A prospective observational study of pancreatic cancer risk in men and women with pathogenic variants in BRCA1 or BRCA2

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We explored incidence rate and cumulative risk of PC in a large prospective cohort of confirmed carriers. Methods: BRCA1/2 carrierswithout PC prior to genetic testing were identified from the clinical registry at Section for Hereditary Cancer, Oslo University Hospital. Cancer diagnoses were collected from Cancer Registry of Norway (CRN). Standardized incidence ratios (SIRs) were derived from national reference rates. The Kaplan-Meier method was used to calculate cumulative risk. Results: Among 2681 BRCA1 carriers, we observed 13 cases versus 4.7 expected (SIR 2.8, 95% CI 2.1-5.0). In 1476 BRCA2 carriers, we observed 9 cases versus 1.9 expected (SIR 4.8, 95% CI 2.2–9.0). The highest risk was observed for female BRCA2 carriers (SIR 6.5, 95% CI 2.8–12.9, 8 cases) and male BRCA1 carriers (SIR 5.5, 95% CI 2.5–10.5, 9 cases), who had a cumulative risk at 70 years of 1.2% and 2.5% respectively. Conclusions: BRCA1/2 carriers had three times more cases of PC than expected, but a statistically significant increased incidence was only observed for female BRCA2 and male BRCA1 carriers. Cumulative risk of PC at 70 years in these two groups was less than 3%. Background The tumor suppressor genes BRCA1 and BRCA2 were identified in the mid-1990s. Since then, numerous studies have confirmed that women with pathogenic variants in these genes ( BRCA1/2 carriers) have a high lifetime risk of developing breast and ovarian cancer [ 1 , 2 ]. Somewhat later research showed that male BRCA2 carriers have an elevated risk of prostate cancer [ 3 ]. Clinical guidelines have been established for early detection and/or prevention of breast, ovarian and prostate cancer in BRCA1/2 carriers. To provide carriers with evidence-based advice regarding follow-up, it is important to know whether pathogenic variants in BRCA1/2 are associated with increased risk of other common or severe cancers, such as pancreatic cancer (PC) known to have a high lethality. In retrospective studies, estimates of the relative risk (RR) of PC have been reported between 2.2 and 3.2 for BRCA1 carriers, and between 3.5 and 6.6 for BRCA2 carriers [ 4 – 7 ]. Retrospective studies are based on historical data on cancer reported in families before genetic testing was done. The estimates may therefore be affected by selection bias, as the families with the strongest family histories of cancer are more inclined to be referred for genetic testing than those with fewer individuals with cancer. In addition, the study cohorts often include both carriers and individuals who have not been tested, and the estimates thereby become more uncertain. In a recent large, international retrospective study it was also noted that the data on family history of cancer was self-reported, and that 7–40% of the diagnoses lacked information on age [ 7 ]. To our knowledge, only one prospective study has investigated risk of PC in female BRCA1/2 carriers [ 8 ]. This study found similar but imprecise risk estimates for the two genes, with standardized incidence ratios (SIR) of 2.6 (95% confidence interval (CI) 0.95–5.67, six cases) for BRCA1 and 2.1 (95% CI 0.25–7.58, two cases) for BRCA2 (CIs derived by the authors of the present article). The low statistical strength allowed no firm conclusion for BRCA2 ( p = 0.3). More than 80% of PC patients are diagnosed with advanced stage disease, when surgery is no longer possible [ 9 ]. Still, the overall 5-year relative survival has improved over the last 20 years from around 3–15% for pancreatic cancer, all histological subtypes taken together [ 10 ]. Some studies have indicated that annual surveillance with magnetic resonance imaging (MRI) and/or endoscopic ultrasound (EUS) may lead to a higher number of resectable cancers and an improved short time survival [ 11 – 16 ]. It has been argued that surveillance should be done in an academic setting to select the high-risk individuals most likely to benefit from it [ 17 ]. Thus, it is important to obtain precise risk estimates in prospective studies of large cohorts of confirmed carriers. The information is also important for the carriers themselves and their families. Section for Hereditary Cancer (SHC) at Oslo University Hospital (OUH), has offered genetic testing of BRCA1/2 since 1994. In August 2020, our clinical registry included 4353 confirmed carriers of pathogenic or likely pathogenic BRCA1/2 variants. The Cancer Registry of Norway (CRN) continuously records individual data on new cancers diagnosed nationally. Linkage to these data is facilitated by unique personal identity numbers, providing reliable data on all PC diagnoses among BRCA1/2 carriers in our cohort, as well as equally reliable comparison data on incidence from the general Norwegian population. The aim of this study was to obtain prospective estimates of PC incidence in confirmed male and female BRCA1/2 carriers compared with the general population, and to investigate their cumulative risk of PC. A secondary aim was to investigate PC incidence in carriers with and without a recorded family history of the disease. Methods Clinical registry for hereditary cancer at Section of Hereditary Cancer (SHC), Oslo University Hospital SHC has offered genetic counseling and testing for familial cancer and hereditary syndromes since the early 1990s. When an individual is referred to the section, a record is created in the section’s clinical registry for hereditary cancer for him or her. For each individual, information is registered on date of birth, personal cancer history, and results of performed genetic analyses. During counseling, information is collected regarding family history of cancer. When the diagnosis is uncertain, detailed information is collected from CRN or medical files. Some family history of cancer is therefore self-reported and some is confirmed. The purpose is to create a family tree for a visual image of how individuals in a family are related, what types of cancer have been diagnosed, whether and when they have been genetically tested, and test results. Some families in the registry span 5–6 generations. Genetic testing of BRCA1 and BRCA2 at SHC BRCA1 and BRCA2 were identified in 1994 and 1995. Until around 2010, the availability of genetic testing for these genes was limited. Genetic analyses could only be done in families with a strong family history of breast and/or ovarian cancer, and when it was possible to get a blood sample from family members diagnosed with such cancer. Most families were only tested for 6–10 known Norwegian BRCA1/2 founder mutations. For many families, blood samples were stored for years before they could be analyzed, or sequenced, and some patients had passed away before the variant was identified. From 2010, all individuals who fulfilled criteria for genetic testing were offered sequencing and Multi Ligation Probe Amplification (MLPA) of both genes. As genetic testing has become more available, the criteria for testing have become more liberal. Today, an individual with one first-degree relative who has breast cancer ≤ 60 years, or one first-degree relative who has ovarian cancer regardless of age, will be offered testing of BRCA1 / 2. In Norway, genetic testing is largely covered by the Norwegian Health Economics Administration (HELFO) and the patient only pays a small deductible. Genetic services are therefore in principle available to the whole population regardless of income or employment status. Knowledge about hereditary breast and ovarian cancer has increased in the general population during the last 10 years, and even in Norway, we saw an Angelina effect, with a 50% increase in the number of referred patients around 2013. Methods This is a prospective observational study of PC risk in confirmed BRCA1/2 carriers. All women and men who had tested positive for a pathogenic or likely pathogenic variant in BRCA1/2 were identified in the clinical registry at SHC by August 2020. Information on all diagnosed cancers in these individuals was collected from CRN, using the unique personal identification numbers covering all Norwegian citizens alive in or born after 1960. The CRN is close-to-complete [ 18 ] and has registered cancer diagnoses in Norway since 1953. At the time of data collection, CRN had completed its registration for 2019. Last date of observation for the study was therefore set to 31st of December 2019. We collected information on all cancer diagnoses (ICD10 codes and date of diagnosis), and for PC classification of histology was provided. From the clinical registry, we collected information on date of birth, gender, affected gene and variant. We extracted manually, data on any recorded first degree/second degree/any relative diagnosed with PC. Some, but not all of these diagnoses were confirmed from CRN or hospital records. We also registered whether these relatives were carriers or whether they had unknown carrier status. For individuals who had been diagnosed with PC we registered whether they had relatives with PC prior to their own diagnosis. To reduce the likelihood of selection bias, we identified a sub-cohort within the total cohort of carriers, including only those who had tested positive for a BRCA1/2 variant while they were alive (“at risk” of PC), not diagnosed with PC before they were genetically tested, and tested before 31st of December 2019. The prospective analyses of SIR and cumulative risk were only performed within this sub-cohort, referred to as the prospective cohort in the following. Statistics Only pancreatic adenocarcinomas were included in the descriptive analyses, the logistic regression and the analysis of cumulative risk. Follow up years was counted from date of birth to date of PC diagnosis/date of death/date of last follow up (31.12.2019) for the whole cohort. For the prospective cohort we also calculated follow up years from date of genetic testing. Because population data on frequencies of PC from the CRN includes all histologies, we included all prospective cases regardless of histology for the SIR analysis. SIR was calculated for comparing incidence of PC in this cohort with the incidence in comparable age and birth cohort distributions (data obtained from CRN). 95% confidence intervals for SIR were estimated using a Poisson distribution. Statistical tests are performed as two-sided tests at the 0.05 significance level. A Cox proportional hazards model was fitted to analyze associations between cumulative risk of PC and covariates gender and gene status ( BRCA1/2 variant status) and to calculate hazard ratios for these factors. Additional models included the interaction effect between gender and gene, and family history. Stata/SE Version 16.1 was used for SIR and cumulative risk analyses. Results The total cohort included 4453 BRCA1/2 carriers, 2851 (64.0%) BRCA1 carriers, 1597 (35.9%) BRCA2 carriers, and 5 carried a pathogenic variant in both BRCA1 and BRCA2 . The carriers belonged to 1319 registered families in the clinical registry. Follow up years was 236626.6 for the whole cohort. The prospective cohort included slightly fewer individuals, 4162 carriers, 2681 (64.4%) BRCA1 carriers, 1476 (35.5%) BRCA2 carriers, and 5 carriers of both a BRCA1 and a BRCA2 variant. Follow up years counted from date of birth was 221036.7 and 33650.2 counted from date of genetic testing (Table 1 ). Table 1 Description of study cohort Total cohort All BRCA1 BRCA2 BRCA1 and BRCA2 Number of carriers 4453 2851 1597 5 Female Male 3204 (72%) 1249 (28%) 2072 (73%) 779 (27%) 1127 (71%) 470 (29%) 5 - Age (median) at positive test result 44 years 43 46 39 Tested after death 172 (4%) 116 (4%) 56 (4%) - Tested while alive 4281 (96%) 2735 (96%) 1541 (96%) 5 Follow up years 236626.6 152383.4 84029.8 213.3 Mean follow up years 53.1 53.5 52.6 42.7 Total number of families 1319 823 493 3 Number of families with more than one member registered 1091 (83%) 689 (84%) 399 (81%) 3* Average number of carriers per family with more than one individual registered 5 5 5 Prospective cohort Number of carriers 4162 2681 1476 5 Female 2969 (71%) 1928 (72%) 1036 (70%) 5 Male 1193 (29%) 753 (28%) 440 (30%) Age (median) at positive test result 44 43 46 39 Follow up years counted from birth 221036.7 143241.3 77582.1 213.3 Mean follow up years counted from birth 53.1 53.4 52.6 42.7 Follow up years counted from genetic testing 33650.2 24501.4 9128.7 20.1 Mean follow up years counted from genetic testing 8.1 9.1 6.2 4.0 Total number of families 1240 781 456 3 Number of families with more than one member registered 1041 (84%) 663 (85%) 375 (82%) 3* Average number of carriers per family with more than one member registered 5 5 5 - Pancreatic cancer in the total cohort In the total cohort, 33 (33/4453 = 0.7%) BRCA1/2 carriers had been diagnosed with PC, one of them a sarcoma located in the pancreas diagnosed in a female BRCA1 carrier. The rest were adenocarcinomas. Excluding the sarcoma, the 32 PCs (32/4453 = 0.7% of all carriers) were distributed with 16 (16/2851 = 0.6%) in BRCA1 carriers and 16 (16/1597 = 1%) in BRCA2 carriers. None of the 5 combined BRCA1 and a BRCA2 carriers had been diagnosed with PC. Mean age at diagnosis was 67 years (range 37–87) for all. The gender distribution showed the highest proportion of PC among male BRCA1 carriers and female BRCA2 carriers, respectively, 6 times the proportion in the opposite gender for BRCA1 and 3 times the proportion for BRCA2 (Table 2 ). The 32 patients with PC belonged to 29 different families. Five of them (5/32 = 15.6%) had a first-degree relative, and 7 (7/32 = 21.9%) any relative (carrier or obligate carrier of the same pathogenic variant) reported with PC (confirmed or not clinically confirmed) before their own PC diagnosis (Table 2 ). Table 2 Pancreatic cancer in the study cohort Total cohort of carriers All carriers* ( n = 4453) BRCA1 ( n = 2851) BRCA2 ( n = 1597) No. of pancreatic cancers (percent of category) 32 (0.7%) 16 (0.6%) 16 (1%) F ( n = 3204) 19 (0.6%) M ( n = 1249) 13 (1.0%) F ( n = 2072) 5 (0.2%) M ( n = 779) 11 (1.4%) F ( n = 1127) 14 (1.2%) M ( n = 470) 2 (0.4%) Mean age at diagnosis 66.9 (37.1–87.2) 67.2 (47.7–87.2) 64.5 (37.1–87.0) F 67.8 (37.1–87.2) M 63.0 (44.6–82.5) F 72.1 (56.0–87.2) M 66.7 (47.7–82.5) F 66.2 (37.1–87.0) M 52.2 (44.6–59.8) First-degree relatives with variant and PC n = 32 5 (15.6%) n = 16 2 (12.5%) n = 16 3 (18.8%) Second degree relatives with variant and PC n = 32 1 (3.1%) - n = 16 1 (6.3%) Any relative with variant and PC n = 32 7 (21.9%) n = 16 3 (18.8%) n = 16 4 (25%) First-degree relatives with PC n = 32 7 (21.9%) n = 16 3 (18.8%) n = 16 4 (25%) Second degree relatives with PC n = 32 4 (12.5%) n = 16 2 (12.5%) n = 16 2 (12.5%) Any relative with PC n = 32 12 (37.5%) n = 16 6 (37.5%) n = 16 6 (37.5%) Prospective cohort All carriers* BRCA1 BRCA2 Pancreatic cancer ( n = 4162) 21 (0.5%) ( n = 2681) 12 (0.4%) ( n = 1476) 9 (0.6%) F ( n = 2969) 11 (0.4%) M ( n = 1193) 10 (0.8%) F ( n = 1928) 3 (0.2%) M ( n = 753) 9 (1.2%) F ( n = 1036) 8 (0.8%) M ( n = 440) 1 (0.2%) Mean age at diagnosis 67.0 (37.1–87.2) 70.1 (47.7–87.2) 62.8 (37.1–87.0) F 67.3 (37.1–87.2) M 66.5 (47.7–82.5) F 78.4 (66.2–87.2) M 67.3 (47.7–82.5) F 63.2 (37.1–87.0) M 59.8 First-degree relatives with variant and PC n = 21 2 (9.5%) n = 12 1 (8.3%) n = 9 1 (11.1%) Any relative with variant and PC n = 21 4 (19%) n = 12 2 (16.7%) n = 9 2 (22.2%) First-degree relatives with PC n = 21 3 (14.3%) n = 12 1 (8.3%) n = 9 2 (22.2%) Any relative with PC n = 21 7 (33.3%) n = 12 4 (33.3%) n = 9 3 (33.3%) Pancreatic cancer in the prospective cohort In the prospective cohort there were 21 (21/4162 = 0.5%) cases of PC (adenocarcinomas), 12 among BRCA1 carriers (12/2681 = 0.4%) and 9 among BRCA2 carriers (9/1476 = 0.6%). In addition to the 21 adenocarcinomas, the sarcoma of the pancreas was found prospectively in a female BRCA1 carrier. The proportion among BRCA1 carriers was 3/1928 = 0.2% for female and 9/753 = 1.2% for male carriers. Among BRCA2 carriers, 8/1036 = 0.8% women and 1/440 = 0.2% men were diagnosed with PC. Seventeen out of 21 (81%) of all PC were diagnosed in male BRCA1 carriers or female BRCA2 carriers. Mean age at onset was 67 years (range 37–87). Two out of the 21 (9.5%) had a first-degree relative carrying the same variant and diagnosed with PC prior to their own diagnosis, and 4/21 (19%) had any relative with the same variant and PC (Table 2 ). Characterization of families with cases of pancreatic cancer In addition to the 33 diagnoses (32 adenocarcinomas and one sarcoma) collected from CRN for this study, there were 136 individuals recorded with a PC in the 1319 families with a pathogenic variant in BRCA1/BRCA2 . These 136 PC patients were either obligate carriers or had unknown carrier status (one of the obligate carriers had both a BRCA1 and a BRCA2 variant). The total of 169 individuals with confirmed or unconfirmed PC belonged to 139 (10.5%) out of all 1319 families. In 115 (83%) out of the 139 families, only a single PC case was recorded. Eighteen families (18/139 = 12.9%) had two PC cases, and five families (5/139 = 3.6%) had three or four PC cases, three families with BRCA2 variants and two families with BRCA1 variants. Standardized incidence ratios of pancreatic cancer in prospective cohort For the calculations of SIR, we included the sarcoma diagnosed prospectively in a female BRCA1 carrier, giving a total of 22 prospective PC cases. In all carrier sub-groups by gender and gene, there were more cases of PC observed than expected from the background rates, although they were statistically significant different from 1 only for the sub-groups of male BRCA1 carriers and female BRCA2 carriers, as indicated by the 95% CI not including 1 for these subgroups. Among the 2681 BRCA1 carriers of both genders, the SIR was 2.8 (95% CI 1.5–4.70, 13 cases), and among the 1476 BRCA2 carriers, the SIR was 4.8 (95% CI 2.2–9.0, 9 cases). Elevated risks were most clearly seen in female BRCA2 carriers with an SIR of 6.5 (95% CI 2.8–12.9, 8 cases), and in male BRCA1 carriers with SIR = 5.5 (95% CI 2.5–10.5, 9 cases). The number of cases in the remaining gender-specific groups was low, with corresponding imprecise SIRs: female BRCA1 carriers with an SIR of 1.5 (95% CI 0.4–3.9, 4 cases) and male BRCA2 carriers with an SIR of 2.2 (95% CI 0.1–12.3, 1 case) (Table 3 ). Table 3 Standardized incidence ratios in the prospective cohort Expected Observed SIR (95% confidence interval) All carriers 6.62 22 3.32 (2.08–5.03) All women 3.83 12 3.13 (1.62–5.47) All men 2.09 10 4.79 (2.3–8.82) BRCA1 men and women 4.73 13 2.75 (1.46–4.70) BRCA1 women 2.6 4 1.54 (0.42–3.94) BRCA1 men 1.63 9 5.51 (2.52–10.47) BRCA2 men and women 1.89 9 4.76 (2.18–9.04) BRCA2 women 1.23 8 6.52 (2.82–12.85) BRCA2 men 0.45 1 2.2 (0.06–12.27) For the sub-groups with the largest numbers of cases, i.e. female BRCA2 carriers and male BRCA1 carriers, we looked at risks according to family history of PC. There was a higher number of observed vs expected number of cases both among those who had a family history of PC and among those with no such history (Supplementary table 1 ). Cumulative risk of pancreatic cancer in prospective cohort Cumulative risk of developing PC by 70 years was 0.3% for female BRCA1 carriers and 2.5% for male carriers. For BRCA2 carriers it was 1.2% for females and 0.7% for males (Table 4 ). Based on the observed SIRs and estimates for cumulative risk for the different groups, we hypothesized that male BRCA1 carriers had a higher risk than female BRCA1 carriers, and that female BRCA2 carriers had a higher risk than male BRCA2 carriers. We tested this by using a Cox proportional hazard regression model including gender and gene as covariates. We found that there was a statistically significant interaction effect between gender and BRCA1/BRCA2 ( p = 0.043). When we added family history of PC to the model, gender and gene and its interaction remained statistically significant. A family history of one or more relatives with PC resulted in an increase in the hazard for being diagnosed with PC in this model, for both genes, but the hazard ratio was not statistically significant (HR 2.33, p = 0.07). Table 4 Cumulative risk of pancreatic adenocarcinoma among BRCA1/2 mutation carriers in the prospective cohort 50 years 60 years 70 years 80 years All carriers 0.1% (SE 0.000) [0.000, 0.002]* 0.2% (SE 0.001) [0.001, 0.006] 1.1% (SE 0.003) [0.006, 0.019] 1.6% (SE 0.005) [0.008, 0.027] BRCA1 All 0.1% (SE 0.001) [0.000, 0.003] 0.1% (SE 0.001) [0.000, 0.003] 1.2% (SE 0.004) [0.005, 0.022] 1.2% (SE 0.004) [0.005, 0.022] Female carriers 0.3% (SE 0.003) [0.000, 0.014] 0.3% (SE 0.003) [0.000, 0.014] Male carriers 0.2% (SE 0.002) [0.000, 0.010] 0.2% (SE 0.002) [0.000, 0.010] 2.5% (SE 0.01) [0.011, 0.049] 2.5% (SE 0.01) [0.011, 0.049] BRCA2 All 0.1% (SE 0.001) [0.000, 0.005] 0.6% (SE 0.003) [0.002, 0.014] 1% (SE 0.004) [0.004, 0.022] 2.5% (SE 0.012) [0.009, 0.057] Female carriers 0.1% (SE 0.001) [0.000, 0.007] 0.5% (SE 0.003) [0.001, 0.015] 1.2% (SE 0.005) [0.004, 0.027] 3.2% (SE 0.016) [0.010, 0.075] Male carriers 0.7% (SE 0.007) [0.001, 0.034] 0.7% (SE 0.007) [0.001, 0.034] 0.7% (SE 0.007) [0.001, 0.034] Norwegian women** 0.04% 0.2% 0.5% 1.2% Norwegian men** 0.04% 0.2% 0.6% 1.5% *95% confidence intervals **Derived from summing one-year age-specific rates of all histological types of PC [10 Discussion To our knowledge, this is the first prospective study of PC providing risk estimates for confirmed BRCA1/2 carriers. Overall, there were three times more cases of PC among known carriers than expected in a similar cohort with population risk. We found a statistically significant higher incidence of PC for both BRCA1 and BRCA2 carriers, with SIRs of 2.8 and 4.8, respectively. However, when SIR was calculated for men and women separately, statistically significant increased incidence was only evident in male BRCA1 carriers (SIR 5.5) and female BRCA2 carriers (SIR 6.5), although the numbers of observed cases were higher than expected even in the remaining groups. Correspondingly, in the groups with clearly elevated SIR, the cumulative risk by age 70 was 2.5% (male BRCA1 ) and 1.2% (female BRCA2 ), i.e. around two to three times the cumulative risk in the reference population (0.7% and 0.5% in all Norwegian males and females observed until age 70, 2017–2021, CRN data). Our observations confirmed the association between pathogenic germline variants in BRCA1 and BRCA2 and PC risk. Retrospective studies have previously demonstrated a relative risk of PC between 2.2 and 3.2 for BRCA1 carriers, and between 3.5 and 6.6 for BRCA2 carriers [ 4 – 7 ]. Thus, our estimates lie largely within the ranges suggested in earlier retrospective studies. We found that increased incidence was especially pronounced in male BRCA1 carriers (SIR 5.5) and female BRCA2 carriers (6.5). Cox proportional hazard regression models confirmed that there was a statistically significant interaction effect between gender and gene, which indicated that the PC cumulative risk differs between male and female carriers. Only one previous study has calculated gender-specific risks in carriers of BRCA1/2 mutations [ 7 ]. In this retrospective study, the authors reported on data from 3184 BRCA1 and 2157 BRCA2 families, with individuals followed from birth until first primary cancer diagnosis. No statistically significant difference in relative risk between female and male BRCA1/2 carriers was found. In their study, female and male BRCA1 carriers had a relative risk of 4.27 (95% CI 2.01–9.05) and 1.92 (95% CI 1.12–3.28), and female and male BRCA2 carriers 4.34 (95% CI 2.19–8.62) and 2.96 (95% CI 1.78–4.94) [ 7 ]. Their study is different from our current study in several aspects: It is based on retrospective data, they only included the first cancer diagnosis, they included confirmed and assumed carriers, and cancer diagnoses in relatives were self-reported. These differences hamper a direct comparison with our observations, and further prospective studies with large sample sizes are needed to confirm the possible gender difference in risk of PC among BRCA1 and BRCA2 carriers. Due to the limited knowledge on the long-term benefit of PC surveillance, the CAPS-consortium (International Cancer of the Pancreas Screening Consortium) recommends that screening is only offered to those at the highest risk and within an academic setting [ 17 ]. They have previously suggested that surveillance is offered to those with a lifetime risk of more than 5% or a fivefold increased relative risk [ 19 ]. The current NCCN (National Comprehensive Cancer Network) guidelines recommend that surveillance is considered in all BRCA2 carriers irrespective of family history of PC, and the guidelines issued by ASGE (American Society of Gastrointestinal Endoscopy) recommends surveillance for both BRCA1 and BRCA2 carriers [ 20 , 21 ]. In our study, both male BRCA1 carriers and female BRCA2 carriers had a more than fivefold increase in PC incidence compared to the general population. However, none of the groups of carries had a cumulative risk of PC of 5% at the age of 80. For female BRCA2 carriers it was 1.2% at 70 years and 3.2% at 80 and for male BRCA1 carriers it was 2.5% at 70 and 80 years. For male BRCA2 and female BRCA1 carriers it was below 1% at 80 years. More information is needed, but based on our observations, it is not clear that BRCA1/2 carriers as a group has a sufficiently high risk to be recommended surveillance. Family history of PC is often included in guidelines for screening: The CAPS-consortium recommends that surveillance is offered to BRCA2 carries who have at least one affected first-degree relative with PC [ 17 ] and the NCCN guidelines recommends that it is considered in BRCA1 carriers with a family history of PC [ 20 ]. However, no earlier studies have demonstrated that family history impacts PC risk in BRCA1/2 carriers. Two recent studies found no association between having a first-degree relative with PDAC and PC risk but they included only 294 and 204 BRCA1/2 carriers respectively [ 22 , 23 ]. A secondary aim of our study was to investigate the impact of family history on PC risk. We found a higher number of observed vs expected cases of PC in female BRCA2 carriers and male BRCA1 carriers both with and without a family history of PC. Indeed, the highest SIRs were observed for BRCA2 female carriers with 1 or more relatives with PC who were confirmed carriers and for BRCA1 male carriers with 1 or more relatives with PC. However, the number of cases was small and the confidence intervals wide. Thus, further studies and larger sample sizes are needed to explore this question and for a firm conclusion to be drawn. Our data also indicated that family history of PC had a limited predictive value. In the prospective cohort, only 25% of the BRCA1 and 33% of the BRCA2 carriers who had been diagnosed with PC had reported a first or a second degree relative with PC. In other words, 65–75% of those who were diagnosed with PC after they were found to carry a BRCA1/2 mutation did not have a family history of the disease. This is in line with earlier reports where only a minority of PC patients found to be BRCA1/2 carriers had a relative with the disease [ 24 , 25 ]. In the present study, among 139 families with a known case of PC, 83% of the families only had this single case of PC. This is a prospective study of PC risk in a cohort including only confirmed BRCA1/2 carriers and all PC diagnoses have been confirmed from CRN. The design of the study limits the risks of ascertainment bias found in studies based on retrospective data. Even though the prospective cohort included as many as 4162 carriers, mean follow up years counting from date of birth was 53.1, and only 21 cases of PC had been diagnosed after genetic testing. We cannot exclude that more cases of PC will occur as the individuals in this cohort grow older, and this may affect the risk estimates. In this prospective study including confirmed BRCA1/2 carriers, we observed around three times more cases of PC than expected from the reference population, with a higher risk suggested in BRCA2 than in BRCA1 carriers. There were higher numbers of observed than expected cases across gene and gender, but a statistically significant elevated standardized incidence ratio was only confirmed in male BRCA1 carriers (SIR 5.5) and female BRCA2 carriers (SIR 6.5). The cumulative risk of PC at age 70 in these two groups of carriers was higher than that of the general population, but less than 3%. Our findings of differences in risk according to gene and gender need to be confirmed in other studies. Further studies are also needed to clarify whether BRCA1/2 carries as a group are at sufficiently high risk to be recommended screening, and to elucidate the effect of family history of PC on risk. Declarations Additional information Acknowledgements: The data for this study has been made available by the Cancer Registry of Norway. Preliminary findings has been presented as a poster at the International Symposium on Hereditary Breast and Ovarian Cancer in Montreal in on the third of May 2023. The title of the poster was: Prospective Pancreatic Cancer in a Large Norwegian Cohort of Confirmed BRCA1/BRCA2 Carriers. The abstract was not published to other than the participants attending the conference. Author’ contributions: Study design: EMG, LOM, TKG, MZ. Data collection: EMG, TKG. Data analysis: All authors. Manuscript preparation: All authors. Review of final manuscript: All authors. Ethics approval and consent to participate: The study was approved by the Regional Ethics Committee (Approval number 2019/308) and the Data Protection Officer at Oslo University Hospital (Approval number 19/09703). The approval from the ethics committee included an exemption from the requirement to obtain consent from the participants. The study was performed in accordance with the Declaration of Helsinki. Data availability: The data included in the study are stored on the secure server of Oslo University Hospital. They are available upon reasonable request. Competing Interests: The authors declare no conflict of interest. Funding information: This study was funded by the Norwegian Cancer Society, grant number 212734-2019 “The Norwegian Cancer Society’s National Group of Expertise on Pancreatic Cancer Research”. References Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72, 1117–30 (2003). doi: 10.1086/375033 . King MC, Marks JH, Mandell JB; New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302, 643–6 (2003) doi: 10.1126/science.1088759 . Edwards SM, Kote-Jarai Z, Meitz J, Hamoudi R, Hope Q, Osin P, et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72, 1–12 (2003) doi: 10.1086/345310 . Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91, 1310–6 (1999) doi: 10.1093/jnci/91.15.1310 . Thompson D, Easton DF; Breast Cancer Linkage Consortium. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94, 1358–65 (2002) doi: 10.1093/jnci/94.18.1358 . Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98, 1694–706 (2006) doi: 10.1093/jnci/djj465 . Li S, Silvestri V, Leslie G, Rebbeck TR, Neuhausen SL, Hopper JL, et al. Cancer risks associated with BRCA1 and BRCA2 pathogenic variants. J Clin Oncol 40, 1529–4 (2022). doi: 10.1200/JCO.21.02112 . Iqbal J, Ragone A, Lubinski J, Lynch HT, Moller P, Ghadirian P, et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 107, 2005–9 (2012). doi: 10.1038/bjc.2012.483 . Annual report for 2023 for the Quality Registry of Pancreatic cancer at The Cancer Registry of Norway, page 11. https://www.kreftregisteret.no/globalassets/publikasjoner-og-rapporter/arsrapporter/publisert-2024/arsrapport-2023-kvalitetsregister-for-pankreaskreft.pdf accessed on January 20th 2025 Cancer Registry of Norway. Norwegian Institute of Public Health. Cancer in Norway 2023 - Cancer incidence, mortality, survival and prevalence in Norway. Oslo: Cancer Registry of Norway, 2024. Lu C, Xu CF, Wan XY, Zhu HT, Yu CH, Li YM. Screening for pancreatic cancer in familial high-risk individuals: a systematic review. World J Gastroenterol 21, 8678–86 (2015) doi: 10.3748/wjg.v21.i28.8678 . Vasen H, Ibrahim I, Ponce CG, Slater EP, Matthäi E, Carrato A, et al. Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers. J Clin Oncol 34, 2010–9 (2016) doi: 10.1200/JCO.2015.64.0730 . Canto MI, Almario JA, Schulick RD, Yeo CJ, Klein A, Blackford A, et al. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology 155, 740–51 (2018) doi: 10.1053/j.gastro.2018.05.035 . Overbeek KA, Levink IJM, Koopmann BDM, Harinck F, Konings ICAW, Ausems MGEM, et al. Long-term yield of pancreatic cancer surveillance in high-risk individuals. Gut 71, 1152–60 (2022). doi: 10.1136/gutjnl-2020-323611 . Klatte DCF, Boekestijn B, Wasser MNJM, Feshtali Shahbazi S, Ibrahim IS, Mieog JSD, et al. Pancreatic Cancer Surveillance in Carriers of a Germline CDKN2A Pathogenic Variant: Yield and Outcomes of a 20-Year Prospective Follow-Up. J Clin Oncol 40, 3267–3277 (2022) doi: 10.1200/JCO.22.00194 . Laish I, Schechter M, Dancour A, Lieberman S, Levi Z, Goldberg Y, et al. The benefit of pancreatic cancer surveillance in carriers of germline BRCA1/2 pathogenic variants. Cancer 130, 256–266 (2024). doi: 10.1002/cncr.35052 . Epub 2023 Oct 20. Goggins M, Overbeek KA, Brand R, Syngal S, Del Chiaro M, Bartsch DK, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut 69, 7–17 (2020). doi: 10.1136/gutjnl-2019-319352 . Larsen IK, Småstuen M, Johannesen TB, Langmark F, Parkin DM, Bray F, et al. Data quality at the Cancer Registry of Norway: an overview of comparability, completeness, validity and timeliness. Eur J Cancer 45, 1218–31 (2009) doi: 10.1016/j.ejca.2008.10.037 . Canto MI, Harinck F, Hruban RH, Offerhaus GJ, Poley JW, Kamel I, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 62, 339–47 (2013). doi: 10.1136/gutjnl-2012-303108 . NCCN clinical Practice Guidelines in Oncology (NCCN Guidelines®) Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate, Version 2.2025-November 7,2024 Sawhney MS, Calderwood AH, Thosani NC, Rebbeck TR, Wani S, Canto MI, et al. ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations. Gastrointest Endosc 95, 817–826 (2022) doi: 10.1016/j.gie.2021.12.001 . Shah I, Silva-Santisteban A, Germansky KA, Kandasamy C, Mlabasati J, Huang DC, et al.. Association Between Family History and Risk of Pancreatic Cancer in Patients With BRCA1 and BRCA2 Pathogenic Variants. Pancreas 51, 733–738 (2022) doi: 10.1097/MPA.0000000000002104 . PMID: 36395396. Roch AM, Schneider J, Carr RA, Lancaster WP, House MG, Zyromski NJ, et al. Are BRCA1 and BRCA2 gene mutation patients underscreened for pancreatic adenocarcinoma? J Surg Oncol 119, 777–783 (2019) doi: 10.1002/jso.25376 . Hu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA 319, 2401–9 (2018). doi: 10.1001/jama.2018.6228 . Shindo K, Yu J, Suenaga M, Fesharakizadeh S, Cho C, Macgregor-Das A, et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J Clin Oncol 35, 3382–90 (2017). doi: 10.1200/JCO.2017.72.3502 . Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7131529","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":506563571,"identity":"4662a97c-59a0-4957-a41c-3d729e6a5de9","order_by":0,"name":"Eli Marie Grindedal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuklEQVRIiWNgGAWjYDACdsYGBoYKEIuH4QNxWphBWs6AtTDOIFILEDO2kaKFn5m5+XXlPJvE+Q28BxsYd9gQ1iLZzNhmeXZbWuKGA3yJDYxn0ghrMTjM2GbYuO1w4gb5N+YPGNsOE9ZiD9Yy5zDQYTyGDURpMWBmbH7Y2HA4seEAsVokgLYwNhxLM94A0pLYRoRf+NvbH39sqLGRBTvsYxsRIQYEbBJwZgJRGoCRSWQ6GQWjYBSMghELANa3OTvPCH7vAAAAAElFTkSuQmCC","orcid":"","institution":"Oslo University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Eli","middleName":"Marie","lastName":"Grindedal","suffix":""},{"id":506563573,"identity":"4fd520c2-a568-4f8b-924f-e0b2596ca176","order_by":1,"name":"Manuela Zucknick","email":"","orcid":"","institution":"University of Oslo","correspondingAuthor":false,"prefix":"","firstName":"Manuela","middleName":"","lastName":"Zucknick","suffix":""},{"id":506563575,"identity":"6afd6c73-a8f0-4039-a37e-90a9b252bcd2","order_by":2,"name":"Sigrid Tronsli Hovland","email":"","orcid":"","institution":"Oslo University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sigrid","middleName":"Tronsli","lastName":"Hovland","suffix":""},{"id":506563578,"identity":"02280f72-ceed-4d62-8c33-ef462b25b04e","order_by":3,"name":"Tom Kristian Grimsrud","email":"","orcid":"","institution":"Norwegian Institute of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Tom","middleName":"Kristian","lastName":"Grimsrud","suffix":""},{"id":506563582,"identity":"603f3cda-6901-4eca-8d8a-476361216d5a","order_by":4,"name":"Lovise Maehle","email":"","orcid":"","institution":"Oslo University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lovise","middleName":"","lastName":"Maehle","suffix":""}],"badges":[],"createdAt":"2025-07-15 14:23:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7131529/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7131529/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90392266,"identity":"64b1728a-f4aa-4ecd-8a13-5be129e5726d","added_by":"auto","created_at":"2025-09-02 08:50:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":899902,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7131529/v1/b21fa5db-fabc-4859-bdf6-8e90fdf3695c.pdf"},{"id":90390712,"identity":"386de185-d8a0-457d-9425-d0371049ac09","added_by":"auto","created_at":"2025-09-02 08:26:35","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":24664,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7131529/v1/3a274f0158f7be8446fec2ea.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eA prospective observational study of pancreatic cancer risk in men and women with pathogenic variants in \u003cem\u003eBRCA1\u003c/em\u003e or \u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eThe tumor suppressor genes \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e were identified in the mid-1990s. Since then, numerous studies have confirmed that women with pathogenic variants in these genes (\u003cem\u003eBRCA1/2\u003c/em\u003e carriers) have a high lifetime risk of developing breast and ovarian cancer [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Somewhat later research showed that male \u003cem\u003eBRCA2\u003c/em\u003e carriers have an elevated risk of prostate cancer [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Clinical guidelines have been established for early detection and/or prevention of breast, ovarian and prostate cancer in \u003cem\u003eBRCA1/2\u003c/em\u003e carriers.\u003c/p\u003e\u003cp\u003eTo provide carriers with evidence-based advice regarding follow-up, it is important to know whether pathogenic variants in \u003cem\u003eBRCA1/2\u003c/em\u003e are associated with increased risk of other common or severe cancers, such as pancreatic cancer (PC) known to have a high lethality. In retrospective studies, estimates of the relative risk (RR) of PC have been reported between 2.2 and 3.2 for \u003cem\u003eBRCA1\u003c/em\u003e carriers, and between 3.5 and 6.6 for \u003cem\u003eBRCA2\u003c/em\u003e carriers [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Retrospective studies are based on historical data on cancer reported in families before genetic testing was done. The estimates may therefore be affected by selection bias, as the families with the strongest family histories of cancer are more inclined to be referred for genetic testing than those with fewer individuals with cancer. In addition, the study cohorts often include both carriers and individuals who have not been tested, and the estimates thereby become more uncertain. In a recent large, international retrospective study it was also noted that the data on family history of cancer was self-reported, and that 7–40% of the diagnoses lacked information on age [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. To our knowledge, only one prospective study has investigated risk of PC in female \u003cem\u003eBRCA1/2\u003c/em\u003e carriers [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This study found similar but imprecise risk estimates for the two genes, with standardized incidence ratios (SIR) of 2.6 (95% confidence interval (CI) 0.95–5.67, six cases) for \u003cem\u003eBRCA1\u003c/em\u003e and 2.1 (95% CI 0.25–7.58, two cases) for \u003cem\u003eBRCA2\u003c/em\u003e (CIs derived by the authors of the present article). The low statistical strength allowed no firm conclusion for \u003cem\u003eBRCA2\u003c/em\u003e (\u003cem\u003ep\u003c/em\u003e = 0.3).\u003c/p\u003e\u003cp\u003eMore than 80% of PC patients are diagnosed with advanced stage disease, when surgery is no longer possible [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Still, the overall 5-year relative survival has improved over the last 20 years from around 3–15% for pancreatic cancer, all histological subtypes taken together [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Some studies have indicated that annual surveillance with magnetic resonance imaging (MRI) and/or endoscopic ultrasound (EUS) may lead to a higher number of resectable cancers and an improved short time survival [\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e–\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. It has been argued that surveillance should be done in an academic setting to select the high-risk individuals most likely to benefit from it [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Thus, it is important to obtain precise risk estimates in prospective studies of large cohorts of confirmed carriers. The information is also important for the carriers themselves and their families.\u003c/p\u003e\u003cp\u003eSection for Hereditary Cancer (SHC) at Oslo University Hospital (OUH), has offered genetic testing of \u003cem\u003eBRCA1/2\u003c/em\u003e since 1994. In August 2020, our clinical registry included 4353 confirmed carriers of pathogenic or likely pathogenic \u003cem\u003eBRCA1/2\u003c/em\u003e variants. The Cancer Registry of Norway (CRN) continuously records individual data on new cancers diagnosed nationally. Linkage to these data is facilitated by unique personal identity numbers, providing reliable data on all PC diagnoses among \u003cem\u003eBRCA1/2\u003c/em\u003e carriers in our cohort, as well as equally reliable comparison data on incidence from the general Norwegian population. The aim of this study was to obtain prospective estimates of PC incidence in confirmed male and female \u003cem\u003eBRCA1/2\u003c/em\u003e carriers compared with the general population, and to investigate their cumulative risk of PC. A secondary aim was to investigate PC incidence in carriers with and without a recorded family history of the disease.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eClinical registry for hereditary cancer at Section of Hereditary Cancer (SHC), Oslo University Hospital\u003c/span\u003e\u003c/p\u003e\u003cp\u003eSHC has offered genetic counseling and testing for familial cancer and hereditary syndromes since the early 1990s. When an individual is referred to the section, a record is created in the section’s \u003cem\u003eclinical registry for hereditary cancer\u003c/em\u003e for him or her. For each individual, information is registered on date of birth, personal cancer history, and results of performed genetic analyses. During counseling, information is collected regarding family history of cancer. When the diagnosis is uncertain, detailed information is collected from CRN or medical files. Some family history of cancer is therefore self-reported and some is confirmed. The purpose is to create a family tree for a visual image of how individuals in a family are related, what types of cancer have been diagnosed, whether and when they have been genetically tested, and test results. Some families in the registry span 5–6 generations.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eGenetic testing of\u003c/span\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eBRCA1\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eand\u003c/span\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eBRCA2\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eat SHC\u003c/span\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e were identified in 1994 and 1995. Until around 2010, the availability of genetic testing for these genes was limited. Genetic analyses could only be done in families with a strong family history of breast and/or ovarian cancer, and when it was possible to get a blood sample from family members diagnosed with such cancer. Most families were only tested for 6–10 known Norwegian \u003cem\u003eBRCA1/2\u003c/em\u003e founder mutations. For many families, blood samples were stored for years before they could be analyzed, or sequenced, and some patients had passed away before the variant was identified. From 2010, all individuals who fulfilled criteria for genetic testing were offered sequencing and Multi Ligation Probe Amplification (MLPA) of both genes. As genetic testing has become more available, the criteria for testing have become more liberal. Today, an individual with \u003cem\u003eone\u003c/em\u003e first-degree relative who has breast cancer ≤ 60 years, or \u003cem\u003eone\u003c/em\u003e first-degree relative who has ovarian cancer regardless of age, will be offered testing of \u003cem\u003eBRCA1\u003c/em\u003e/\u003cem\u003e2.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eIn Norway, genetic testing is largely covered by the Norwegian Health Economics Administration (HELFO) and the patient only pays a small deductible. Genetic services are therefore in principle available to the whole population regardless of income or employment status. Knowledge about hereditary breast and ovarian cancer has increased in the general population during the last 10 years, and even in Norway, we saw an Angelina effect, with a 50% increase in the number of referred patients around 2013.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eMethods\u003c/span\u003e\u003c/p\u003e\u003cp\u003eThis is a prospective observational study of PC risk in confirmed \u003cem\u003eBRCA1/2\u003c/em\u003e carriers. All women and men who had tested positive for a pathogenic or likely pathogenic variant in \u003cem\u003eBRCA1/2\u003c/em\u003e were identified in the clinical registry at SHC by August 2020. Information on all diagnosed cancers in these individuals was collected from CRN, using the unique personal identification numbers covering all Norwegian citizens alive in or born after 1960. The CRN is close-to-complete [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and has registered cancer diagnoses in Norway since 1953. At the time of data collection, CRN had completed its registration for 2019. Last date of observation for the study was therefore set to 31st of December 2019. We collected information on all cancer diagnoses (ICD10 codes and date of diagnosis), and for PC classification of histology was provided.\u003c/p\u003e\u003cp\u003eFrom the clinical registry, we collected information on date of birth, gender, affected gene and variant. We extracted manually, data on any recorded first degree/second degree/any relative diagnosed with PC. Some, but not all of these diagnoses were confirmed from CRN or hospital records. We also registered whether these relatives were carriers or whether they had unknown carrier status. For individuals who had been diagnosed with PC we registered whether they had relatives with PC \u003cem\u003eprior\u003c/em\u003e to their own diagnosis.\u003c/p\u003e\u003cp\u003eTo reduce the likelihood of selection bias, we identified a sub-cohort within the total cohort of carriers, including only those who had tested positive for a \u003cem\u003eBRCA1/2\u003c/em\u003e variant while they were alive (“at risk” of PC), not diagnosed with PC before they were genetically tested, and tested before 31st of December 2019. The \u003cem\u003eprospective analyses\u003c/em\u003e of SIR and cumulative risk were only performed within this sub-cohort, referred to as the \u003cem\u003eprospective cohort\u003c/em\u003e in the following.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStatistics\u003c/span\u003e\u003c/p\u003e\u003cp\u003eOnly pancreatic adenocarcinomas were included in the descriptive analyses, the logistic regression and the analysis of cumulative risk. Follow up years was counted from date of birth to date of PC diagnosis/date of death/date of last follow up (31.12.2019) for the whole cohort. For the prospective cohort we also calculated follow up years from date of genetic testing. Because population data on frequencies of PC from the CRN includes all histologies, we included all prospective cases regardless of histology for the SIR analysis. SIR was calculated for comparing incidence of PC in this cohort with the incidence in comparable age and birth cohort distributions (data obtained from CRN). 95% confidence intervals for SIR were estimated using a Poisson distribution. Statistical tests are performed as two-sided tests at the 0.05 significance level. A Cox proportional hazards model was fitted to analyze associations between cumulative risk of PC and covariates gender and gene status (\u003cem\u003eBRCA1/2\u003c/em\u003e variant status) and to calculate hazard ratios for these factors. Additional models included the interaction effect between gender and gene, and family history. Stata/SE Version 16.1 was used for SIR and cumulative risk analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe total cohort included 4453 \u003cem\u003eBRCA1/2\u003c/em\u003e carriers, 2851 (64.0%) \u003cem\u003eBRCA1\u003c/em\u003e carriers, 1597 (35.9%) \u003cem\u003eBRCA2\u003c/em\u003e carriers, and 5 carried a pathogenic variant in both \u003cem\u003eBRCA1 and BRCA2\u003c/em\u003e. The carriers belonged to 1319 registered families in the clinical registry. Follow up years was 236626.6 for the whole cohort. The prospective cohort included slightly fewer individuals, 4162 carriers, 2681 (64.4%) \u003cem\u003eBRCA1\u003c/em\u003e carriers, 1476 (35.5%) \u003cem\u003eBRCA2\u003c/em\u003e carriers, and 5 carriers of both a \u003cem\u003eBRCA1\u003c/em\u003e and a \u003cem\u003eBRCA2\u003c/em\u003e variant. Follow up years counted from date of birth was 221036.7 and 33650.2 counted from date of genetic testing (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDescription of study cohort\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eTotal cohort\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of carriers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4453\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2851\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1597\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3204 (72%)\u003c/p\u003e\u003cp\u003e1249 (28%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2072 (73%)\u003c/p\u003e\u003cp\u003e779 (27%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1127 (71%)\u003c/p\u003e\u003cp\u003e470 (29%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (median) at positive test result\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTested after death\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e172 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e116 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e56 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTested while alive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4281 (96%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2735 (96%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1541 (96%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFollow up years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e236626.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e152383.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e84029.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e213.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean follow up years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e52.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e42.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal number of families\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1319\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e823\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e493\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of families with more than one member registered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1091 (83%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e689 (84%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e399 (81%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAverage number of carriers per family with more than one individual registered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eProspective cohort\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of carriers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4162\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2681\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1476\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2969 (71%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1928 (72%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1036 (70%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1193 (29%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e753 (28%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e440 (30%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (median) at positive test result\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFollow up years counted from birth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e221036.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e143241.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e77582.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e213.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean follow up years counted from birth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e52.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e42.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFollow up years counted from genetic testing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33650.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24501.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9128.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e20.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean follow up years counted from genetic testing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal number of families\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1240\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e781\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e456\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of families with more than one member registered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1041 (84%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e663 (85%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e375 (82%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAverage number of carriers per family with more than one member registered\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ePancreatic cancer in the total cohort\u003c/span\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIn the total cohort, 33 (33/4453\u0026thinsp;=\u0026thinsp;0.7%) \u003cem\u003eBRCA1/2\u003c/em\u003e carriers had been diagnosed with PC, one of them a sarcoma located in the pancreas diagnosed in a female \u003cem\u003eBRCA1\u003c/em\u003e carrier. The rest were adenocarcinomas. Excluding the sarcoma, the 32 PCs (32/4453\u0026thinsp;=\u0026thinsp;0.7% of all carriers) were distributed with 16 (16/2851\u0026thinsp;=\u0026thinsp;0.6%) in \u003cem\u003eBRCA1\u003c/em\u003e carriers and 16 (16/1597\u0026thinsp;=\u0026thinsp;1%) in \u003cem\u003eBRCA2\u003c/em\u003e carriers. None of the 5 combined \u003cem\u003eBRCA1\u003c/em\u003e and a \u003cem\u003eBRCA2\u003c/em\u003e carriers had been diagnosed with PC. Mean age at diagnosis was 67 years (range 37\u0026ndash;87) for all. The gender distribution showed the highest proportion of PC among male \u003cem\u003eBRCA1\u003c/em\u003e carriers and female \u003cem\u003eBRCA2\u003c/em\u003e carriers, respectively, 6 times the proportion in the opposite gender for \u003cem\u003eBRCA1\u003c/em\u003e and 3 times the proportion for \u003cem\u003eBRCA2\u003c/em\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe 32 patients with PC belonged to 29 different families. Five of them (5/32\u0026thinsp;=\u0026thinsp;15.6%) had a first-degree relative, and 7 (7/32\u0026thinsp;=\u0026thinsp;21.9%) any relative (carrier or obligate carrier of the same pathogenic variant) reported with PC (confirmed or not clinically confirmed) before their own PC diagnosis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePancreatic cancer in the study cohort\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eTotal cohort of carriers\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eAll carriers*\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4453)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2851)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1597)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eNo. of pancreatic cancers (percent of category)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e32 (0.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e16 (0.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e16 (1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3204)\u003c/p\u003e\u003cp\u003e19 (0.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1249)\u003c/p\u003e\u003cp\u003e13 (1.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2072)\u003c/p\u003e\u003cp\u003e5 (0.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;779)\u003c/p\u003e\u003cp\u003e11 (1.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1127)\u003c/p\u003e\u003cp\u003e14 (1.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;470)\u003c/p\u003e\u003cp\u003e2 (0.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMean age at diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e66.9\u003c/p\u003e\u003cp\u003e(37.1\u0026ndash;87.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e67.2\u003c/p\u003e\u003cp\u003e(47.7\u0026ndash;87.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e64.5\u003c/p\u003e\u003cp\u003e(37.1\u0026ndash;87.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e67.8\u003c/p\u003e\u003cp\u003e(37.1\u0026ndash;87.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e63.0\u003c/p\u003e\u003cp\u003e(44.6\u0026ndash;82.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e72.1\u003c/p\u003e\u003cp\u003e(56.0\u0026ndash;87.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e66.7\u003c/p\u003e\u003cp\u003e(47.7\u0026ndash;82.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e66.2\u003c/p\u003e\u003cp\u003e(37.1\u0026ndash;87.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e52.2\u003c/p\u003e\u003cp\u003e(44.6\u0026ndash;59.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst-degree relatives with variant and PC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;32\u003c/p\u003e\u003cp\u003e5 (15.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003cp\u003e3 (18.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSecond degree relatives with variant and PC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;32\u003c/p\u003e\u003cp\u003e1 (3.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003cp\u003e1 (6.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny relative with variant and PC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;32\u003c/p\u003e\u003cp\u003e7 (21.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003cp\u003e3 (18.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003cp\u003e4 (25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst-degree relatives with PC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;32\u003c/p\u003e\u003cp\u003e7 (21.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003cp\u003e3 (18.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003cp\u003e4 (25%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSecond degree relatives with PC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;32\u003c/p\u003e\u003cp\u003e4 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003cp\u003e2 (12.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny relative with PC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;32\u003c/p\u003e\u003cp\u003e12 (37.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003cp\u003e6 (37.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e\u003cp\u003e6 (37.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eProspective cohort\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eAll carriers*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ePancreatic cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4162)\u003c/p\u003e\u003cp\u003e21 (0.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2681)\u003c/p\u003e\u003cp\u003e12 (0.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1476)\u003c/p\u003e\u003cp\u003e9 (0.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2969)\u003c/p\u003e\u003cp\u003e11 (0.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1193)\u003c/p\u003e\u003cp\u003e10 (0.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1928)\u003c/p\u003e\u003cp\u003e3 (0.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;753)\u003c/p\u003e\u003cp\u003e9 (1.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1036)\u003c/p\u003e\u003cp\u003e8 (0.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;440)\u003c/p\u003e\u003cp\u003e1 (0.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMean age at diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e67.0 (37.1\u0026ndash;87.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e70.1 (47.7\u0026ndash;87.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e62.8 (37.1\u0026ndash;87.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e67.3\u003c/p\u003e\u003cp\u003e(37.1\u0026ndash;87.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e66.5\u003c/p\u003e\u003cp\u003e(47.7\u0026ndash;82.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e78.4\u003c/p\u003e\u003cp\u003e(66.2\u0026ndash;87.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e67.3\u003c/p\u003e\u003cp\u003e(47.7\u0026ndash;82.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eF\u003c/p\u003e\u003cp\u003e63.2\u003c/p\u003e\u003cp\u003e(37.1\u0026ndash;87.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eM\u003c/p\u003e\u003cp\u003e59.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst-degree relatives with variant and PC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21\u003c/p\u003e\u003cp\u003e2 (9.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e\u003cp\u003e1 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e\u003cp\u003e1 (11.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny relative with variant and PC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21\u003c/p\u003e\u003cp\u003e4 (19%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e\u003cp\u003e2 (16.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e\u003cp\u003e2 (22.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst-degree relatives with PC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21\u003c/p\u003e\u003cp\u003e3 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e\u003cp\u003e1 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e\u003cp\u003e2 (22.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny relative with PC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21\u003c/p\u003e\u003cp\u003e7 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e\u003cp\u003e4 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e\u003cp\u003e3 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ePancreatic cancer in the prospective cohort\u003c/span\u003e\u003c/p\u003e\u003cp\u003eIn the prospective cohort there were 21 (21/4162\u0026thinsp;=\u0026thinsp;0.5%) cases of PC (adenocarcinomas), 12 among \u003cem\u003eBRCA1\u003c/em\u003e carriers (12/2681\u0026thinsp;=\u0026thinsp;0.4%) and 9 among \u003cem\u003eBRCA2\u003c/em\u003e carriers (9/1476\u0026thinsp;=\u0026thinsp;0.6%). In addition to the 21 adenocarcinomas, the sarcoma of the pancreas was found prospectively in a female \u003cem\u003eBRCA1\u003c/em\u003e carrier. The proportion among \u003cem\u003eBRCA1\u003c/em\u003e carriers was 3/1928\u0026thinsp;=\u0026thinsp;0.2% for female and 9/753\u0026thinsp;=\u0026thinsp;1.2% for male carriers. Among \u003cem\u003eBRCA2\u003c/em\u003e carriers, 8/1036\u0026thinsp;=\u0026thinsp;0.8% women and 1/440\u0026thinsp;=\u0026thinsp;0.2% men were diagnosed with PC. Seventeen out of 21 (81%) of all PC were diagnosed in male \u003cem\u003eBRCA1\u003c/em\u003e carriers or female \u003cem\u003eBRCA2\u003c/em\u003e carriers. Mean age at onset was 67 years (range 37\u0026ndash;87).\u003c/p\u003e\u003cp\u003eTwo out of the 21 (9.5%) had a first-degree relative carrying the same variant and diagnosed with PC prior to their own diagnosis, and 4/21 (19%) had any relative with the same variant and PC (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eCharacterization of families with cases of pancreatic cancer\u003c/span\u003e\u003c/p\u003e\u003cp\u003eIn addition to the 33 diagnoses (32 adenocarcinomas and one sarcoma) collected from CRN for this study, there were 136 individuals recorded with a PC in the 1319 families with a pathogenic variant in \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e. These 136 PC patients were either obligate carriers or had unknown carrier status (one of the obligate carriers had both a \u003cem\u003eBRCA1\u003c/em\u003e and a \u003cem\u003eBRCA2\u003c/em\u003e variant). The total of 169 individuals with confirmed or unconfirmed PC belonged to 139 (10.5%) out of all 1319 families. In 115 (83%) out of the 139 families, only a single PC case was recorded. Eighteen families (18/139\u0026thinsp;=\u0026thinsp;12.9%) had two PC cases, and five families (5/139\u0026thinsp;=\u0026thinsp;3.6%) had three or four PC cases, three families with \u003cem\u003eBRCA2\u003c/em\u003e variants and two families with \u003cem\u003eBRCA1\u003c/em\u003e variants.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStandardized incidence ratios of pancreatic cancer in prospective cohort\u003c/span\u003e\u003c/p\u003e\u003cp\u003eFor the calculations of SIR, we included the sarcoma diagnosed prospectively in a female \u003cem\u003eBRCA1\u003c/em\u003e carrier, giving a total of 22 prospective PC cases. In all carrier sub-groups by gender and gene, there were more cases of PC observed than expected from the background rates, although they were statistically significant different from 1 only for the sub-groups of male \u003cem\u003eBRCA1\u003c/em\u003e carriers and female \u003cem\u003eBRCA2\u003c/em\u003e carriers, as indicated by the 95% CI not including 1 for these subgroups. Among the 2681 \u003cem\u003eBRCA1\u003c/em\u003e carriers of both genders, the SIR was 2.8 (95% CI 1.5\u0026ndash;4.70, 13 cases), and among the 1476 \u003cem\u003eBRCA2\u003c/em\u003e carriers, the SIR was 4.8 (95% CI 2.2\u0026ndash;9.0, 9 cases). Elevated risks were most clearly seen in female \u003cem\u003eBRCA2\u003c/em\u003e carriers with an SIR of 6.5 (95% CI 2.8\u0026ndash;12.9, 8 cases), and in male \u003cem\u003eBRCA1\u003c/em\u003e carriers with SIR\u0026thinsp;=\u0026thinsp;5.5 (95% CI 2.5\u0026ndash;10.5, 9 cases). The number of cases in the remaining gender-specific groups was low, with corresponding imprecise SIRs: female \u003cem\u003eBRCA1\u003c/em\u003e carriers with an SIR of 1.5 (95% CI 0.4\u0026ndash;3.9, 4 cases) and male \u003cem\u003eBRCA2\u003c/em\u003e carriers with an SIR of 2.2 (95% CI 0.1\u0026ndash;12.3, 1 case) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStandardized incidence ratios in the prospective cohort\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExpected\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eObserved\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSIR (95% confidence interval)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAll carriers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.32 (2.08\u0026ndash;5.03)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAll women\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.13 (1.62\u0026ndash;5.47)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAll men\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.79 (2.3\u0026ndash;8.82)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e men and women\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.75 (1.46\u0026ndash;4.70)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e women\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.54 (0.42\u0026ndash;3.94)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eBRCA1\u003c/em\u003e men\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.51 (2.52\u0026ndash;10.47)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e men and women\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.76 (2.18\u0026ndash;9.04)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e women\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.52 (2.82\u0026ndash;12.85)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eBRCA2\u003c/em\u003e men\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.2 (0.06\u0026ndash;12.27)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFor the sub-groups with the largest numbers of cases, i.e. female \u003cem\u003eBRCA2\u003c/em\u003e carriers and male \u003cem\u003eBRCA1\u003c/em\u003e carriers, we looked at risks according to family history of PC. There was a higher number of observed vs expected number of cases both among those who had a family history of PC and among those with no such history (Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eCumulative risk of pancreatic cancer in prospective cohort\u003c/span\u003e\u003c/p\u003e\u003cp\u003eCumulative risk of developing PC by 70 years was 0.3% for female \u003cem\u003eBRCA1\u003c/em\u003e carriers and 2.5% for male carriers. For \u003cem\u003eBRCA2\u003c/em\u003e carriers it was 1.2% for females and 0.7% for males (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Based on the observed SIRs and estimates for cumulative risk for the different groups, we hypothesized that male \u003cem\u003eBRCA1\u003c/em\u003e carriers had a higher risk than female \u003cem\u003eBRCA1\u003c/em\u003e carriers, and that female \u003cem\u003eBRCA2\u003c/em\u003e carriers had a higher risk than male \u003cem\u003eBRCA2\u003c/em\u003e carriers. We tested this by using a Cox proportional hazard regression model including gender and gene as covariates. We found that there was a statistically significant interaction effect between gender and \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043). When we added family history of PC to the model, gender and gene and its interaction remained statistically significant. A family history of one or more relatives with PC resulted in an increase in the hazard for being diagnosed with PC in this model, for both genes, but the hazard ratio was not statistically significant (HR 2.33, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.07).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCumulative risk of pancreatic adenocarcinoma among \u003cem\u003eBRCA1/2\u003c/em\u003e mutation carriers in the prospective cohort\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50 years\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e60 years\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e70 years\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e80 years\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAll carriers\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.1% (SE 0.000)\u003c/p\u003e\u003cp\u003e[0.000, 0.002]*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2% (SE 0.001)\u003c/p\u003e\u003cp\u003e[0.001, 0.006]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.1% (SE 0.003)\u003c/p\u003e\u003cp\u003e[0.006, 0.019]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.6% (SE 0.005)\u003c/p\u003e\u003cp\u003e[0.008, 0.027]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eBRCA1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eAll\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.1% (SE 0.001)\u003c/p\u003e\u003cp\u003e[0.000, 0.003]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.1% (SE 0.001)\u003c/p\u003e\u003cp\u003e[0.000, 0.003]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.2% (SE 0.004)\u003c/p\u003e\u003cp\u003e[0.005, 0.022]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.2% (SE 0.004)\u003c/p\u003e\u003cp\u003e[0.005, 0.022]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eFemale carriers\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.3% (SE 0.003)\u003c/p\u003e\u003cp\u003e[0.000, 0.014]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.3% (SE 0.003)\u003c/p\u003e\u003cp\u003e[0.000, 0.014]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eMale carriers\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.2% (SE 0.002)\u003c/p\u003e\u003cp\u003e[0.000, 0.010]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2% (SE 0.002)\u003c/p\u003e\u003cp\u003e[0.000, 0.010]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.5% (SE 0.01)\u003c/p\u003e\u003cp\u003e[0.011, 0.049]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.5% (SE 0.01)\u003c/p\u003e\u003cp\u003e[0.011, 0.049]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eBRCA2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eAll\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.1% (SE 0.001)\u003c/p\u003e\u003cp\u003e[0.000, 0.005]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.6% (SE 0.003)\u003c/p\u003e\u003cp\u003e[0.002, 0.014]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1% (SE 0.004)\u003c/p\u003e\u003cp\u003e[0.004, 0.022]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.5% (SE 0.012)\u003c/p\u003e\u003cp\u003e[0.009, 0.057]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eFemale carriers\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.1% (SE 0.001)\u003c/p\u003e\u003cp\u003e[0.000, 0.007]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.5% (SE 0.003)\u003c/p\u003e\u003cp\u003e[0.001, 0.015]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.2% (SE 0.005)\u003c/p\u003e\u003cp\u003e[0.004, 0.027]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.2% (SE 0.016)\u003c/p\u003e\u003cp\u003e[0.010, 0.075]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eMale carriers\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.7% (SE 0.007)\u003c/p\u003e\u003cp\u003e[0.001, 0.034]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.7% (SE 0.007)\u003c/p\u003e\u003cp\u003e[0.001, 0.034]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.7% (SE 0.007)\u003c/p\u003e\u003cp\u003e[0.001, 0.034]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNorwegian women**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.04%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.5%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.2%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNorwegian men**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.04%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.6%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.5%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e*95% confidence intervals\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e**Derived from summing one-year age-specific rates of all histological types of PC [10\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first prospective study of PC providing risk estimates for confirmed \u003cem\u003eBRCA1/2\u003c/em\u003e carriers. Overall, there were three times more cases of PC among known carriers than expected in a similar cohort with population risk. We found a statistically significant higher incidence of PC for both \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e carriers, with SIRs of 2.8 and 4.8, respectively. However, when SIR was calculated for men and women separately, statistically significant increased incidence was only evident in male \u003cem\u003eBRCA1\u003c/em\u003e carriers (SIR 5.5) and female \u003cem\u003eBRCA2\u003c/em\u003e carriers (SIR 6.5), although the numbers of observed cases were higher than expected even in the remaining groups. Correspondingly, in the groups with clearly elevated SIR, the cumulative risk by age 70 was 2.5% (male \u003cem\u003eBRCA1\u003c/em\u003e) and 1.2% (female \u003cem\u003eBRCA2\u003c/em\u003e), i.e. around two to three times the cumulative risk in the reference population (0.7% and 0.5% in all Norwegian males and females observed until age 70, 2017\u0026ndash;2021, CRN data).\u003c/p\u003e\u003cp\u003eOur observations confirmed the association between pathogenic germline variants in \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e and PC risk. Retrospective studies have previously demonstrated a relative risk of PC between 2.2 and 3.2 for \u003cem\u003eBRCA1\u003c/em\u003e carriers, and between 3.5 and 6.6 for \u003cem\u003eBRCA2\u003c/em\u003e carriers [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Thus, our estimates lie largely within the ranges suggested in earlier retrospective studies. We found that increased incidence was especially pronounced in male \u003cem\u003eBRCA1\u003c/em\u003e carriers (SIR 5.5) and female \u003cem\u003eBRCA2\u003c/em\u003e carriers (6.5). Cox proportional hazard regression models confirmed that there was a statistically significant interaction effect between gender and gene, which indicated that the PC cumulative risk differs between male and female carriers. Only one previous study has calculated gender-specific risks in carriers of \u003cem\u003eBRCA1/2\u003c/em\u003e mutations [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In this retrospective study, the authors reported on data from 3184 \u003cem\u003eBRCA1\u003c/em\u003e and 2157 \u003cem\u003eBRCA2\u003c/em\u003e families, with individuals followed from birth until first primary cancer diagnosis. No statistically significant difference in relative risk between female and male \u003cem\u003eBRCA1/2\u003c/em\u003e carriers was found. In their study, female and male \u003cem\u003eBRCA1\u003c/em\u003e carriers had a relative risk of 4.27 (95% CI 2.01\u0026ndash;9.05) and 1.92 (95% CI 1.12\u0026ndash;3.28), and female and male \u003cem\u003eBRCA2\u003c/em\u003e carriers 4.34 (95% CI 2.19\u0026ndash;8.62) and 2.96 (95% CI 1.78\u0026ndash;4.94) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Their study is different from our current study in several aspects: It is based on retrospective data, they only included the first cancer diagnosis, they included confirmed and assumed carriers, and cancer diagnoses in relatives were self-reported. These differences hamper a direct comparison with our observations, and further prospective studies with large sample sizes are needed to confirm the possible gender difference in risk of PC among \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e carriers.\u003c/p\u003e\u003cp\u003eDue to the limited knowledge on the long-term benefit of PC surveillance, the CAPS-consortium (International Cancer of the Pancreas Screening Consortium) recommends that screening is only offered to those at the highest risk and within an academic setting [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. They have previously suggested that surveillance is offered to those with a lifetime risk of more than 5% or a fivefold increased relative risk [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The current NCCN (National Comprehensive Cancer Network) guidelines recommend that surveillance is considered in all \u003cem\u003eBRCA2\u003c/em\u003e carriers irrespective of family history of PC, and the guidelines issued by ASGE (American Society of Gastrointestinal Endoscopy) recommends surveillance for both \u003cem\u003eBRCA1\u003c/em\u003e and \u003cem\u003eBRCA2\u003c/em\u003e carriers [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In our study, both male \u003cem\u003eBRCA1\u003c/em\u003e carriers and female \u003cem\u003eBRCA2\u003c/em\u003e carriers had a more than fivefold increase in PC incidence compared to the general population. However, none of the groups of carries had a cumulative risk of PC of 5% at the age of 80. For female \u003cem\u003eBRCA2\u003c/em\u003e carriers it was 1.2% at 70 years and 3.2% at 80 and for male \u003cem\u003eBRCA1\u003c/em\u003e carriers it was 2.5% at 70 and 80 years. For male \u003cem\u003eBRCA2\u003c/em\u003e and female \u003cem\u003eBRCA1\u003c/em\u003e carriers it was below 1% at 80 years. More information is needed, but based on our observations, it is not clear that \u003cem\u003eBRCA1/2\u003c/em\u003e carriers as a group has a sufficiently high risk to be recommended surveillance.\u003c/p\u003e\u003cp\u003eFamily history of PC is often included in guidelines for screening: The CAPS-consortium recommends that surveillance is offered to \u003cem\u003eBRCA2\u003c/em\u003e carries who have at least one affected first-degree relative with PC [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and the NCCN guidelines recommends that it is considered in \u003cem\u003eBRCA1\u003c/em\u003e carriers with a family history of PC [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, no earlier studies have demonstrated that family history impacts PC risk in \u003cem\u003eBRCA1/2\u003c/em\u003e carriers. Two recent studies found no association between having a first-degree relative with PDAC and PC risk but they included only 294 and 204 \u003cem\u003eBRCA1/2\u003c/em\u003e carriers respectively [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A secondary aim of our study was to investigate the impact of family history on PC risk. We found a higher number of observed vs expected cases of PC in female \u003cem\u003eBRCA2\u003c/em\u003e carriers and male \u003cem\u003eBRCA1\u003c/em\u003e carriers both with and without a family history of PC. Indeed, the highest SIRs were observed for \u003cem\u003eBRCA2\u003c/em\u003e female carriers with 1 or more relatives with PC who were confirmed carriers and for \u003cem\u003eBRCA1\u003c/em\u003e male carriers with 1 or more relatives with PC. However, the number of cases was small and the confidence intervals wide. Thus, further studies and larger sample sizes are needed to explore this question and for a firm conclusion to be drawn. Our data also indicated that family history of PC had a limited predictive value. In the prospective cohort, only 25% of the \u003cem\u003eBRCA1\u003c/em\u003e and 33% of the \u003cem\u003eBRCA2\u003c/em\u003e carriers who had been diagnosed with PC had reported a first or a second degree relative with PC. In other words, 65\u0026ndash;75% of those who were diagnosed with PC after they were found to carry a \u003cem\u003eBRCA1/2\u003c/em\u003e mutation did not have a family history of the disease. This is in line with earlier reports where only a minority of PC patients found to be \u003cem\u003eBRCA1/2\u003c/em\u003e carriers had a relative with the disease [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In the present study, among 139 families with a known case of PC, 83% of the families only had this single case of PC.\u003c/p\u003e\u003cp\u003eThis is a prospective study of PC risk in a cohort including only confirmed \u003cem\u003eBRCA1/2\u003c/em\u003e carriers and all PC diagnoses have been confirmed from CRN. The design of the study limits the risks of ascertainment bias found in studies based on retrospective data. Even though the prospective cohort included as many as 4162 carriers, mean follow up years counting from date of birth was 53.1, and only 21 cases of PC had been diagnosed after genetic testing. We cannot exclude that more cases of PC will occur as the individuals in this cohort grow older, and this may affect the risk estimates.\u003c/p\u003e\u003cp\u003eIn this prospective study including confirmed \u003cem\u003eBRCA1/2\u003c/em\u003e carriers, we observed around three times more cases of PC than expected from the reference population, with a higher risk suggested in \u003cem\u003eBRCA2\u003c/em\u003e than in \u003cem\u003eBRCA1\u003c/em\u003e carriers. There were higher numbers of observed than expected cases across gene and gender, but a statistically significant elevated standardized incidence ratio was only confirmed in male \u003cem\u003eBRCA1\u003c/em\u003e carriers (SIR 5.5) and female \u003cem\u003eBRCA2\u003c/em\u003e carriers (SIR 6.5). The cumulative risk of PC at age 70 in these two groups of carriers was higher than that of the general population, but less than 3%. Our findings of differences in risk according to gene and gender need to be confirmed in other studies. Further studies are also needed to clarify whether \u003cem\u003eBRCA1/2\u003c/em\u003e carries as a group are at sufficiently high risk to be recommended screening, and to elucidate the effect of family history of PC on risk.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eThe data for this study has been made available by the Cancer Registry of Norway. Preliminary findings has been presented as a poster at the International Symposium on Hereditary Breast and Ovarian Cancer in Montreal in on the third of May 2023. The title of the poster was: Prospective Pancreatic Cancer in a Large Norwegian Cohort of Confirmed \u003cem\u003eBRCA1/BRCA2\u003c/em\u003e Carriers. The abstract was not published to other than the participants attending the conference. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor’ contributions:\u003c/strong\u003e Study design: EMG, LOM, TKG, MZ. Data collection: EMG, TKG. Data analysis: All authors. Manuscript preparation: All authors. Review of final manuscript: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e The study was approved by the Regional Ethics Committee (Approval number 2019/308) and the Data Protection Officer at Oslo University Hospital (Approval number 19/09703). The approval from the ethics committee included an exemption from the requirement to obtain consent from the participants. The study was performed in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eThe data included in the study are stored on the secure server of Oslo University Hospital. They are available upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information:\u003c/strong\u003e This study was funded by the Norwegian Cancer Society, grant number 212734-2019 “The Norwegian Cancer Society’s National Group of Expertise on Pancreatic Cancer Research”.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAntoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. \u003cem\u003eAm J Hum Genet\u003c/em\u003e 72, 1117\u0026ndash;30 (2003). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1086/375033\u003c/span\u003e\u003cspan address=\"10.1086/375033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKing MC, Marks JH, Mandell JB; New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. \u003cem\u003eScience\u003c/em\u003e 302, 643\u0026ndash;6 (2003) doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1126/science.1088759\u003c/span\u003e\u003cspan address=\"10.1126/science.1088759\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEdwards SM, Kote-Jarai Z, Meitz J, Hamoudi R, Hope Q, Osin P, et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. \u003cem\u003eAm J Hum Genet\u003c/em\u003e 72, 1\u0026ndash;12 (2003) doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1086/345310\u003c/span\u003e\u003cspan address=\"10.1086/345310\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBreast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. \u003cem\u003eJ Natl Cancer Inst\u003c/em\u003e 91, 1310\u0026ndash;6 (1999) doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/jnci/91.15.1310\u003c/span\u003e\u003cspan address=\"10.1093/jnci/91.15.1310\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThompson D, Easton DF; Breast Cancer Linkage Consortium. Cancer incidence in BRCA1 mutation carriers. \u003cem\u003eJ Natl Cancer Inst\u003c/em\u003e 94, 1358\u0026ndash;65 (2002) doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/jnci/94.18.1358\u003c/span\u003e\u003cspan address=\"10.1093/jnci/94.18.1358\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRisch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. \u003cem\u003eJ Natl Cancer Inst\u003c/em\u003e 98, 1694\u0026ndash;706 (2006) doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/jnci/djj465\u003c/span\u003e\u003cspan address=\"10.1093/jnci/djj465\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi S, Silvestri V, Leslie G, Rebbeck TR, Neuhausen SL, Hopper JL, et al. Cancer risks associated with BRCA1 and BRCA2 pathogenic variants. \u003cem\u003eJ Clin Oncol\u003c/em\u003e 40, 1529\u0026ndash;4 (2022). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.21.02112\u003c/span\u003e\u003cspan address=\"10.1200/JCO.21.02112\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIqbal J, Ragone A, Lubinski J, Lynch HT, Moller P, Ghadirian P, et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. \u003cem\u003eBr J Cancer\u003c/em\u003e 107, 2005\u0026ndash;9 (2012). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/bjc.2012.483\u003c/span\u003e\u003cspan address=\"10.1038/bjc.2012.483\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAnnual report for 2023 for the Quality Registry of Pancreatic cancer at The Cancer Registry of Norway, page 11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.kreftregisteret.no/globalassets/publikasjoner-og-rapporter/arsrapporter/publisert-2024/arsrapport-2023-kvalitetsregister-for-pankreaskreft.pdf\u003c/span\u003e\u003cspan address=\"https://www.kreftregisteret.no/globalassets/publikasjoner-og-rapporter/arsrapporter/publisert-2024/arsrapport-2023-kvalitetsregister-for-pankreaskreft.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e accessed on January 20th 2025\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCancer Registry of Norway. Norwegian Institute of Public Health. Cancer in Norway 2023 - Cancer incidence, mortality, survival and prevalence in Norway. Oslo: Cancer Registry of Norway, 2024.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLu C, Xu CF, Wan XY, Zhu HT, Yu CH, Li YM. Screening for pancreatic cancer in familial high-risk individuals: a systematic review. \u003cem\u003eWorld J Gastroenterol\u003c/em\u003e 21, 8678\u0026ndash;86 (2015) doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3748/wjg.v21.i28.8678\u003c/span\u003e\u003cspan address=\"10.3748/wjg.v21.i28.8678\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVasen H, Ibrahim I, Ponce CG, Slater EP, Matth\u0026auml;i E, Carrato A, et al. Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers. \u003cem\u003eJ Clin Oncol\u003c/em\u003e 34, 2010\u0026ndash;9 (2016) doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2015.64.0730\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2015.64.0730\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCanto MI, Almario JA, Schulick RD, Yeo CJ, Klein A, Blackford A, et al. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. \u003cem\u003eGastroenterology\u003c/em\u003e 155, 740\u0026ndash;51 (2018) doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/j.gastro.2018.05.035\u003c/span\u003e\u003cspan address=\"10.1053/j.gastro.2018.05.035\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOverbeek KA, Levink IJM, Koopmann BDM, Harinck F, Konings ICAW, Ausems MGEM, et al. Long-term yield of pancreatic cancer surveillance in high-risk individuals. \u003cem\u003eGut\u003c/em\u003e 71, 1152\u0026ndash;60 (2022). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/gutjnl-2020-323611\u003c/span\u003e\u003cspan address=\"10.1136/gutjnl-2020-323611\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKlatte DCF, Boekestijn B, Wasser MNJM, Feshtali Shahbazi S, Ibrahim IS, Mieog JSD, et al. Pancreatic Cancer Surveillance in Carriers of a Germline \u003cem\u003eCDKN2A\u003c/em\u003e Pathogenic Variant: Yield and Outcomes of a 20-Year Prospective Follow-Up. \u003cem\u003eJ Clin Oncol\u003c/em\u003e 40, 3267\u0026ndash;3277 (2022) doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.22.00194\u003c/span\u003e\u003cspan address=\"10.1200/JCO.22.00194\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLaish I, Schechter M, Dancour A, Lieberman S, Levi Z, Goldberg Y, et al. The benefit of pancreatic cancer surveillance in carriers of germline BRCA1/2 pathogenic variants. \u003cem\u003eCancer\u003c/em\u003e 130, 256\u0026ndash;266 (2024). doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cncr.35052\u003c/span\u003e\u003cspan address=\"10.1002/cncr.35052\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2023 Oct 20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGoggins M, Overbeek KA, Brand R, Syngal S, Del Chiaro M, Bartsch DK, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. \u003cem\u003eGut\u003c/em\u003e 69, 7\u0026ndash;17 (2020). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/gutjnl-2019-319352\u003c/span\u003e\u003cspan address=\"10.1136/gutjnl-2019-319352\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLarsen IK, Sm\u0026aring;stuen M, Johannesen TB, Langmark F, Parkin DM, Bray F, et al. Data quality at the Cancer Registry of Norway: an overview of comparability, completeness, validity and timeliness. \u003cem\u003eEur J Cancer\u003c/em\u003e 45, 1218\u0026ndash;31 (2009) doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ejca.2008.10.037\u003c/span\u003e\u003cspan address=\"10.1016/j.ejca.2008.10.037\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCanto MI, Harinck F, Hruban RH, Offerhaus GJ, Poley JW, Kamel I, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. \u003cem\u003eGut\u003c/em\u003e 62, 339\u0026ndash;47 (2013). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/gutjnl-2012-303108\u003c/span\u003e\u003cspan address=\"10.1136/gutjnl-2012-303108\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNCCN clinical Practice Guidelines in Oncology (NCCN Guidelines\u0026reg;) Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate, Version 2.2025-November 7,2024\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSawhney MS, Calderwood AH, Thosani NC, Rebbeck TR, Wani S, Canto MI, et al. ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations. \u003cem\u003eGastrointest Endosc\u003c/em\u003e 95, 817\u0026ndash;826 (2022) doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.gie.2021.12.001\u003c/span\u003e\u003cspan address=\"10.1016/j.gie.2021.12.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShah I, Silva-Santisteban A, Germansky KA, Kandasamy C, Mlabasati J, Huang DC, et al.. Association Between Family History and Risk of Pancreatic Cancer in Patients With BRCA1 and BRCA2 Pathogenic Variants. \u003cem\u003ePancreas\u003c/em\u003e 51, 733\u0026ndash;738 (2022) doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MPA.0000000000002104\u003c/span\u003e\u003cspan address=\"10.1097/MPA.0000000000002104\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 36395396.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoch AM, Schneider J, Carr RA, Lancaster WP, House MG, Zyromski NJ, et al. Are BRCA1 and BRCA2 gene mutation patients underscreened for pancreatic adenocarcinoma? \u003cem\u003eJ Surg Oncol\u003c/em\u003e 119, 777\u0026ndash;783 (2019) doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jso.25376\u003c/span\u003e\u003cspan address=\"10.1002/jso.25376\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. \u003cem\u003eJAMA\u003c/em\u003e 319, 2401\u0026ndash;9 (2018). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2018.6228\u003c/span\u003e\u003cspan address=\"10.1001/jama.2018.6228\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShindo K, Yu J, Suenaga M, Fesharakizadeh S, Cho C, Macgregor-Das A, et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. \u003cem\u003eJ Clin Oncol\u003c/em\u003e 35, 3382\u0026ndash;90 (2017). doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2017.72.3502\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2017.72.3502\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bjc-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BJC Reports](https://www.springer.com/journal/44276) ","snPcode":"44276","submissionUrl":"https://submission.springernature.com/new-submission/44276/3","title":"BJC Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7131529/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7131529/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003e\u003cem\u003eBRCA1 \u003c/em\u003eand\u003cem\u003e BRCA2 \u003c/em\u003ecarriers have increased risk of pancreatic cancer (PC). We explored incidence rate and cumulative risk of PC in a large prospective cohort of confirmed carriers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003e\u003cem\u003eBRCA1/2\u003c/em\u003e carrierswithout PC prior to genetic testing were identified from the clinical registry at Section for Hereditary Cancer, Oslo University Hospital. Cancer diagnoses were collected from Cancer Registry of Norway (CRN). Standardized incidence ratios (SIRs) were derived from national reference rates. The Kaplan-Meier method was used to calculate cumulative risk.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Among 2681 \u003cem\u003eBRCA1 \u003c/em\u003ecarriers, we observed 13 cases \u003cem\u003eversus\u003c/em\u003e 4.7 expected (SIR 2.8, 95% CI 2.1-5.0). In 1476 \u003cem\u003eBRCA2\u003c/em\u003e carriers, we observed 9 cases \u003cem\u003eversus\u003c/em\u003e1.9 expected (SIR 4.8, 95% CI 2.2–9.0). The highest risk was observed for female \u003cem\u003eBRCA2\u003c/em\u003e carriers (SIR 6.5, 95% CI 2.8–12.9, 8 cases) and male \u003cem\u003eBRCA1\u003c/em\u003ecarriers (SIR 5.5, 95% CI 2.5–10.5, 9 cases), who had a cumulative risk at 70 years of 1.2% and 2.5% respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e \u003cem\u003eBRCA1/2\u003c/em\u003e carriers had three times more cases of PC than expected, but a statistically significant increased incidence was only observed for female \u003cem\u003eBRCA2\u003c/em\u003e and male \u003cem\u003eBRCA1\u003c/em\u003e carriers. Cumulative risk of PC at 70 years in these two groups was less than 3%.\u003c/p\u003e","manuscriptTitle":"A prospective observational study of pancreatic cancer risk in men and women with pathogenic variants in BRCA1 or BRCA2","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-02 08:26:30","doi":"10.21203/rs.3.rs-7131529/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-16T14:37:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-11T01:17:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"246653160532036638509958040146370862905","date":"2025-09-09T20:58:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-08T23:11:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"179523294502722925851297939934327527950","date":"2025-08-27T21:12:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-25T12:38:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-19T18:47:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-24T13:32:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BJC Reports","date":"2025-07-15T14:09:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bjc-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BJC Reports](https://www.springer.com/journal/44276) ","snPcode":"44276","submissionUrl":"https://submission.springernature.com/new-submission/44276/3","title":"BJC Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1149d0c1-8abe-4aad-9775-70272c59b305","owner":[],"postedDate":"September 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-19T23:08:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-02 08:26:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7131529","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7131529","identity":"rs-7131529","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}