Ruta Sahasrabudhe, PhD

In the current manuscript, &ldquo;Dramatic Response to Olaparib in a Patient With Metastatic Castration-Resistant Prostate Cancer: Patient Harboring a BRCA2 Germline Mutation,&rdquo; the authors describe a patient with metastatic castration-resistant prostate cancer (mCRPC) with visceral disease and a poor performance status of ECOG 3. His poor performance status is secondary to worsening pulmonary metastases from CRPC. The patient has already progressed on multiple lines of hormonal and chemotherapeutic agents for mCRPC. Normally, these patients have a median time to progression of 1 to 2 months and median overall survival ranging from 6 months to 9 months, thus consistent with a very poor overall outcome. The patient developed a rapid and durable response lasting for 9 months with single-agent olaparib (Lynparza), a PARP inhibitor. This article adds to the growing body of literature on the role of PARP inhibitors in tumors with DNA repair defects.

Homologous recombination (HR) is a form of DNA repair mechanism in which a sister chromatid is used as a template to accurately repair DNA damage. BRCA2 is a key regulator of HR and interacts and recruits multiple proteins, including RAD51, at the site of DNA double-strand breaks (DSBs). BRCA2 mutation carriers are primarily predisposed to hereditary breast and ovarian cancers as well as cancers of the prostate and pancreas. Deleterious mutations in BRCA2 are reported throughout the length of the gene. Exon 11 of the BRCA2 gene is highly conserved and contains BRC repeats responsible for interacting with RAD51. The mutation reported in this patient involves the BRC repeats in the BRCA2 gene required for binding to RAD51. BRCA2 is a known tumor-suppressor gene, and germline mutations in BRCA2 are often accompanied by loss of heterozygosity (LOH) in the tumor tissue. Interestingly, the germline mutation reported in this patient was not accompanied by LOH. This finding is consistent with a previous study that suggests that loss of wild-type copy of BRCA2 may not be required for BRCA2-mediated tumorigenesis in breast cancer.

Tumors deficient in BRCA1 or 2 often share phenotypic characteristics referred to as BRCAness. BRCAness-exhibiting tumors are hypersensitive to processes or chemicals that induce DNA DSBs. One such class of chemicals is PARP inhibitors. PARP inhibitors stall normal progression of replication forks, creating DSBs. In BRCA-deficient cells, these exacerbated DSBs remain unrepaired, resulting in cell death.

This synthetic lethality between BRCAness-exhibiting tumors and PARP inhibitors can be exploited as a cancer therapy.

With rapid advances in sequencing, and the advent of next-generation sequencing (NGS), NGS can be offered to patients at nominal cost and with a fairly rapid turnaround time.

Primary tissue and cell-free DNA using liquid biopsies are both amenable to targeted exome sequencing. These look at different aspects of tumor biology and are generally thought to be complementary. Based on results from The Cancer Genome Atlas Research Network, nearly 19% of primary prostate adenocarcinomas may have mutations in DNA repair genes, including BRCA1, BRCA2, BRIP1, CHK1, CHK2, or ATM. The prevalence of these mutations with BRCAness phenotype may be even higher in advanced or castration-resistant prostate cancers. While evaluation of all metastatic patients using NGS may become a reality in the future, we recommend its use in specific situations: Patients of a young age; with multiple malignancies; with family history of breast, ovarian, pancreatic or prostate cancer; with unusual clinical presentation; or who have no FDA-approved therapy options should be offered DNA testing.

The current case also highlights the role of a multidisciplinary approach, with close collaboration among the pathologist, urologist, medical oncologist, and geneticist for the patient&rsquo;s care. With the rapid integration of NGS into clinical practice, the need for multidisciplinary molecular tumor boards exists now more than ever.

King TA, Li W, Brogi E, et al. Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis. Ann Surg Oncol. 2007;14(9):2510-2518.

Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16(2):110-120. doi: 10.1038/nrc.2015.21.

MacConaill LE. Existing and emerging technologies for tumor genomic profiling. J Clin Oncol. 2013;31(15):1815-1824. doi: 10.1200/JCO.2012.46.5948.

van der Velden DL, van Herpen CML, van Laarhoven HWM, et al. Molecular Tumor Boards: current practice and future needs. Ann Oncol. 2017;28(12):3070-3075. doi: 10.1093/annonc/mdx528.

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Reviewers Commentary: This article&nbsp;adds to the growing body of literature on the role of PARP inhibitors in tumors with DNA repair defects.

Ruta Sahasrabudhe, PhD | Authors

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Olaparib for Patients With DNA Repair Defects and Metastatic Prostate Cancer: Is it Time Yet?