Abstract 595P
Background
Germline testing is advised for all metastatic prostate cancer patients (pts) and particularly for those with alterations in cancer-predisposition genes found through tumor profiling. To date, no patient or tumor characteristics have been unequivocally correlated with germline mutations to assist clinicians in prioritizing genetic testing.
Methods
The aim of our analysis was to correlate alterations in Homologous Recombination (HR) genes identified in prostate tumors and/or plasma with the presence of germline mutations. We screened men with metastatic prostate cancer for germline mutations in genes related to cancer predisposition syndromes using a panel that includes the HR genes ATM, BRCA1, BRCA2, BRIP1, CHEK2, FANCA, PALB2, RAD51C and RAD51D. mCRPC pts were screened for HR alterations using different commercial assays either in the primary tumor and/or in plasma. As the genes analysed vary among platforms, we focussed on alterations in BRCA1, BRCA2, ATM, CHEK2 and FANCA, reported in all of them.
Results
We performed germline and tumor testing in 121 men with metastatic prostate cancer (30 mHSPC and 89 mCRPC). A germline mutation was identified in 24 of them (14 BRCA2, 3 ATM, 2 BRCA1, 2 FANCA, 1 CHEK2, 1 PALB2, 1 RAD51C) although 42% of carriers lacked a family history of cancer. Tumor testing was successful in 76 out of 89 (85%) mCRPC pts. 57 alterations in BRCA1, BRCA2, ATM, CHEK2 and FANCA (54% gene deletions; 40% frameshift, nonsense or missense mutations; 5% others) were reported in 37 pts. Overall, 41% of tumor alterations in BRCA2, 66% in BRCA1, 20% in ATM, 20% in CHEK2, 22% in FANCA and 100% in PALB2 were already detected as germline. When considering the type of alterations in the tumor, only 6% of pts with gene deletions alone (mono- or bi- allelic) were found to be germline carriers (1FANCA, 1PALB2), compared to 72% of pts with a mutation detected in the tumor (66% BRCA2, 100% BRCA1, 66% ATM, 100% CHEK2, 100% FANCA).
Conclusions
A significant proportion of the alterations in HR genes found in prostate tumors are germline, however the likelihood of a germline finding varies with the gene affected and the type of alteration detected in tumor.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Instituto de Salud Carlos III.
Disclosure
C. Llacer Perez: Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Other, Travel, accommodation: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, accommodation: Angelini Pharma; Financial Interests, Personal, Other, Travel, accommodation: AstraZeneca; Non-Financial Interests, Institutional, Principal Investigator: Roche; Non-Financial Interests, Institutional, Principal Investigator: Janssen; Non-Financial Interests, Institutional, Principal Investigator: Novartis. L. Oliva Fernandez: Financial Interests, Personal, Other, Travel, accommodation: EUSA Pharma. M.I. Sáez: Financial Interests, Personal, Speaker’s Bureau: Sanofi; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Personal, Other, Travel, accommodation: Roche; Financial Interests, Personal, Other, Travel, accommodation: Sanofi; Financial Interests, Personal, Other, Travel, accommodation: Pfizer. R. Villatoro: Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: Sanofi; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: Ipsen; Financial Interests, Personal, Speaker’s Bureau: Kyowa Kirin; Financial Interests, Personal, Speaker’s Bureau: PM Farma; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Bristol; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Kyowa Kirin; Financial Interests, Personal, Advisory Board: PM Farma; Financial Interests, Personal, Other, Travel, accommodation: Roche; Financial Interests, Personal, Other, Travel, accommodation: Sanofi; Financial Interests, Personal, Other, Travel, accommodation: Bristol; Financial Interests, Personal, Other, Travel, accommodation: Astellas; Financial Interests, Personal, Other, Travel, accommodation: Janssen; Financial Interests, Personal, Other, Travel, accommodation: MSD; Financial Interests, Personal, Other, Travel, accommodation: Ipsen. A. Montesa Pino: Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Janssen-Cilag; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Astellas Pharma; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Other, Travel, accommodation: Pfizer. B. Herrera Imbroda: Financial Interests, Personal, Advisory Board, Research Grant: Astellas Pharma; Financial Interests, Personal, Advisory Board, Research Grant: Janssen-Cilag; Financial Interests, Personal, Advisory Board, Research Grant: Bayer Health; Financial Interests, Personal, Advisory Board, Research Grant: Myriad Genetics; Financial Interests, Personal, Advisory Board, Research Grant: Ipsen; Financial Interests, Personal, Advisory Board, Research Grant: Palex. D. Hernández: Financial Interests, Personal, Advisory Board: Janssen. R. Lozano Mejorada: Financial Interests, Personal, Speaker’s Bureau: Sanofi; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Other, Travel, accommodation: Sanofi; Financial Interests, Personal, Other, Travel, accommodation: Roche; Financial Interests, Personal, Other, Travel, accommodation: Astellas; Financial Interests, Personal, Other, Travel, accommodation: Janssen; Financial Interests, Personal, Other, Travel, accommodation: MSD. N. Romero Laorden: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Pfizer. D. Olmos: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Clovis; Financial Interests, Personal, Advisory Role: Daiichi-Sankyo; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bayer (&Orion); Financial Interests, Institutional, Principal Investigator: Bayer (&Orion); Financial Interests, Institutional, Principal Investigator: F. Hoffman La Roche; Financial Interests, Institutional, Principal Investigator: Janssen; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Pfizer; Non-Financial Interests, Personal, Other, Clinical Trial Steering committee member: AstraZeneca; Non-Financial Interests, Personal, Other, Clinical Trial Steering committee member: Bayer; Non-Financial Interests, Personal, Other, Clinical Trial Steering committee member: F. Hoffman La Roche/Genetech; Non-Financial Interests, Personal, Other, Clinical Trial Steering committee member: Janssen; Non-Financial Interests, Personal, Leadership Role, EORTC board of directors member: EORTC; Financial Interests, Personal, Other, Travel support to attaned scientific meetings: AstraZeneca; Financial Interests, Personal, Other, Travel support to attaned scientific meetings: Bayer; Financial Interests, Personal, Other, Travel support to attaned scientific meetings: F. Hoffman-LaRoche; Financial Interests, Personal, Other, Travel support to attaned scientific meetings: Ipsen; Financial Interests, Personal, Other, Travel support to attaned scientific meetings: Janssen. E. Castro: Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Invited Speaker: Clovis; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Invited Speaker: Janssen; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Funding: Pfizer. All other authors have declared no conflicts of interest.