Cancers with mutations in BRCA2 have defective DNA repair capacity which is potentially targetable with poly-ADP(ribose) polymera se (PARP) inhibitors such as olaparib and rucaparib. However, the development of a secondary mutation that restores BRCA2 function is a well-documented mechanism of resistance to PARP inhibitors. Here, we present a case report of a man with metastatic castration-resistant prostate cancer with a germline BRCA2 frameshift mutation. Treatment with olaparib resulted in an initial response but was followed by progression. Cell-free DNA testing after progression revealed the presence of polyclonal BRCA2 mutations that were estimated to restore it into the correct reading frame. We describe his treatment course and genetic testing results and then discuss the biological mechanisms driving this mechanism of resistance.
Cancer treatment and research communications. 2021 Oct 20 [Epub ahead of print]
Taylor Ryan McFarland, Clara Elizabeth Tandar, Neeraj Agarwal, Umang Swami
Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States., Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States. Electronic address: ., Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States. Electronic address: .