Predictive Value and Therapeutic Significance of Somatic BRCA Mutation in Solid Tumors

Abstract

Ten percent of patients with breast cancer, and probably somewhat more in patients with ovarian cancer, have inherited germline DNA mutations in the breast and ovarian cancer genes BRCA1 and BRCA2. In the remaining cases, the disease is caused by acquired somatic genetic and epigenetic alterations. Targeted therapeutic agents, such as poly ADP-ribose polymerases (PARP) inhibitors (PARPi), have emerged in treating cancers associated with germline BRCA mutations since 2014. The first PARPi was FDA-approved initially for ovarian cancer patients with germline BRCA mutations. Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency status have been strong predictors of response to PARPi in a few solid tumors since then. However, the relevance of somatic BRCA mutations is less clear. Somatic BRCA-mutated tumors might also respond to this new class of therapeutics. Although the related literature is often controversial, recently published case reports and/or randomized studies demonstrated the effectiveness of PARPi in treating patients with somatic BRCA mutations. The aim of this review is to summarize the predictive role of somatic BRCA mutations and to provide further assistance for clinicians with the identification of patients who could potentially benefit from PARPi.

Keywords: PARP inhibition; breast neoplasms; ovarian neoplasms; pancreatic neoplasms; prostatic neoplasms; somatic BRCA1/2.

Figure 1

Schematic representation of germline and somatic BRCA gene mutations. In the case of germline mutation, all cells of the body contain the mutated gene variant, and it is always passed on from parent to offspring. Somatic mutations occur at a later stage of ontogeny, and the random mutations develop during normal mitotic cell divisions. Note: The schematic human figure, the embryo, and the oocyte were created with the assistance of DALL·E 2; otherwise, the authors did every other aspect of the figure, including the different coloring, arrangement, and labeling. The normal and mutated DNA sequence is courtesy of Wikimedia Commons; the unmodified original was created by NASA/David Herring and distributed under the CC0 1.0 license.