Family History of Pancreatic Cancer in a High‐Risk Cancer Clinic: Implications for Risk Assessment

Abstract

Detailed family history is a critical element of cancer risk assessment. The relative importance of pancreatic cancer (PC) in a close family member, particularly in hereditary breast-ovarian syndrome (HBOS), is not clearly defined. We use a case-control design to investigate the importance of a family history of PC to cancer risk assessment. Case and control families were identified from the University of Chicago Cancer Risk database (1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005). Pedigrees were analyzed for personal and familial clinical cancer data. Cases included all new subjects (probands) reporting a close relative (first or second degree) with PC. Controls included the probands enrolled in the database immediately prior to and subsequent to each case (i.e. two controls for each case). From 1,231 pedigrees, 103 PC were reported by the proband in 87 unique families. Many probands reported multiple or early-onset PCs: one third (28/87) of case families met criteria for a familial PC syndrome [≥2 first-degree relatives with PC (n=10) or PC diagnosed ≤50 (n=18)]. Of these families, the majority (75%) concurrently met criteria suggestive of hereditary breastovarian syndrome (HBOS). Because of a family history consistent with HBOS, at least one individual from each of 29 case and 55 control families underwent genetic testing for BRCA1/2. Among case families, 19 of 29 (66%) had a BRCA1/2 mutation compared with 16 of 55 (29%) controls. A significant association between family history of PC and a BRCA1/2 mutation was seen (OR 3.78,). This point estimate was strengthened but less precise in the nonAshkenazi Jewish subset of tested families (OR 6.03,. In a high-risk population, a family history of PC, though infrequently reported, is nonetheless clinically meaningful. In risk assessment for HBOS, identifying a family history of PC should strongly raise the suspicion of an unrecognized BRCA1/2 mutation.

Geographic and Ethnic Heterogeneity of Germline BRCA1 or BRCA2 Mutation Prevalence Among Patients With Metastatic Pancreatic Cancer Screened for Entry Into the POLO Trial

“…The highest rates of gBRCAm prevalence, both newly identified and in the total screened population, were observed in the United States (9.5% and 12.8%, respectively), with rates in Israel also high (7.4% and 10.4%, respectively); this is expected because these populations are enriched for an Ashkenazi Jewish population, who have a high frequency of certain BRCA1 and BRCA2 mutations as a result of a founder effect. 5,6 When the United States and Israel were excluded from the analysis, the newly identified gBRCAm prevalence rate fell to 5.1%. In contrast, the lowest newly identified gBRCAm prevalence rates were observed in Australia and Canada (0% and 3.3%, respectively), although patient numbers in these countries were small (53 and 90, respectively).…”

“…3 A study of 151 patients with pancreatic cancer offered genetic testing at a US institution that was based on their personal and family histories reported a gBRCAm prevalence of 11.3% 4 ; the higher prevalence in this study may be due to the US population being enriched in Ashkenazi Jews, who are known to have a high frequency of certain BRCA1 and BRCA2 mutations referred to as founder mutations. 5,6 Recently updated guidelines from the National Comprehensive Cancer Network (NCCN) state that regardless of age at diagnosis or family history, all patients diagnosed with pancreatic cancer should undergo genetic testing. 7 The poly(ADP-ribose) polymerase inhibitor olaparib can exploit homologous recombination repair deficiencies in tumor cells with a BRCA mutation to produce synthetic lethality, targeting BRCA1and BRCA2-deficient cells across several preclinical models.…”

What Black Women Know and Want to Know About Counseling and Testing for BRCA1/2

“…Culturally tailored outreach and education activities are needed in the Black community, as Blacks and other minorities have been “left behind” in the important genomic revolution [57, 58, 77]. Basic introduction to the general process, benefits, and risks of testing and counseling for BRCA1/2 in the Black community may help to inform women and increase their readiness for genomic-based medicine when it is appropriate.…”

The genetics of ductal adenocarcinoma of the pancreas in the year 2020: dramatic progress, but far to go

“…Deleterious germline variants in BRCA1 and BRCA2 are more common in individuals of Ashkenazi Jewish heritage, helping to explain why pancreatic cancer is more common in this group [28,36,37,59,79]. Remarkably, deleterious germline variants in genes coding for members of the Fanconi anemia pathway have been reported in~5% of pancreatic cancer patients without a family history of cancer [18,29,31,44,59,67,68,75,80,81].…”