Impact of mutations in homologous recombination repair genes on treatment outcomes for metastatic castration resistant prostate cancer.

Abstract

INTRODUCTION:

A significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination (HR) repair genes, with some of these mutations associating with increased tumor susceptibility to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. While mutations in some HR repair genes (e.g., BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating HR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ARSIs) or taxane-based chemotherapy have yielded conflicting results.

METHODS:

We conducted a single-center retrospective analysis to assess clinical outcomes to conventional, regulatory-approved therapies in mCRPC patients with somatic (monoallelic and biallelic) and/or germline HR repair mutations compared to patients without alterations as determined by clinical-grade next-generation sequencing assays. The primary endpoint was PSA30/PSA50 response, defined as ≥30%/≥50% prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints of PSA progression-free survival (pPFS) and clinical/radiographic progression-free survival (crPFS) were estimated using Kaplan-Meier methods.

RESULTS:

A total of 90 consecutively selected patients were included in this analysis, of which 33 (37%) were identified to have HR repair gene mutations. Age, race, Gleason score, prior surgery, and receipt of prior radiation therapy were comparable between carriers and non-carriers. There was no evidence that PSA30/PSA50 differed by HR gene mutational status. Median pPFS and crPFS ranged 3-14 months across treatment modalities, but there was no evidence either differed by HR gene mutational status (all p>0.05). There was also no difference in outcomes between those with BRCA2 or PALB2 mutations (n = 17) compared to those without HR repair mutations.

CONCLUSION:

HR gene mutational status was associated with comparable clinical outcomes following treatment with ARSIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.

• Authors: Alexander S Carlson, Rigo I Acevedo, Daniel M Lim, Roman Gulati, Agnes Gawne, Alexandra O Sokolova, Heather H Cheng, Peter S Nelson, R Bruce Montgomery, Evan Y Yu, Michael T Schweizer
• Journal: PloS one (PLoS One) Vol. 15 Issue 9 Pg. e0239686 ( 2020) ISSN: 1932-6203 [Electronic] United States
• PMID: 32997692 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• BRCA2 Protein
• BRCA2 protein, human
• Fanconi Anemia Complementation Group N Protein
• MRE11 protein, human
• PALB2 protein, human
• Poly(ADP-ribose) Polymerase Inhibitors
• Steroid Synthesis Inhibitors
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• CDK12 protein, human
• Cyclin-Dependent Kinases
• MRE11 Homologue Protein

Topics

• Aged
• Antineoplastic Agents (therapeutic use)
• Ataxia Telangiectasia Mutated Proteins (genetics)
• BRCA2 Protein (genetics)
• Cyclin-Dependent Kinases (genetics)
• Drug Resistance, Neoplasm
• Fanconi Anemia Complementation Group N Protein (genetics)
• Humans
• MRE11 Homologue Protein (genetics)
• Male
• Middle Aged
• Mutation
• Neoplasm Metastasis
• Poly(ADP-ribose) Polymerase Inhibitors (therapeutic use)
• Progression-Free Survival
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• Recombinational DNA Repair (genetics)
• Steroid Synthesis Inhibitors (therapeutic use)