5% to 10% of all breast cancers are monogenic in origin. In other words, there is a mutation of the genes BRCA1, BRCA2 or other high-risk genes. In this edition of Deutsches Ärzteblatt International (Dtsch Arztebl Int 2011; 108(19): 323 30), Alfons Meindl of the Klinikum rechts der Isar (Munich) and coauthors report on new insights into the pathogenesis and treatment of hereditary breast and ovarian cancer and newly-discovered risk genes.

Meindl et al. evaluated data including those derived from the work of the German Consortium for Hereditary Breast and Ovarian Cancer. It was shown that if BRCA1 or BRCA2 is mutated, there is a breast cancer risk of up to 85% and an ovarian cancer risk of up to 50%. Another predisposing gene for breast and ovarian cancer is RAD51C. Like BRCA1 and BRCA2, it plays a central role in DNA repair and is mutated in approximately 1.5% to 4% of all families predisposed towards breast and ovarian cancer.

When there is evidence of a high-risk gene mutation, the authors recommend intensive risk-adjusted screening. Risk can be reduced by prophylactic bilateral removal of the breasts and ovaries. In the future, drug-based approaches to risk reduction may also be possible.

In Germany, breast cancer is the most common malignant disease in women and ovarian cancer the gynecological tumor with the highest mortality rate. There may be a hereditary cancer burden even if only two or more women, or one young woman, in a family develop the disease.

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Contact: Prof. Dr. Alfons Meindl
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Deutsches Aerzteblatt International

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Hereditary Breast and Ovarian Cancer
New Genes, New Treatments, New Concepts

Background: Every year, 60 000 women in Germany are found to have breast cancer, and 9000 to have ovarian cancer. Familial clustering of carcinoma is seen in about 20% of cases.

Methods: We selectively review relevant articles published up to December 2010 that were retrieved by a search in PubMed, and we also discuss findings from the experience of the German Consortium for Hereditary Breast and Ovarian Cancer.

Results: High risk is conferred by the highly penetrant BRCA1 and BRCA2 genes as well as by other genes such as RAD51C. Genes for breast cancer that were originally designated as moderately penetrant display higher penetrance than previously thought in families with a hereditary predisposition. The role these genes play in DNA repair is thought to explain why tumors associated with them are sensitive to platin derivatives and PARP inhibitors. In carriers of BRCA1 and BRCA2, prophylactic bilateral mastectomy and adnexectomy significantly lowers the incidence of breast and ovarian cancer. Moreover, prophylactic adnexectomy also lowers the breast-and-ovarian-cancer-specific mortality, as well as the overall mortality. If a woman bearing a mutation develops cancer in one breast, her risk of developing cancer in the other breast depends on the particular gene that is mutated and on her age at the onset of disease.

Conclusion: About half of all monogenically determined carcinomas of the breast and ovary are due to a mutation in one or the other of the highly penetrant BRCA genes (BRCA1 and BRCA2). Women carrying a mutated gene have an 80% to 90% chance of developing breast cancer and a 20% to 50% chance of developing ovarian cancer. Other predisposing genes for breast and ovarian cancer have been identified. Clinicians should develop and implement evidence-based treatments on the basis of these new findings.

In Germany, breast cancer is the most common malignant disease in women and ovarian cancer the gynecological tumor with the highest mortality rate (e1). There may be a hereditary cancer burden even if only two or more women, or one young woman, in a family develop the disease. Current work has shown that this may be caused by a monogenic or polygenic inheritance in which DNA repair genes are mutated. As yet there are no differences between the treatments provided for sporadic and hereditary breast and ovarian cancer,  although there are indications that targeted therapy is effective in women with BRCA1/BRCA2-associated tumors .  Retrospective studies reveal a high level of sensitivity to platin derivatives in BRCA-associated tumors (4), and initial clinical trials show good efficacy and tolerability for PARPs,  or poly ADP (adenosine diphosphate)-ribose polymerase inhibitors,  in mutation carriers with advanced breast and ovarian cancers. As PARPs are particularly effective on the tumor cells of mutation carriers, they might also potentially be used in chemoprevention.  Thanks to multimodal screening,  breast cancer in BRCA1/2 mutation carriers can be diagnosed at an early stage.  The selection of optimum examination methods and intervals and their possible effects on mortality are the subjects of ongoing studies.

As yet there is no efficient screening for ovarian cancer.  However,  the benefits of risk-reducing prophylactic surgery in mutation carriers have been confirmed. The German Consortium for Hereditary Breast and Ovarian Cancer (Deutsches Konsortium für Familiären Brust- und Eierstockkrebs) has centers in   12   universities   throughout   Germany   (http://url.health.am/333/-in German) and aims to provide structured, validated genetic diagnostics and the resulting diagnostic and therapeutic interventions in gynecological oncology,  via a multi disciplinary approach. This is possible not least thanks to central recording of inclusion criteria relating to patients’ medical histories for genetic testing and of genetic, histological, clinical, and follow-up data in the Consortium’s central database at the University of Leipzig (Institute for Medical Computing, Statistics and Epidemiology [Institut für Medizinische   Informatik,  Statistik und Epidemiologie, IMISE]).

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Alfons Meindl, Nina Ditsch, Karin Kast, Kerstin Rhiem, Rita K. Schmutzler
Meindl A, Ditsch N, Kast K, Rhiem K, Schmutzler RK: Hereditary breast and ovarian cancer-new genes, new treatments, new concepts. 
Dtsch Arztebl Int 2011; 108(19): 323–30.  DOI: 10.3238/arztebl.2011.0323

Hereditary Breast and Ovarian Cancer