1383P - Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA)

Background

BRCA1-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to BRCA2-mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of BRCA1 versus BRCA2 co-segregating genes.

Methods

Patients with advanced prostate cancer who underwent CGP of cfDNA by a CLIA-certified laboratory (Guardant360 testing) between 11/2016 to 8/2020 were eligible. First available cfDNA CGP results from consecutive patients were evaluated for the presence of BRCA1 and/or BRCA2 mutations. All variants of unknown significance were excluded from the analysis. Differences in the genomic landscape of co-segregating genes was investigated by Fisher’s exact test and probabilistic graphical models (PGMs).

Results

In a large dataset of 7,707 men with advanced prostate cancer, 614 men harbored BRCA1 and/or BRCA2 alterations. Results summarized in the table. BRCA1 was significantly associated with 6 other genes, while BRCA2 was not significantly associated with any gene. These findings suggest BRCA2 may be the main driver mutation, while BRCA1 mutations tend to co-segregate with mutations in other molecular pathways contributing to prostate cancer progression. Table: 1383P

NS = not significant; Fisher’s exact p-values after Bonferroni correction.

Conclusions

These hypothesis generating data may explain the increased sensitivity of PARP inhibitors to BRCA2 mutations due to fewer concurrent resistance pathways and guide towards development of combinatorial drug regimens in those with BRCA1 mutation. The limitations of this study include the lack of clinical annotation such as the disease state and treatment exposure.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

U. Swami: Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Advisory Board: Seagen, Exelixis; Financial Interests, Institutional, Research Grant: Janssen, Exelixis; Financial Interests, Institutional, Invited Speaker: Astellas/Seattle Genetics. E.J. Hernandez: Financial Interests, Personal, Advisory Role: Fabric Genomics. S. Wesolowski: Financial Interests, Personal, Full or part-time Employment: Recursion Pharmaceuticals. L. Kiedrowski: Financial Interests, Personal, Full or part-time Employment: Guardant Health; Financial Interests, Personal, Stocks/Shares: Guardant Health. P.M. Coelho Barata: Financial Interests, Personal, Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, Clovis Oncology, Dendreon; Financial Interests, Personal, Speaker’s Bureau: Caris Life Sciences, Bayer, Pfizer/Astellas; Financial Interests, Personal, Funding: Blue Earth Diagnostics, AVEO, Pfizer, Merck. G. Lemmon: Financial Interests, Personal, Advisory Role: Backdrop Health. M.A. Bilen: Financial Interests, Personal, Advisory Role: Exelixis, Sanofi, Nektar, EMD Serono, Eisai, Janssen, Genomic Health, Pfizer, BMS, Bayer, Calithera Biosciences, AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Funding: Bayer, BMS, Genentech, Incyte, Nektar, AstraZeneca, Tricon pharmaceuticals, Pfizer, Xencor, Exelixis, Advanced accelerator applications, Genome & Company, Peloton therapeutics, Merck. E. Heath: Financial Interests, Personal, Other, Consulting/Advisory Role, Paid Travel: Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb; Financial Interests, Personal, Other, Paid Travel: Caris Life Science; Financial Interests, Personal, Advisory Board, Speaker's Bureau, Paid Travel: Sanofi; Financial Interests, Personal, Advisory Board, Paid Travel: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, Celldex, Corcept, Curemeta, Dendreon, eFFECTOR, Esanik, Fortis, Genenctech/Roche, Glaxo Smith Kline, Ignyta, Inovio, Medivation, Merck Sharpe Dohme, Merck, Millenium, Oncolys, Plexxikon, tokai, Zenith; Financial Interests, Personal, Other, Executive Committee Member Precision Oncology Alliance: Caris Life Science; Financial Interests, Personal, Invited Speaker: Seattle Genetics. H. Babiker: Financial Interests, Advisory Role: Endocyte, Celgene, Idera, Myovant Sciences, Novocure; Financial Interests, Speaker’s Bureau: Guardant Health. S.K. Pal: Financial Interests, Personal, Advisory Role: F. Hoffman Laroche, Roche; Financial Interests, Personal, Other, Travel expenses: Genentech, Seattle Genetics; Financial Interests, Institutional, Funding: Eisai, Genentech, Roche, Exelixis, Pfizer. M.B. Lilly: Financial Interests, Personal, Speaker’s Bureau: Guardant Health; Financial Interests, Institutional, Funding: Bavarian Nordic, Bayer. B.L. Maughan: Financial Interests, Personal, Advisory Role: AbbVie, Pfizer, AVEO oncology, Janssen, Astellas, Bristol Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology and Peloton Therapeutics; Financial Interests, Institutional, Funding: Exelixis (Inst), Bavarian-Nordic (Inst), Clovis (Inst), Genentech (Inst) and Bristol Myers Squibb (Inst). M. Yandell: Financial Interests, Leadership Role: Backdrop Health, IDbyDNA. O. Sartor: Financial Interests, Personal, Advisory Role: AAA, Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien Meunchen, Janssen, Myovant, Myriad, Noria Therapeutics,; Financial Interests, Institutional, Research Grant: AAA, Amgen, AstraZeneca, Bayer, Constellation, Endocyte, Invitae, Janssen, Lantheus, Merck, Progenics, and Tenebio.; Financial Interests, Personal, Other, travel expemses: Bayer, J&J, Sanofi, AstraZeneca, Progenics; Financial Interests, Personal, Expert Testimony: sanofi; Financial Interests, Personal, Other, patent: Koochekpour, Sartor AO, inventors. Saposin C and receptors as targets for treatment of benign and malignant disorders. US patent awarded January 23, 2007 (patent no. 7,166,691).; Financial Interests, Personal, Stocks/Shares: Lilly, GSK, AbbVie, Cardinal Health, United Health group, PSMA therapeutics, Clarity pharmaceuticals, Noria therapeutics, Clovis Oncology. N. Agarwal: Financial Interests, Personal, Advisory Role: Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics.; Financial Interests, Institutional, Funding: Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis,. All other authors have declared no conflicts of interest.