'BRCAness' and its implications for platinum action in gynecologic cancer

Gynecological carcinomas are major therapeutic targets of platinum-containing regimens. They may be particularly susceptible to these agents if their origins are related to hereditary breast cancer (BRCA) mutations; this implicates defective DNA repair secondary to inherited alterations in BRCA function. The concept of 'BRCAness' was introduced by Ashworth and colleagues in order to identify phenotypic changes in sporadic cancer that would lead to analogous treatment susceptibility. In fact, recent analyses of genetic alterations in ovarian cancer have led to further extending this concept to all women with high-grade serous cancer, the predominant form of ovarian cancer arising in association with hereditary mutations in BRCA genes. Presumably, most serous types of cancer of gynecological origin share BRCA dysfunction to some extent. This renders these types of cancer susceptible to platinum and to other DNA-damaging agents, justifying the general inclusion of this histology in trials of new drugs and therapeutic strategies that have shown activity against hereditary cancer. More recently, however, differences in outcome between BRCA mutation carriers vis-à-vis those with no mutations or those with epigenetic or acquired forms of BRCA genes (somatic mutations) in their respective tumors have been identified. These findings raise additional questions on modifiers of 'BRCAness' and other pathways that appear to contribute to the effects of platinum and other DNA-damaging agents in ovarian cancer. The Cancer Genome Atlas analyses delineate the complexity of genomic alterations in ovarian cancer and other malignancies of Mullerian epithelial origin promising further refinements of the 'BRCAness' concept.