To further characterize the molecular associations with germline BRCA2 alterations and the clinical impact of these associations, Dr. Lozano and colleagues conducted a multicenter, matched case-control study where gBRCA2 patients were matched 1:2 with non-carriers. The goal of this study was to confirm the independent prognostic value of gBRCA2 on prostate-cancer specific mortality, and secondarily, to examine molecular associations between gBRCA2 and copy number as assessed by FISH for BRCA2, RB1, MYC, PTEN, and TMPSS2-ERG fusion. Germline BRCA1 alterations were included as an exploratory cohort. The flowchart of the study is shown here.
The clinical and molecular characteristics of this cohort have been previously reported and are summarized here. In analysis of prostate-cancer specific survival as associated with molecular features studied, germline BRCA2 mutation status, somatic BRCA2 and RB1 co-deletion, and MYC amplification were associated with shorter survival. As shown in the Kaplain-Meier plot below, germline BRCA alteration was associated with worse cancer specific survival in this cohort at a median follow-up of 12 years.
Within germline BRCA2 altered patients, the presence of additional genomic alterations in the gene studied was also associated with poorer patient outcomes.
These additional alterations (MYC amplification, somatic BRCA2 and RB1 co-deletion) were also associated with worse outcomes in non-germline BRCA2 altered patients.
In summary, PROREPAIR-A is a large series of germline BRCA2 altered patients with prostate cancer that has shown (1) the independent negative prognostic impact of germline BRCA2 alterations, (2) the increased incidence of somatic alterations such as somatic BRCA2 deletion, RB1 deletion and MYC amplification in tumors from patients with germline BRCA2 alterations, and (3) confirmed the independent prognostic negative impact of these somatic alterations regardless of BRCA2 germline status.
Presented by: Rebeca Lozano, MD, Clinical Research Fellow at the Prostate Cancer Clinical Research Unit of the Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2020 European Society for Medical Oncology Virtual Congress (#ESMO20), September 19th-September 21st, 2020.