Close relatives of patients with pancreatic cancer at higher risk for several malignancies
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Key takeaways:
- First-degree female relatives of probands who carried BRCA1 mutations had an increased risk for ovarian cancer.
- First-degree relatives of probands with a CDKN2A variant had an increased risk for melanoma.
First-degree relatives of individuals with pancreatic ductal adenocarcinoma who harbored certain cancer-associated pathogenic germline variants had significantly higher risk for developing several cancer types, study results showed.
The findings, published in JAMA Oncology, revealed an approximately ninefold higher risk for breast cancer among first-degree female relatives of probands who carry BRCA1 variants, compared with the general population, investigators noted.
“Although the first-degree relatives may know they are at increased risk [for] developing pancreatic ductal adenocarcinoma, they may not realize that they are also at increased risk [for] extra-pancreatic malignancies, such as ovarian, breast, uterine, colon and melanoma,” Kari Rabe, MS, principal biostatistician in the department of quantitative health sciences at Mayo Clinic, told Healio. “Ultimately, we hope that our research will lead to advances in identifying cancer at an earlier stage, which will — in turn — improve survival of patients.”
Background
Pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer, and previous research has shown that approximately 5% to 10% of those diagnosed with the disease harbor a pathogenic variant in a cancer-associated gene, according to Rabe.
This knowledge has led to the recommendation that first-degree relatives of those with pancreatic ductal adenocarcinoma undergo blood-based genetic testing to determine if they carry any known cancer-related pathogenic variants, she added.
“The importance of these genetic tests is that they can guide treatment options and also determine if family members of the patient should be tested to enhance pancreatic ductal adenocarcinoma risk prediction, toward the goal of early detection,” Rabe said. “For this study, we hypothesized that the risk [for] pancreatic ductal adenocarcinoma in first-degree relatives differed depending on which gene was present in the family. [Because] some of these genes confer risk for extra-pancreatic malignancies, we wondered if the first-degree relatives were also at increased risk [for] the additional cancers.”
Methodology
Rabe and colleagues conducted a case-series study to evaluate the risk for developing both pancreatic ductal adenocarcinoma and other syndrome-associated cancers among first-degree relatives of individuals with pancreatic ductal adenocarcinoma who harbor one of nine known cancer-associated genetic germline variations.
Investigators included ATM, BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2 and CDKN2A as the pathogenic germline variants evaluated in the study.
The study population comprised 1,670 first-degree relatives (mean age, 58.1 ± 17.8 years; 51.1% men) of 234 probands (mean age, 62.5 ± 10.1 years; 53% men; 94.4% white; 98.7% non-Hispanic or non-Latino) enrolled in the Mayo Clinic Biospecimen Resource for Pancreas Research registry. Most registry participants underwent germline genetic testing, with study participants carrying at least one of the nine variants being evaluated.
Study participants had demographic and cancer-related family histories collected via questionnaire, with data obtained between Oct. 1, 2000, and Dec. 31, 2021.
Researchers expressed results as estimated standardized incidence ratios (SIRs) with 95% CIs to compare the observed number of first-degree relatives with a cancer of interest (ovarian, breast, uterine, endometrial, colon, malignant melanoma or pancreatic) with the expected age- and sex-specific incidence rates among the SEER 21 database population.
Key findings
Results showed a significantly increased risk for ovarian cancer among first-degree female relatives of probands who harbored BRCA1 (SIR = 9.49; 95% CI, 3.06-22.14) and BRCA2 (SIR = 3.72; 95% CI, 1.36-8.11) variants compared with the SEER population.
First-degree female relatives of probands who harbored the BRCA2 variant also had higher breast cancer risk (SIR = 2.62; 95% CI, 1.89-3.54). Likewise, first-degree female relatives of individuals who carried Lynch syndrome mismatch repair variants (MLH1, MSH2, MSH6 or PMS2) had increased risk for uterine or endometrial cancer (SIR = 6.53; 95% CI, 2.81-12.86) and colon cancer (SIR = 5.83; 95% CI, 3.7-8.75).
Investigators observed increased risk for developing pancreatic ductal adenocarcinoma among first-degree relatives of probands who harbored pathogenic variants in ATM (SIR = 4.53; 95 % CI, 2.69-7.16), BRCA2 (SIR = 3.45; 95% CI, 1.72-6.17), CDKN2A (SIR = 7.38; 95% CI, 3.18-14.54) and PALB2 (SIR = 5.39; 95% CI, 1.45-13.79).
Researchers also observed significantly elevated melanoma risk among first-degree relatives of probands with CDKN2A variants (SIR = 7.47; 95% CI, 3.97-12.77).
Clinical implications
The results demonstrate that first-degree relatives of pancreatic ductal adenocarcinoma probands had an increased risk for both pancreatic ductal adenocarcinoma and six other cancer types compared with the reference SEER population, according to Rabe.
“When evaluating patients who have at least one first-degree relative with pancreatic ductal adenocarcinoma, clinicians should further inquire about genetic testing,” Rabe told Healio. “If the first-degree relative reports having a pathogenic variant in a cancer-syndrome associated gene in their family, our study provides additional justification for clinicians to encourage genetic testing for the first-degree relative and to recommend appropriate cancer-specific surveillance and screening.”
For more information:
Kari Rabe, MS, can be reached at Mayo Clinic, Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, 200 First St. SW, Minnesota BioBusiness Building, 5th Floor, Rochester, MN 55905; email: rabe.kari@mayo.edu.
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