Abstract
Background
The lifetime risk of pancreatic cancer in women with a germline mutation in BRCA1 and BRCA2 is not well established. In an international prospective cohort of female carriers of BRCA1 and BRCA2 mutations, the cumulative incidence of pancreatic cancer from age 40 until 80 years was estimated.
Methods
A total of 8295 women with a BRCA1 or BRCA2 mutation were followed for new cases of pancreatic cancer. Subjects were followed from the date of baseline questionnaire or age 40 years (whichever came last) until a new diagnosis of pancreatic cancer, death from another cause, or date of last follow‐up.
Results
Thirty‐four incident pancreatic cancer cases were identified in the cohort. The annual risk of pancreatic cancer between age 40 and 80 years was 0.04% for BRCA1 carriers and 0.09% for BRCA2 carriers. Via the Kaplan–Meier method, the cumulative incidence from age 40 to 80 years was 2.2% (95% CI, 1.1%–4.3%) for BRCA1 carriers and 2.7% (95% CI, 1.3%–5.4%) for BRCA2 carriers. Only two of the 34 cases reported a first‐degree relative with pancreatic cancer (hazard ratio, 4.75; 95% CI, 1.13–19.9; p = .03). Risk factors for pancreatic cancer included alcohol intake and a history of diabetes. The 5‐year survival rate for the 34 cases was 8.8%.
Conclusions
The lifetime risk of pancreatic cancer is approximately 2% in women with a BRCA1 mutation and 3% for women with a BRCA2 mutation. The poor survival in hereditary pancreatic cancer underscores the need for novel antitumoral strategies.
Keywords: BRCA1, BRCA2, incidence, pancreatic cancer, survival
Short abstract
A total of 8295 women with a BRCA1 or BRCA2 mutation were followed for new cases of pancreatic cancer. Thirty‐four incident pancreatic cancer cases were identified in the cohort. The cumulative incidence of pancreatic cancer from age 40 to 80 years was 2.2% for BRCA1 carriers and 2.7% for BRCA2 carriers. Only two of the 34 cases reported a first‐degree relative with pancreatic cancer. Risk factors for pancreatic cancer included family history, alcohol intake, and a history of diabetes.
INTRODUCTION
Germline mutations in BRCA1 and BRCA2 are increasingly being identified, with the prevalence of mutations estimated to be between one in 200 and one in 400 individuals, which depends on the population being studied. 1 The cancer risk spectrum for BRCA1 and BRCA2 mutation carriers classically includes breast, ovarian, and pancreatic cancers. 2 , 3 For male BRCA2 carriers, the risk also includes prostate cancer. 4 In some populations, there has been a reported increase in gastric cancer as well. 2 , 5 , 6 Pancreatic cancer is of particular concern to patients and providers because of its difficulty to diagnose at an early stage and its poor survival. 7
Only a small proportion of pancreatic cancer cases carry a mutation in BRCA1 or BRCA2. In a case‐control study including 3030 adults with pancreatic cancer, compared to reference controls there was a statistically significant association between pancreatic cancer and BRCA1 mutation carriers (0.6% of cases and 0.2% of controls; odds ratio [OR], 2.58) and BRCA2 mutation carriers (1.9% of cases and 0.3% of controls; OR, 6.20). 8 A meta‐analysis of pancreatic cancer risk based on family histories estimated BRCA1 and BRCA2 mutation carriers to have a relative risk of pancreatic cancer of 1.7 (p = .007) and 5.1 (p ≤ .00001), respectively. 9 Recent data from the Consortium of Investigators of Modifiers of BRCA1/2 showed that male BRCA1 and BRCA2 mutation carriers had relative risks of pancreatic cancer of 1.9 and 4.3, respectively; for females, the relative risks were 3.0 and 4.3, respectively. 2 On the basis of these relative risks, these authors estimated the absolute risk to age 80 years to be 2.9% for male BRCA1/2 mutation carriers and 2.3% for female BRCA1/2 mutation carriers. The risk before age 50 years was less than 0.2%. It is possible that the risk of pancreatic cancer differs by ethnic background. A recent study showed much higher pancreatic cancer risks in Japanese carriers for BRCA1 (OR, 12.6; 95% CI, 3.7–42.8) and BRCA2 (OR, 10.7; 95% CI, 5.1–22.6) mutations, which translated into a cumulative risk to age 85 years of nearly 15%. 6
In the general population, risk factors for pancreatic cancer include smoking, alcohol, obesity, chronic pancreatitis, and diabetes mellitus. 10 It is unclear whether these risk factors are also pertinent in carriers of BRCA1 or BRCA2 mutations. It is also not clear whether a family history of pancreatic cancer modifies the risk in BRCA1/BRCA2 carriers. However, a family history of pancreatic cancer is reported in only a small proportion of BRCA1/2 carriers with pancreatic cancer. 8
Knowledge of pancreatic cancer incidence rates and risk factors for pancreatic cancer among BRCA1/2 mutation carriers is important for genetic counseling and for risk management. Previous studies of pancreatic cancer risk in BRCA1/2 mutation carriers are based on case‐control studies and family history reviews wherein the diagnosis of pancreatic cancer in relatives relied on information provided by a family member. Furthermore, in many earlier studies, the BRCA1/2 carrier status of the family members with pancreatic cancer was unknown. In an earlier study of this cohort, our group reported a 2‐fold increase in the incidence of pancreatic cancer in women with a BRCA1 or BRCA2 mutation. 11 Herein, we update the cumulative incidence of pancreatic cancer in a prospective study of women who carry either a BRCA1 or BRCA2 mutation, and report on survival as well.
MATERIALS AND METHODS
Study subjects
The current study included females with a germline pathogenic (or likely pathogenic) variant (“mutation” hereafter) in the BRCA1 or BRCA2 gene who were enrolled in a longitudinal study of high‐risk women. Participants previously sought genetic testing for BRCA mutations because of a personal and/or family history of cancer at one of the participating cancer genetics clinics. The criteria for genetic testing varied from center to center but the majority of subjects had a personal history of cancer or a family history of cancer. In general, a family history of pancreatic cancer was not a criterion for testing. Women were eligible to be in the cohort if they were alive and had been identified as carrying a deleterious mutation in BRCA1 or BRCA2. Although a wide range of techniques was used for genetic testing, all nucleotide sequences were confirmed by direct sequencing of DNA. The cohort was established in 1995, and has since expanded to include a total of 17,900 individuals with a baseline questionnaire; of these, 13,211 had at least one follow‐up questionnaire and were potentially eligible for the study. The study protocol was approved by the institutional review boards of the participating host institutions, and all study participants provided written informed consent. There were 66 centers from 12 countries that participated in this study.
Data collection
At the time of study enrollment, participants completed a baseline questionnaire that requested detailed information on various exposures, including a personal and family history of cancer, reproductive and medical history, as well as exogenous hormone and medication use. The baseline questionnaire was completed either at the time of a clinic appointment, at their home at a later time, or at the time of recruitment into the research study. A follow‐up questionnaire was requested every 2 years thereafter. These questionnaires were either mailed or emailed to each participant to complete and return or were administered over the phone by a genetic counselor or research assistant.
For the present study, women with a history of colon cancer, lung cancer, pancreatic cancer, or ovarian cancer before the baseline questionnaire were excluded (n = 2722). These women were excluded because of the difficulty of diagnosing pancreatic cancer in the presence of another intra‐abdominal cancer or lung cancer. Women with a past history of breast cancer were included. Eighty‐seven women had data missing on key variables (date of birth, vital status, date of questionnaires, or gene mutation) and were excluded. Women whose last follow‐up was before age 40 years were excluded (n = 1967), which left 8295 women in the final analysis. Information was collected on smoking history (ever/never), alcohol use (drinks per week), body mass index (BMI) at age 40 years, and family history (one or more first‐ or second‐degree relatives with pancreatic cancer). We recorded whether the women had breast cancer before the baseline questionnaire and whether chemotherapy had been administered. We also recorded whether the women had taken medication for the treatment of diabetes.
The diagnosis of pancreatic cancer was confirmed by reference to a pathology report or medical record where possible. In the event that the patient had died of pancreatic cancer and the date of diagnosis was not recorded, we considered the date of diagnosis to be 1 year before the date of death (n = 4).
The annual age‐specific incidence rates of pancreatic cancer were calculated for various age groups (40–49, 50–59, 60–69, 70–79, and 80+ years) with the cancer count as the numerator and the person‐years at risk as the denominator. We calculated the crude cumulative incidence from age 40 to 70 years and to age 80 years by applying the Kaplan–Meier method. Women were followed from the date at the baseline questionnaire or age 40 years (whichever came last) until the date of the last questionnaire, the diagnosis of pancreatic cancer, age 70 (or 80) years, or death from another cause. The data were stratified by mutation (BRCA1 vs. BRCA2). We then performed a Cox regression analysis to identify the risk factors for pancreatic cancer in the cohort. Women were followed from the date at the baseline questionnaire until the date of the last questionnaire, the diagnosis of pancreatic cancer, or death from another cause. We included the following covariates: age at the baseline questionnaire, mutation (BRCA1 or BRCA2), smoking (ever/never), BMI at age 40 years, history of breast cancer at baseline, history of drug use for diabetes at baseline, alcohol use (drinks per week), and family history of pancreatic cancer (one or more first‐ or second‐degree relatives with pancreatic cancer).
We then estimated the overall survival for pancreatic cancer via the Kaplan–Meier method. Patients with pancreatic cancer were followed from the date of pancreatic cancer diagnosis to the date of death from pancreatic cancer, date of death from other causes, or date of last follow‐up.
RESULTS
Incidence
A total of 8295 women in our database of BRCA1 and BRCA2 mutation carriers were followed for a mean of 8.6 years (Table 1). The mean age at last follow‐up was 57 years (range, 40–103 years). We identified 34 incident cases of pancreatic cancer in the cohort; 32 of the 34 cases (94%) were confirmed by pathology report or medical record, and two were based on the patient questionnaire. Of the 34 incident pancreatic cancer cases, 17 cases occurred in BRCA1 mutation carriers and 17 cases occurred in BRCA2 mutation carriers. The mean age at diagnosis of pancreatic cancer was 62.3 years for BRCA1 mutation carriers and 61.5 years for BRCA2 mutation carriers. Six of the 34 cases of pancreatic cancer were preceded by a diagnosis of another cancer after baseline but before the pancreatic cancer, including breast cancer (three), melanoma (one), skin cancer (one), and fallopian tube cancer (one).
TABLE 1.
Characteristics of the 8295 BRCA mutation carriers included in the study.
| Variables | N = 8295 |
|---|---|
| Year of birth, mean (range) | 1957.5 (1908–1982) |
| Year at baseline questionnaire, mean (range) | 2005.9 (1992.0–2021.0) |
| Age at baseline questionnaire, mean (range), years | 48.4 (21–94) |
| Follow‐up, mean (range), years | 8.6 (0.1–25.9) |
| Age at last follow‐up, mean (range), years | 57.0 (40–102) |
| BMI at age 40 years, No. (%), kg/m2 | |
| ≤20 | 688 (12.6) |
| 20.1–25.0 | 3013 (55.1) |
| 25.1–30.0 | 1216 (22.2) |
| >30.0 | 551 (10.1) |
| Missing | 2827 |
| BRCA mutation, No. (%) | |
| BRCA1 | 5827 (70.3) |
| BRCA2 | 2438 (29.4) |
| BRCA1 and BRCA2 | 30 (0.4) |
| Oophorectomy, No. (%) | |
| No | 1837 (22.6) |
| Yes | 6415 (77.4) |
| Missing | 7 |
| Breast cancer, No. (%) | |
| No | 3622 (43.7) |
| Yes | 4673 (56.3) |
| Yes, no chemotherapy | 1072 |
| Yes, had chemotherapy | 3168 |
| Yes, chemotherapy missing | 433 |
| HRT use, No. (%) | |
| Never | 5711 (68.9) |
| Ever | 2477 (31.1) |
| Missing | 7 |
| Smoking history, No. (%) | |
| No | 4523 (56.4) |
| Yes | 3504 (43.6) |
| Missing | 259 |
| Alcohol use, No. (%) | |
| No | 2442 (31.0) |
| Yes | 5426 (69.0) |
| Missing | 427 |
| First‐degree relative with pancreatic cancer, No. (%) | |
| No | 6787 (98.8) |
| Yes | 81 (1.2) |
| Missing | 1427 |
| Second‐degree relative with pancreatic cancer, No. (%) | |
| No | 6824 (99.4) |
| Yes | 44 (0.6) |
| Missing | 1427 |
| Diabetes at baseline, No. (%) | |
| No | 8143 (98.2) |
| Yes | 152 (1.8) |
| Country of residence, No. (%) | |
| Poland | 2430 (29.3) |
| United States | 2382 (28.7) |
| Canada | 2300 (27.7) |
| Norway | 463 (5.6) |
| Israel | 184 (2.2) |
| Italy | 164 (2.0) |
| Austria | 150 (1.8) |
| The Netherlands | 67 (0.8) |
| The Bahamas | 44 (0.5) |
| China | 39 (0.5) |
| France | 39 (0.5) |
| Spain | 33 (0.4) |
Abbreviations: BMI, body mass index; HRT, hormone replacement therapy.
The annual incidence rates by gene and age group are presented in Table 2. For women aged older than 40 years, the annual incidence rate was 38 per 100,000 per year for BRCA1 mutation carriers (95% CI, 20–40) and 99 per 100,000 per year for BRCA2 mutation carriers (95% CI, 50–150). For BRCA1 mutation carriers, the annual risk was 25 per 100,000 per year (95% CI, 10–40) for women aged 40–60 years and 80 per 100,000 per year for women aged 60–80 years (95% CI, 30–130). For BRCA2 mutation carriers, the annual risk was 67 per 100,000 per year for women aged 40–60 years (95% CI, 20–110) and 140 per 100,000 per year for women aged 60–80 years (95% CI, 40–230). Via the Kaplan–Meier method, the cumulative incidence of pancreatic cancer from age 40 to 70 years was 0.6% for BRCA1 carriers (95% CI, 0.02%–0.2%) and 1.2% for BRCA2 carriers (95% CI, 0.7%–2.2%). The cumulative incidence from age 40 to 80 years was 2.2% (95% CI, 1.1%–4.3%) for BRCA1 carriers and 2.7% (95% CI, 1.3%–5.4%) for BRCA2 carriers (Figure 1).
TABLE 2.
Annual incidence rate of pancreatic cancer by age group and BRCA mutation.
| Age, years | All subjects | BRCA1 | BRCA2 | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Person‐years, No. | Events, No. | Rate, % | Person‐years, No. | Events, No. | Rate, % | Person‐years, No. | Events, No. | Rate, % | |
| 40–49 | 21,847 | 4 | 0.018 | 16,468 | 2 | 0.012 | 5381 | 2 | 0.037 |
| 50–59 | 22,500 | 12 | 0.053 | 15,886 | 6 | 0.038 | 6615 | 6 | 0.091 |
| 60–69 | 12,570 | 9 | 0.072 | 8335 | 4 | 0.048 | 4238 | 5 | 0.118 |
| 70–79 | 4562 | 8 | 0.171 | 2879 | 5 | 0.173 | 1682 | 3 | 0.178 |
| 80+ | 955 | 1 | 0.105 | 647 | 0 | 0.00 | 308 | 1 | 0.325 |
| All | 62,434 | 34 | 0.054 | 44,215 | 17 | 0.038 | 18,224 | 17 | 0.093 |
FIGURE 1.
Cumulative risk of pancreatic cancer, from age 40 to 80 years, by BRCA gene.
The hazard ratios (HRs) and confidence limits for various risk factors are presented in Table 3 (BRCA1 and BRCA2 combined). BRCA2 mutation carriers were at a statistically significantly increased pancreatic cancer risk compared to BRCA1 mutation carriers (HR, 2.08; p = .04). Of 152 women who reported a history of diabetes at baseline, three developed pancreatic cancer (crude HR, 6.31; p = .0002). Women who reported consuming more than nine drinks a week at baseline had a 7‐fold risk of pancreatic cancer compared to nondrinkers (HR, 6.66; p = .0005). Neither smoking nor BMI at age 40 years was a risk factor for pancreatic cancer in this cohort. Two of the 34 incident cases of pancreatic cancer had a first‐degree relative with pancreatic cancer (HR, 4.75; 95% CI, 1.13–19.9; p = .03). Three of the 34 incident cases of pancreatic cancer had no first‐degree relative but did have at least one second‐degree relative with pancreatic cancer. In total, six of the 34 individuals with pancreatic cancer reported a family history of pancreatic cancer (Table 4).
TABLE 3.
Hazard ratios for pancreatic cancer for all subjects for selected variables.
| Variables | Cases/total, No. | Univariate RR (95% CI) p | Multivariate RR (95% CI) p |
|---|---|---|---|
| Age at baseline questionnaire, years | |||
| <50 | 11/4899 | 1 | 1 |
| 50–60 | 12/2219 | 2.93 (1.29–6.66) .01 | 2.52 (1.04–6.12) .04 |
| >60 | 11/1177 | 5.54 (2.39–12.8) <.0001 | 5.00 (2.00–12.5) .0006 |
| BMI at age 40 years, kg/m2 | |||
| ≤25 | 19/3701 | 1 | 1 |
| >25 | 9/1767 | 1.00 (0.45–2.20) .99 | 0.93 (0.41–2.12) .87 |
| Missing | 6/2827 | ||
| BRCA mutation | |||
| BRCA1 | 17/5857 | 1 | 1 |
| BRCA2 | 17/2438 | 2.58 (1.32–5.06) .006 | 2.08 (1.05–4.12) .04 |
| Oophorectomy a | |||
| No | 10/1873 | 1 | 1 |
| Yes | 24/6415 | 0.98 (0.46–2.07) .96 | 0.75 (0.35–1.64) .47 |
| Breast cancer a | |||
| No | 18/3622 | 1 | 1 |
| Yes | 16/4673 | 0.76 (0.39–1.48) .41 | 0.58 (0.29–1.18) .13 |
| Yes, no chemotherapy | 7/1072 | 1.56 (0.65–3.74) .32 | 0.72 (0.29–1.80) .48 |
| Yes, had chemotherapy | 9/3168 | 0.73 (0.33–1.63) .44 | 0.56 (0.24–1.27) .17 |
| HRT use | |||
| Never | 23/5711 | 1 | 1 |
| Ever | 11/2577 | 0.90 (0.44–1.84) .76 | 0.82 (0.38–1.74) .58 |
| Smoking history | |||
| No | 18/4532 | 1 | 1 |
| Yes | 16/3504 | 1.16 (0.59–2.28) .66 | 1.18 (0.59–2.34) .64 |
| Alcohol use | |||
| No | 8/2442 | 1 | 1 |
| Yes | 25/5426 | 1.18 (0.53–2.61) .69 | 1.35 (0.59–3.09) .48 |
| Missing | 1/427 | ||
| Yes, 0–3 drinks/week | 13/4224 | 0.77 (0.32–1.87) .57 | 0.94 (0.38–2.33) .90 |
| Yes, 4–9 drinks/week | 5/896 | 1.46 (0.48–4.48) .50 | 1.64 (0.51–5.29) .41 |
| Yes, >9 drinks/week | 6/247 | 6.66 (2.31–19.2) .0005 | 7.37 (2.38–22.8) .0005 |
| First‐degree relative with pancreatic cancer | |||
| No | 30/6787 | 1 | 1 |
| Yes | 2/81 | 4.75 (1.13–19.9) .03 | 4.77 (1.10–20.6) .04 |
| Missing | 2/1427 | ||
| Second‐degree relative with pancreatic cancer | |||
| No | 31/6824 | 1 | 1 |
| Yes | 1/44 | 4.13 (0.56–30.2) .16 | 4.01 (0.53–30.3) .18 |
| Missing | 2/1427 | ||
| First‐ or second‐degree relative with pancreatic cancer | |||
| No | 29/6474 | 1 | 1 |
| Yes | 3/121 | 4.84 (1.47–15.9) .009 | 5.06 (1.50–17.1) .009 |
| Missing | 2/1427 | ||
| Diabetes at baseline | |||
| No | 31/8143 | 1 | 1 |
| Yes | 3/152 | 6.31 (1.93–20.7) .0002 | 4.63 (1.33–16.1) .02 |
Abbreviations: BMI, body mass index; HRT, hormone replacement therapy; RR, relative risk.
Time‐dependent variable.
TABLE 4.
BRCA1 and BRCA2 carriers with pancreatic cancer who also had a family history of pancreatic cancer.
| Age of pancreatic cancer in index case, years | Family history from pedigree |
|---|---|
| 77 | One nephew diagnosed with pancreatic cancer at age 67 years |
| 67 | Two maternal aunts diagnosed with pancreatic cancer |
| 78 | One maternal male cousin diagnosed with pancreatic cancer at age 66 years |
| One maternal female cousin diagnosed with pancreatic cancer at age 71 years | |
| One maternal female cousin diagnosed with pancreatic cancer at age 52 years | |
| One nephew diagnosed with pancreatic cancer at age 55 years | |
| 56 | Father died of (suspected) pancreatic cancer at age 69 years |
| 45 | Father died of pancreatic cancer |
| 58 | One maternal male cousin diagnosed with pancreatic cancer at age 51 years |
Survival
Thirty‐two of the 34 subjects died during the follow‐up study; 30 died of pancreatic cancer, one died from breast cancer, and one died from sepsis. The median survival from pancreatic cancer diagnosis to death was 0.9 years (Figure 2). The 5‐year survival rate was 8.8%.
FIGURE 2.
Five‐year survival after pancreatic cancer for the 34 cases.
DISCUSSION
In this study, we prospectively followed 8295 women who carried a BRCA1 or BRCA2 mutation and estimated the cumulative incidence and annual risk of pancreatic cancer. To our knowledge, this is the largest prospective study of pancreatic cancer in BRCA1 and BRCA2 mutation carriers to date.
We estimated the cumulative risk of pancreatic cancer to age 80 years among women who are BRCA1 mutation carriers to be 2.2% and BRCA2 mutation carriers to be 2.7%. This is similar to the pancreatic cancer risk in other studies of BRCA1/2 mutation carriers, 2 and our data also support the position that BRCA2 mutation carriers have a higher risk of pancreatic cancer compared to BRCA1 mutation carriers. 9 BRCA1/2‐related pancreatic cancer is rare in young individuals, 2 with only four of our 34 incident cancers (12%) occurring before age 50 years. We estimated the annual risk of developing pancreatic cancer for women aged between 40 and 80 years to be 0.05% for BRCA1 mutation carriers and 0.09% for BRCA2 mutation carriers. In comparison, the annual risk of breast cancer in BRCA1 and BRCA2 mutation carriers in this cohort and age range is estimated to be 2.2% and 2.4%, respectively (data not shown). Having accurate risk data, including both annual and cumulative risk as well as age at presentation, is relevant for both patient and clinician decision‐making. Specifically, these risk estimates may allow patients who are newly found to carry a BRCA1 or BRCA2 mutation to prioritize cancer screening and risk management strategies on the basis of information about the age‐specific risks of various cancers.
Several risk factors are thought to play a role in the development of pancreatic cancer. 10 In our cohort, alcohol use of more than nine drinks per week as well as a diagnosis of diabetes were both found to confer statistically significantly increased risks of pancreatic cancer. Female carriers of a BRCA1 or BRCA2 mutation should be aware of the potential for increased pancreatic cancer risk with excessive alcohol use. New‐onset diabetes is a well‐recognized risk factor for pancreatic cancer, with an estimated 1% of individuals who develop diabetes at age 50 years or older developing pancreatic cancer within 3 years of the diabetes diagnosis. 12 , 13 , 14 This information may prove useful for clinicians following women carriers of a BRCA1 or BRCA2 mutation who develop diabetes.
Pancreatic cancer surveillance has been recommended for select high‐risk BRCA1/2 mutation carriers. 15 , 16 , 17 , 18 , 19 Most guidelines recommend that pancreatic cancer surveillance only be performed in BRCA1/2 mutation carriers who have a family history of pancreatic cancer starting at age 50 years, or earlier if there is a young family member with pancreatic cancer. 15 , 16 , 17 , 18 However, more recent guidelines from the American Society for Gastrointestinal Endoscopy broadened the inclusion criteria to recommend surveillance for all BRCA1/2 mutation carriers, regardless of family history. 19 Notably, in our cohort, only three of the BRCA1/2 mutation carriers who developed pancreatic cancer had a first‐ or second‐degree relative with pancreatic cancer. Therefore, if family history had been used for eligibility, the majority of our affected BRCA1/2 mutation carriers would not have been eligible for surveillance before their diagnosis.
Pancreatic surveillance has been shown to downstage pancreatic cancer diagnosis and to improve survival in some studies 20 , 21 , 22 , 23 ; however, positive outcomes have not been observed in all studies. 24 , 25 In recent data from the multicenter Cancer of Pancreas Screening‐5 study, pancreatic surveillance led to a survival benefit; however, fewer than a quarter of the subjects were BRCA1 or BRCA2 mutation carriers. In the international, multicenter Pancreatic Cancer Early Detection Consortium, which is one of the largest prospective pancreatic cancer surveillance studies to date, 29% of the individuals in the high‐risk cohort were BRCA1/2 mutation carriers. 26 Recently, Blackford et al. reported that the surveillance of high‐risk individuals led to a better survival rate from pancreatic cancer than for patients with pancreatic cancer in the Surveillance, Epidemiology, and End Results registry who were presumably not screened. 23
As more patients are recruited to surveillance studies and as additional prospective surveillance data are obtained, it will be important to determine whether surveillance in a BRCA1/2‐specific cohort can improve survival rates, given the unique nature of BRCA‐associated pancreatic cancers, compared to sporadic and other types of pancreatic cancer. 27 We did not have information on whether the cancers were screen detected or were in symptomatic patients.
In our study, the survival of the incident cases was very poor (median survival, 0.9 years; 5‐year survival, 8.8%). One study has suggested that BRCA2 mutation carriers have better outcomes than BRCA1 mutation carriers. 28 There have been several clinical trials investigating treatment approaches directed at BRCA1/2‐associated pancreatic cancers. 29 These data have demonstrated that BRCA1/2‐associated pancreatic cancers show an enhanced response to platinum‐based chemotherapy agents and also demonstrate response to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. 30 , 31 , 32 , 33 In our cohort, one woman has survived pancreatic cancer for 18 years postdiagnosis who was treated with cisplatin chemotherapy followed by surgical reduction in 2006. However, acquired resistance to platinum‐based chemotherapy regimens and PARP inhibitors does arise in BRCA1/2‐related pancreatic cancer, which highlights the need for better therapeutic strategies. 34
Our study has a number of limitations pertaining to both the estimation of the incidence and overall survival. Our cohort study includes only women, and therefore we cannot estimate the incidence of pancreatic cancer in men who are BRCA1/2 mutation carriers. The mutation carriers in this cohort were identified among those who attended one of many cancer genetics clinics for a personal or family history of cancer, and may not be representative of the carrier population as a whole. The number of incident cases was small (N = 34), and this limits the precision of the risk estimates. We used the Kaplan–Meier method to estimate cumulative incidence. This survival analysis generated cumulative risks that were lower than risks based on applying the annual risks given in Table 2 but is more robust given the small number of cases in many of the age groups in Table 2. It is also possible that some members of the cohort developed and died of pancreatic cancer after the last follow‐up questionnaire and were not recorded. Furthermore, the cohort is relatively young, and the mean age at last follow‐up was 57 years. Few women were followed after age 70 years, and therefore the risk estimates to age 70 years may be more robust than the estimates to age 80 years. It will be important to continue to follow the cohort to get a better estimate of the risk of pancreatic cancer in older women.
In conclusion, we report on the cumulative pancreatic cancer incidence and age‐specific risks among a large cohort of women carrying a BRCA1/2 mutation. Pancreatic cancer risk is higher in BRCA2 mutation carriers than in BRCA1 mutation carriers, and BRCA1/2 mutation carriers rarely develop pancreatic cancer before age 50 years. This information will be important for counseling BRCA1/2 mutation carriers and for developing appropriate risk management strategies.
AUTHOR CONTRIBUTIONS
Bryson W. Katona: Writing–original draft and writing–review and editing. Jan Lubinski: Investigation and data curation. Tuya Pal: Investigation and project administration. Tomasz Huzarski: Investigation and resources. William D. Foulkes: Investigation. Pal Moller: Investigation. Andrea Eisen: Investigation. Susan Randall Armel: Investigation. Susan L. Neuhausen: Investigation. Rebecca Raj: Investigation and data curation. Amber Aeilts: Investigation. Christian F. Singer: Investigation. Louise Bordeleau: Investigation. Beth Karlan: Investigation. Olufunmilayo Olopade: Investigation. Nadine Tung: Investigation. Dana Zakalik: Investigation. Joanne Kotsopoulos: Investigation, funding acquisition, and resources. Robert Fruscio: Investigation. Charis Eng: Investigation. Ping Sun: Methodology, formal analysis, and data curation. Steven A. Narod: Conceptualization, investigation, funding acquisition, writing–original draft, methodology, visualization, writing–review and editing, formal analysis, project administration, data curation, supervision, and resources.
CONFLICT OF INTEREST STATEMENT
Bryson W. Katona reports consulting for Immunovia. Christian F. Singer reports receiving grants from Amgen and Daiichi Sankyo and travel support from Novartis, Daiichi Sankyo, AstraZeneca, and Tesaro. Beth Karlan reports consulting for FujiFilm Pharmaceuticals USA, Natera, Mercy Bioanalytics, and GRAIL. The other authors declare no conflicts of interest.
ACKNOWLEDGMENTS
Funding for this study was obtained from Canadian Institutes of Health Research Foundation Grant 154275 to Steven A. Narod and from the Peter Gilgan Foundation. Steven A. Narod is a Tier 1 Canada Research Chair. Other members of the Hereditary Breast Cancer Clinical Study Group include Kevin Sweet, Leigha Senter, Raymond Kim, Fergus Couch, Jeffrey N. Weitzel, Cezary Cybulski, Jacek Gronwald, Carey A. Cullinane, Howard Saal, Edmond Lemire, Seema Panchal, and Theresa Ramon Y. Cajal.
Katona BW, Lubinski J, Pal T, et al. The incidence of pancreatic cancer in women with a BRCA1 or BRCA2 mutation. Cancer. 2025;e35666. doi: 10.1002/cncr.35666
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.
REFERENCES
- 1. Maxwell KN, Domchek SM, Nathanson KL, Robson ME. Population frequency of germline BRCA1/2 mutations. J Clin Oncol. 2016;34:4183‐4185. doi: 10.1200/jco.2016.67.0554 [DOI] [PubMed] [Google Scholar]
- 2. Li S, Silvestri V, Leslie G, et al. Cancer risks associated with BRCA1 and BRCA2 pathogenic variants. J Clin Oncol. 2022;40(14):1529‐1541. doi: 10.1200/jco.21.02112 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402‐2416. doi: 10.1001/jama.2017.7112 [DOI] [PubMed] [Google Scholar]
- 4. Kote‐Jarai Z, Leongamornlert D, Saunders E, et al. BRCA2 is a moderate penetrance gene contributing to young‐onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011;105(8):1230‐1234. doi: 10.1038/bjc.2011.383 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Buckley KH, Niccum BA, Maxwell KN, Katona BW. Gastric cancer risk and pathogenesis in BRCA1 and BRCA2 carriers. Cancers. 2022;14(23):5953. doi: 10.3390/cancers14235953 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Momozawa Y, Sasai R, Usui Y, et al. Expansion of cancer risk profile for BRCA1 and BRCA2 pathogenic variants. JAMA Oncol. 2022;8(6):871‐878. doi: 10.1001/jamaoncol.2022.0476 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17‐48. doi: 10.3322/caac.21763 [DOI] [PubMed] [Google Scholar]
- 8. Hu C, Hart SN, Polley EC, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA. 2018;319(23):2401‐2409. doi: 10.1001/jama.2018.6228 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. McGarry JL, Creavin B, Kelly ME, Gallagher TK. Risk of pancreatic ductal adenocarcinoma associated with carriage of BRCA1 and/or BRCA2 mutation: a systematic review and meta‐analysis. J Surg Oncol. 2022;126(6):1028‐1037. doi: 10.1002/jso.26994 [DOI] [PubMed] [Google Scholar]
- 10. Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol. 2021;18(7):493‐502. doi: 10.1038/s41575-021-00457-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Iqbal J, Ragone A, Lubinski J, et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2012;107(12):2005‐2009. doi: 10.1038/bjc.2012.483 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM. Probability of pancreatic cancer following diabetes: a population‐based study. Gastroenterology. 2005;129(2):504‐511. doi: 10.1053/j.gastro.2005.05.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Sharma A, Smyrk TC, Levy MJ, Topazian MA, Chari ST. Fasting blood glucose levels provide estimate of duration and progression of pancreatic cancer before diagnosis. Gastroenterology. 2018;155(2):490‐500.e2. doi: 10.1053/j.gastro.2018.04.025 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Sharma A, Kandlakunta H, Nagpal SJS, et al. Model to determine risk of pancreatic cancer in patients with new‐onset diabetes. Gastroenterology. 2018;155(3):730‐739.e3. doi: 10.1053/j.gastro.2018.05.023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Genetic/Familial High‐Risk Assessment: Breast, Ovarian, and Pancreatic, Version 3.2023. National Comprehensive Cancer Network. Accessed January 10, 2024. https://jnccn.org/view/journals/jnccn/19/1/article‐p77.xml [DOI] [PubMed]
- 16. Sessa C, Balmana J, Bober SL, et al. Risk reduction and screening of cancer in hereditary breast‐ovarian cancer syndromes: ESMO clinical practice guideline. Ann Oncol. 2023;34(1):33‐47. doi: 10.1016/j.annonc.2022.10.004 [DOI] [PubMed] [Google Scholar]
- 17. Goggins M, Overbeek KA, Brand R, 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. 2020;69(1):7‐17. doi: 10.1136/gutjnl-2019-319352 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Aslanian HR, Lee JH, Canto MI. AGA clinical practice update on pancreas cancer screening in high‐risk individuals: expert review. Gastroenterology. 2020;159(1):358‐362. doi: 10.1053/j.gastro.2020.03.088 [DOI] [PubMed] [Google Scholar]
- 19. Sawhney MS, Calderwood AH, Thosani NC, et al. ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations. Gastrointest Endosc. 2022;95(5):817‐826. doi: 10.1016/j.gie.2021.12.001 [DOI] [PubMed] [Google Scholar]
- 20. Dbouk M, Katona BW, Brand RE, et al. The multicenter Cancer of Pancreas Screening study: impact on stage and survival. J Clin Oncol. 2022;40(28):3257‐3266. doi: 10.1200/jco.22.00298 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Klatte DCF, Boekestijn B, Onnekink AM, et al. Surveillance for pancreatic cancer in high‐risk individuals leads to improved outcomes: a propensity score‐matched analysis. Gastroenterology. 2023;164(7):1223‐1231.e4. doi: 10.1053/j.gastro.2023.02.032 [DOI] [PubMed] [Google Scholar]
- 22. Laish I, Schechter M, Dancour A, et al. The benefit of pancreatic cancer surveillance in carriers of germline BRCA1/2 pathogenic variants. Cancer. 2023;130(2):256‐266. doi: 10.1002/cncr.35052 [DOI] [PubMed] [Google Scholar]
- 23. Blackford AL, Canto MI, Dbouk M, et al. Pancreatic cancer surveillance and survival of high‐risk individuals. JAMA Oncol. 2024;10(8):1087‐1096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Overbeek KA, Goggins MG, Dbouk M, et al. Timeline of development of pancreatic cancer and implications for successful early detection in high‐risk individuals. Gastroenterology. 2022;162(3):772‐785.e4. doi: 10.1053/j.gastro.2021.10.014 [DOI] [PubMed] [Google Scholar]
- 25. Overbeek KA, Levink IJM, Koopmann BDM, et al. Long‐term yield of pancreatic cancer surveillance in high‐risk individuals. Gut. 2022;71(6):1152‐1160. doi: 10.1136/gutjnl-2020-323611 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Katona BW, Klute K, Brand RE, et al. Racial, ethnic, and sex‐based disparities among high‐risk individuals undergoing pancreatic cancer surveillance. Cancer Prev Res. 2023;16(6):343‐352. doi: 10.1158/1940-6207.capr-22-0529 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Lai E, Ziranu P, Spanu D, et al. BRCA‐mutant pancreatic ductal adenocarcinoma. Br J Cancer. 2021;125(10):1321‐1332. doi: 10.1038/s41416-021-01469-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Boursi B, Wileyto EP, Mamtani R, et al. Analysis of BRCA1‐ and BRCA2‐related pancreatic cancer and survival. JAMA Netw Open. 2023;6(11):e2345013. doi: 10.1001/jamanetworkopen.2023.45013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Keane F, O'Connor CA, Park W, Seufferlein T, O'Reilly EM. Pancreatic cancer: BRCA targeted therapy and beyond. Cancers. 2023;15(11):2955. doi: 10.3390/cancers15112955 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. 2014;111(6):1132‐1138. doi: 10.1038/bjc.2014.418 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Kaufman B, Shapira‐Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244‐250. doi: 10.1200/jco.2014.56.2728 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA‐mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317‐327. doi: 10.1056/nejmoa1903387 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Kindler HL, Hammel P, Reni M, et al. Overall survival results from the POLO trial: a phase III study of active maintenance olaparib versus placebo for germline BRCA‐mutated metastatic pancreatic cancer. J Clin Oncol. 2022;40(34):3929‐3939. doi: 10.1200/jco.21.01604 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Stossel C, Raitses‐Gurevich M, Atias D, et al. Spectrum of response to platinum and PARP inhibitors in germline BRCA‐associated pancreatic cancer in the clinical and preclinical setting. Cancer Discov. 2023;13(8):1826‐1843. doi: 10.1158/2159-8290.cd-22-0412 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.