Abstract 1305P
Background
International guidelines recommend multigene germline (MGP) testing for PC pts, although no surveillance program for high-risk individuals has been validated. The implementation of this recommendation is limited by the uncertainty around its clinical utility. Preliminary data from Italian PC pts showed a high prevalence of CDKN2A PV, regardless of familial status, and BRCA1/2 PVs only in pts<74 yo. Here, we provide a comprehensive analysis by MGP in unselected Italian PC pts.
Methods
We evaluated the prevalence and impact on outcomes of PVs in 51 PC susceptibility genes in a real-life retrospective and prospective series of 422 Italian PC pts. Characteristics of pts with PV were compared to WT pts using Student’s t-test or chi square test. Cox proportional hazard regression models were performed to estimate hazard ratios (HR) and 95% confidential interval (CI).
Results
We found PVs in 70/422 pts (17%). The most frequently altered genes were BRCA1-2 (4.5%, all<70yo), CDKN2A (4.5%), ATM (2.1%), CHEK2 (1,7%) and COL7A1 (1,2%). Overall, mean age was 67yo, 22% were resectable PC at diagnosis, and median follow-up was 9.8 months (0.02–156). When compared with WT (N=352), PVs carriers were associated with younger age at diagnosis (67 vs 64; P=0.02), positive family history (FH) for PC (10 vs 26%; P<.001), breast and ovarian cancer (13 vs 29%, P=.001), and melanoma (4% vs 10%; P=.034) and with personal history of other tumors (13% vs 32%, P<.001). Of note, 46% of pts carrying PVs in CDKN2A, BRCA2 and ATM had no FH. Overall, median OS was 11.5 months (10.3-13.3). Pts carrying any PVs showed a trend for better OS (HR 0.78; 0.59-1.04; P=0.090), compared to WT. This trend may be led by the group with ATM PVs (N=9) that showed a better prognosis (HR 0.33; 0.10-1.02; P=0.054); while no significant differences were observed between pts with PVs in other genes and WT pts.
Conclusions
A High PV overall frequency was found in our cohort (17%), with a 4.5% rate for CDKN2A and for BRCA. ATM PVs were associated with better prognosis. Around 50% of pts would have been missed by traditional referral, since they had no FH. These findings may have a great impact on PC pts management and on high-risk family member genetic counselling and follow-up.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This work was supported by grants from Lega Italiana per la Lotta contro i Tumori (LILT) 5x1000 IG 2019 to Paola Ghiorzo, Italian Ministry of Health (Ospedale Policlinico San Martino Ricerca Corrente and 5x1000 funds to Paola Ghiorzo), Associazione Ricerca Tumori Rari ed Ereditari (AR3) onlus to Paola Ghiorzo.
Disclosure
M.S. Sciallero: Financial Interests, Personal, Invited Speaker: Amgen, Servier, Merck, MSD, AstraZeneca; Financial Interests, Personal, Advisory Board: Novartis. All other authors have declared no conflicts of interest.