those carrying the BRCA2 mutation. The investigators conclude that the risk of ovarian, tubal, and peritoneal cancer is lowered by 80% for carriers of the BRCA1 or BRCA2 mutation who undergo prophylactic oophorectomy. The findings support prophylactic surgery as a very effective risk reduction measure. Both the ovaries and the fallopian tubes should be removed. The residual risk of peritoneal cancer is not high enough to recommend against prophylactic surgery.

/pdf/salpingo-oophorectomy-and-the-risk-of-ovarian-fallopian-tube-1uupnjaccc.pdf

Salpingo -oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation

BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53 . Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.

Significance: Defining the temporal order of tumor-driving somatic events is critical for early detection, risk stratification, and the design of chemopreventive therapies. Our combined experimental and computational approach reveal that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors. Cancer Discov; 2(6); 503–11 . © 2012 AACR .

This article is highlighted in the In This Issue feature, [p. 473][1]

 [1]: /lookup/volpage/2/473?iss=6

/pdf/evolutionary-pathways-in-brca1-associated-breast-tumors-41ka5b6y11.pdf

Evolutionary Pathways in BRCA1-Associated Breast Tumors

Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown clinical activity in patients with germline BRCA1/2 mutation (gBRCAm)-associated breast and ovarian cancers. Accumulating evidence suggests that PARPi may have a wider application in the treatment of cancers defective in DNA damage repair pathways, such as prostate, lung, endometrial, and pancreatic cancers. Several PARPi are currently in phase I/II clinical investigation, as single-agents and/or combination therapy in these solid tumors. Understanding more about the molecular abnormalities involved in BRCA-like phenotype in solid tumors beyond breast and ovarian cancers, exploring novel therapeutic trial strategies and drug combinations, and defining potential predictive biomarkers are critical to expanding the scope of PARPi therapy. This will improve clinical outcome in advanced solid tumors. Here, we briefly review the preclinical data and clinical development of PARPi, and discuss its future development in solid tumors beyond gBRCAm-associated breast and ovarian cancers.

/pdf/beyond-breast-and-ovarian-cancers-parp-inhibitors-for-brca-1um8bpcand.pdf

Beyond Breast and Ovarian Cancers: PARP Inhibitors for BRCA Mutation-Associated and BRCA-Like Solid Tumors.

Identification of germline mutations associated with significant cancer susceptibility has the potential to change all aspects of an individual's care, from screening to cancer treatment. For example, women with germline mutations in BRCA1 and BRCA2 have markedly elevated risks of breast and ovarian cancer and the identification of these germline mutations has led to specific screening and prevention strategies. More recently, advances in the understanding of the biological function of BRCA1 and BRCA2 have led to clinical trials testing targeted therapies in this population, particularly poly(ADP-ribose) polymerase (PARP) inhibitors. Unfortunately, the development of PARP inhibitors has not been as rapid as anticipated and has been more challenging than expected. Somatic mutations identified in many cancer types have allowed the development of therapeutics that target these mutated genes, and many of these agents obtained rapid regulatory approval and are currently in widespread clinical practice. Diagnostic testing has a central role in targeted cancer therapeutics for both somatic and germline mutations. Although the era of molecular medicine and targeted therapies has led to significant changes in the practice of oncology, new challenges continue to arise.

Cancer treatment according to BRCA1 and BRCA2 mutations

Polymorphisms of catechol estrogens metabolism pathway genes and breast cancer risk in Mexican women.

A small, but important, percentage of breast cancer cases is caused by the inheritance of a single copy of a mutated gene. BRCA1 and BRCA2 are the genes most commonly associated with inherited breast cancer; however, mutations in TP53 and PTEN cause Li-Fraumeni syndrome and Cowden syndrome, respectively, both of which are associated with high lifetime risks of breast cancer. Advances in the field of breast cancer genetics have led to an improved understanding of detection and prevention strategies. More recently, strategies to target the underlying genetic defects in BRCA1- and BRCA2-associated breast and ovarian cancers are emerging and may have implications for certain types of sporadic breast cancer.

https://www.hemonc.theclinics.com/article/S0889-8588(10)00093-6/pdf

Breast Cancer Predisposition Syndromes

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Breast Cancer Predisposition Syndromes