BRCA mutations linked to increased risk for pancreatic, male breast, other cancers
Click Here to Manage Email Alerts
Pathogenic variants in BRCA1 and BRCA2 appeared associated with increased risks for prostate cancer, pancreatic cancer, male breast cancer and possibly stomach cancer, according to research published in Journal of Clinical Oncology.
Results of the international, collaborative study should enable researchers to better optimize screening and early detection strategies for both women and men with these mutations, they wrote.
"The findings suggest that in families with BRCA1 and BRCA2 mutations, relatives — men and women — should be informed about their individual cancer risk and be encouraged to be tested for BRCA1 and BRCA2," Antonis C. Antoniou, PhD, professor of cancer risk prediction in the department of public health and primary care at University of Cambridge, told Healio.
Background
Although associations of BRCA1 and BRCA2 mutations with increased risk for breast and ovarian cancers in women have been well-documented, studies examining possible links to other cancers have been limited due to small sample sizes, resulting in imprecise estimates of cancer risk, Antoniou said.
“Having accurate risk estimates is critical for counseling of women and men with genetic faults [on] prevention and screening,” Antoniou said. “We were able to have data on the largest number of families with BRCA1 and BRCA2 genetic faults to date. That enabled us to study these links with greater precision than previously possible.”
Methodology
The analysis included data from 5,341 families in the Consortium of Investigators of Modifiers of BRCA1/2 with one or more members who had a BRCA1 (n = 3,184) or BRCA2 (n = 2,157) mutation. Antoniou and colleagues estimated age-specific relative and absolute risks for 22 first primary cancer types and adjusted for family ascertainment.
Researchers collected the following data from each adult family member for their analysis: familial relationship, BRCA1/2 pathogenic variant status, sex, year of birth, years or age at pedigree data collection, death and cancer diagnoses.
Key findings
Results showed associations of BRCA1 pathogenic variants with risks for male breast cancer (RR = 4.3; 95% CI, 1.09-16.96), pancreatic cancer (RR = 2.36; 95% CI, 1.51-3.68) and stomach cancer (RR = 2.17; 95% CI, 1.25-3.77). The data also suggested associations of these mutations with risks for colorectal and gallbladder cancers.
Researchers reported associations of BRCA2 pathogenic variants with risks for male breast cancer (RR = 44; 95% CI, 21.3-90.9), stomach cancer (RR = 3.69; 95% CI, 2.4-5.67), pancreatic cancer (RR = 3.34; 95% CI, 2.21-5.06) and prostate cancer (RR = 2.22; 95% CI, 1.63-3.03). They observed a higher RR for stomach cancer among women vs. men (6.89 vs. 2.76) but noted the small data set for this rare cancer.
Absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers, and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. Results showed no strong link between BRCA2 and melanoma.
“One finding, which in fact is reassuring for families, is that there was no strong link between BRCA1 and BRCA2 genetic faults and several other cancers that had been previously reported in smaller studies,” Antoniou said.
Implications
The analysis makes the link between BRCA2 and prostate and pancreatic cancer much clearer, Marc Tischkowitz, MD, PhD, professor in the department of medical genetics at University of Cambridge and researcher on the study, said in a press release.
“Overall,” he said, “the results will add to our knowledge on optimizing cancer screening and early detection strategies for people who are known to carry these faulty genes.”
Antoniou said further research to confirm the associations should be conducted among cohorts of unaffected mutation carriers with long-term follow-up.
References:
Faulty BRCA genes linked to prostate and pancreatic cancers. https://www.cam.ac.uk/research/news/faulty-brca-genes-linked-to-prostate-and-pancreatic-cancers. Published Jan. 25, 2022. Accessed Feb. 3, 2022.
Li S, et al. J Clin Oncol. 2022;doi:10.1200/JCO.21.02112.
For more information:
Antonis C. Antoniou, PhD, can be reached at Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, United Kingdom; email: aca20@medschl.cam.ac.uk.
Perspective
Back to Top
Payal D. Shah, MD
As a medical oncologist who counsels patients with inherited pathogenic variants in cancer susceptibility genes, I am often asked a few fundamental questions: How likely am I to develop cancer? Which cancers? When?
More than 25 years after the discovery of BRCA1 and BRCA2, the risks for female breast and ovarian cancers associated with these genes are quantitatively and qualitatively well-delineated. However, less precise data have been available characterizing other BRCA1/2-associated cancer risks. For this reason, the work by Antoniou and colleagues is incredibly informative.
The findings are in part confirmatory with respect to our current understanding of BRCA1/2-associated cancer risks: individuals with pathogenic variants in these genes have an increased risk for male breast and pancreatic cancers. Interestingly, the male breast cancer risk reported is slightly lower than what has been published previously. As it stands, the National Comprehensive Cancer Network has not been firm on mammography in male BRCA1/2 carriers due to limited supporting data, so this finding is unlikely to alter clinical practice.
The pancreatic cancer risks observed in the present study are quantitatively consistent with prior reports, although the elevated relative risk for BRCA2 carriers aged younger than 65 years is interesting. The NCCN recommends consideration of pancreatic cancer screening for individuals with BRCA1/2 pathogenic germline variants and a family history of the disease. The recommended age for screening initiation is 50 years, barring a young family diagnosis, and this recommendation seems in line with the authors’ findings of pancreatic cancer diagnoses under age 65 years.
Another valuable finding from this study is the absence of an association between BRCA1 and overall prostate cancer risk. These data may eventually contribute to the removal of prostate cancer screening as a consideration for men with BRCA1 mutations from NCCN guidelines. I think this would be fair, although it should be mentioned that for a biological male with a BRCA1 germline pathogenic variant, a prostate cancer risk estimate should incorporate other risk factors, including family history, rather than automatically defaulting to population risk.
Among the authors’ findings, I found the BRCA1/2-associated stomach cancer risk most noteworthy. Given the morbidity and mortality associated with stomach cancer, I agree with the authors’ assertion that screening of the upper gastrointestinal tract, including the full stomach in addition to the pancreas, is important in BRCA1/2 carriers. The best modality, age at initiation and frequency of this screening will need to be optimized as data emerge. The illumination of BRCA1/2-associated stomach cancer risk also highlights the significance of cascade testing of male family members.
Although this was a large study, only 3.3% of probands who reported ethnicity data were Hispanic and 1.2% were Black. This is a clear target for improvement given that in many countries, Hispanics and Blacks represent larger proportions of the overall population and are underrepresented in medical research.
Finally, it is important to note that the findings above are as robust and precise as they are due to the large sample size and ability to control for ascertainment bias. This study by Antoniou and colleagues underscores the importance of multicenter collaborations in moving forward advances in genetic syndromes, and the authors are to be congratulated for their joint efforts on this work.
Collapse
Click Here to Manage Email Alerts