Sensitivity of age and family history (FH) criteria for determining pancreatic cancer (PC) surveillance (PCS) eligibility among individuals with hereditary PC risk.

Abstract

10500 Background: PCS for individuals with pathogenic/likely pathogenic germline variants (PGVs) predisposing to PC is associated with earlier stage at diagnosis (dx) and improved survival, compared to historical controls. For those with such PGVs, PCS eligibility is determined based on FH of PC and age (age ≥30 years for those with STK11 PGVs; age ≥40 for CDKN2A ; age ≥50 for other PC risk genes [Table 1]; or 10 years before the youngest PC in the family). For PGV carriers (apart from CDKN2A/STK11 ) , guidelines have required a FH of PC in ≥1 first-/second-degree relatives (FDR/SDR) for PCS eligibility. Limited data have evaluated the sensitivity of these criteria in determining which high-risk individuals benefit from PCS. Methods: We evaluated the sensitivity of age and FH criteria for PCS in the Myriad Collaborative Research Registry (MCRR). Individuals who were diagnosed with PC and underwent germline genetic testing were included. To determine the number of PGV carriers who would have been eligible for PCS at the time of their PC dx, FH of cancer and personal cancer history were ascertained from data contained in MCRR at the time of germline testing. Results: Among 11,248 PC patients who underwent germline testing, 55.5% were female and 59.2% were non-Hispanic White/European. The mean age at PC dx was 64.6 years. PGVs predisposing to PC were detected in 969 (8.6%) individuals [Table 1], of whom 224 (23.1%) met gene-specific PCS criteria. Of the 969, 829 (85.6%) met gene-specific age criteria for PCS. Of the 931 individuals with PGVs in genes requiring FH, only 208 (22.2%) fulfilled FH criteria for PCS. Conclusions: Most individuals with PC who harbor PGVs in PC susceptibility genes would not have met gene-specific age/FH criteria for PCS. FH of PC has particularly poor sensitivity in identifying PGV carriers who go on to develop PC, supporting recent removal of this criterion from NCCN guidelines for BRCA2/ATM . Validation in a clinic-based cohort is ongoing. These data suggest that FH of PC should not be used to determine which PGV carriers are eligible for PCS. Gene (n) Met FH criterion of PC in FDR/SDR - n (%) Met age# criterion - n (%) Met age and FH criteria (%) ATM (186) 47 (25.3) 170 (91.4) 44 (23.7) BRCA1 (137) 28 (20.4) 114 (83.2) 26 (19.0) BRCA2 (428) 101 (23.6) 363 (84.8) 88 (20.6) PALB2 (61) 11 (18.0) 50 (82.0) 10 (16.4) MLH1 (11) / MSH2 (40) / MSH6 (32) 4 (36.4) / 4 (10.0) / 4 (12.5) 9 (81.8) / 27 (67.5) / 27 (84.4) 4 (36.4) / 3 (7.5) / 4 (12.5) TP53* (25) 4 (16.0) 23 (92.0) 4 (16.0) CDKN2A (34) / STK11 (2) NA 33 (97.1) / 2/2 (100) 33 (97.1) / 2/2 (100) > 1 PGV (13) 5/11 (45.5) 11/13 (84.6) 6/13 (46.2) NA: Not applicable. #Age ≥30 years for STK11 ; age ≥40 for CDKN2A ; age ≥50 for other PC risk genes; or 10 years before the youngest PC in the family. *Ancillary testing to confirm germline status vs clonal hematopoiesis/mosaicism is not available.