Identifying cancer risks in BRCA1/2 carriers is important for counseling patients on appropriate strategies for cancer risk management. It was therefore with great interest that we read the recent JNCI article by Mok Oh and colleagues (1). This meta-analysis of 14 studies examining colorectal cancer (CRC) risk in BRCA1/2 carriers concluded that BRCA1 mutation carriers had increased CRC risk (odds ratio [OR] = 1.49, 95% confidence interval [CI] = 1.19 to 1.85), whereas BRCA2 mutation carriers did not (OR = 1.09, 95% CI = 0.75 to 1.58). Although we appreciate this effort to address the important topic of CRC risk in BRCA1/2 carriers, we have some concerns regarding the conclusions drawn and their applicability to the BRCA1/2 community.
First, it is important to highlight that the statistical significance of the observed CRC risk disappeared when subgroup analysis was performed to include confirmed BRCA1/2 carriers, rather than including family members with unknown mutation status. The risk in confirmed mutation carriers provides the most accurate BRCA1/2 dataset with which to calculate CRC risk, giving this subgroup analysis particular relevance. Second, there are many factors known to increase CRC risk that are unable to be accounted for in this analysis and may skew the risk assessment. For example, given the abundance of Ashkenazi Jewish individuals in the analyzed studies, the presence of the moderate-risk CRC gene APC*I1307K, present in approximately 7% of Ashkenazi Jewish individuals (2), may influence CRC risk.
Third, only one study analyzed in the BRCA1 meta-analysis had a calculated odds ratio that was statistically significant (reference 27 from [1]), and it was this study that had the largest weight in the meta-analysis. To our knowledge, this study by Brohet and colleagues is a dissertation that has not yet been published in a peer-reviewed journal (reference 27 from [1]); thus it is not clear that it merits inclusion in a meta-analysis. Additionally, the risk data selected from the Brohet study was for colon cancer risk only (relative risk [RR] = 2.51, 95% CI = 2.02 to 3.07), whereas we believe the more appropriate data to use from this study is the more inclusive CRC risk (RR = 1.29, 95% CI = 1.05 to 1.57), which was substantially lower with inclusion of rectal cancers. Fourth, even if the data from the study is taken “as is,” the clinical significance of an odds ratio for CRC risk of 1.49 and the medical management of at-risk individuals is unclear. This odds ratio is lower than having a first-degree relative with CRC (3) and also lower than the risk estimates for other moderate penetrance CRC genes, such as CHEK2 and APC*I1307K, where risk management also remains uncertain (4).
Although the possibility of a small increase in CRC risk in BRCA1/2 mutation carriers cannot be completely ruled out (including at younger ages), based on the available data, we favor basing CRC screening in BRCA1/2 carriers on family history, because family history likely remains the most important predictor of CRC risk in this cohort. In conclusion, BRCA1/2 carriers have increased cancer risks that require aggressive surveillance and management; however, we believe at this time the data on CRC risk is not strong enough to advocate for enhanced CRC screening in BRCA1/2 individuals.
Funding
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (K08DK106489; BWK) and the National Cancer Institute at the National Institutes of Health (Cancer Center Core Grant P30-CA008748; MER, ZKS).
Notes
Affiliations of authors: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (BWK, SMD); Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (ZKS, MER); Department of Medicine, Weill Cornell Medical College, New York, NY (ZKS, MER).
The funders did not have a role in the writing of this correspondence or the decision to submit it for publication.
Disclaimers: BWK: consulting (Exact Sciences), travel (Janssen); ZKS: immediate family member (Ophthalmology), consulting/advisory role (Allergan, Adverum Biotechnologies, Alimera Sciences, Biomarin, Fortress Biotech, Genentech, Novartis, Optos, Regeneron, Regenxbio, Spark Therapeutics); MER: honoraria (AstraZeneca, Pfizer), consulting/advisory (McKesson, AstraZeneca), research funding (AstraZeneca, Myriad, Invitae, Pfizer, AbbVie, Tesaro, Medivation), travel (AstraZeneca); SMD: honoraria (AstraZeneca, Clovis, Bristol Myers Squibb).
References
- 1. Oh M, McBride A, Yun S, et al. BRCA1 and BRCA2 gene mutations and colorectal cancer risk: systematic review and meta-analysis. J Natl Cancer Inst. 2018;110(11):1178–1189. [DOI] [PubMed] [Google Scholar]
- 2. Locker GY, Lynch HT.. Genetic factors and colorectal cancer in Ashkenazi Jews. Fam Cancer. 2004;3(3–4):215–221. [DOI] [PubMed] [Google Scholar]
- 3. Johns LE, Houlston RS.. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol. 2001;96(10):2992–3003. [DOI] [PubMed] [Google Scholar]
- 4. Katona BW, Yurgelun MB, Garber JE, et al. A counseling framework for moderate-penetrance colorectal cancer susceptibility genes. Genet Med. 2018; 20(11): 1324–1327. [DOI] [PubMed] [Google Scholar]