A, Type and rate of malignant abnormalities stratified by mutation type in a prospectively screened cohort of male BRCA1 (n = 117, blue bars) and BRCA2 (n = 79, dark gray bars) mutation carriers enrolled to a male BRCA clinic. B, Observed and expected cases of malignant abnormalities in the study cohort. Expected number of malignant abnormalities were calculated by multiplying the number of patients entering a specific age interval with the corresponding age-adjusted cancer incidence rates for the general Israeli Jewish male population between 2003 and 2013 retrieved from the Israeli National Cancer Registry.
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Mano R, Tamir S, Kedar I, et al. Malignant Abnormalities in Male BRCA Mutation Carriers: Results From a Prospectively Screened Cohort. JAMA Oncol. 2018;4(6):872–874. doi:10.1001/jamaoncol.2018.0271
Men with germline mutations in BRCA1 and BRCA2 genes have a higher risk of developing malignant abnormalities of the prostate, pancreas, breast, colon, and melanoma.1-3 Moreover, germline BRCA mutations are associated with higher stage, grade, and poor survival rates in patients with prostate cancer.4
In contrast to protocols for women, current screening protocols for men who are BRCA carriers are based on low-level evidence.5 Previous studies evaluating cancer screening in these men focused on prostate cancer rather than all BRCA-associated malignant diseases.6
In the current study, we report the use of a predefined comprehensive screening protocol for evaluating male BRCA carriers enrolled to a dedicated clinic.
Between February 2014 and February 2017 we evaluated 196 BRCA carriers. After obtaining approval from the institutional review board at Rabin Medical Center and written informed consent, we screened patients 40 years or older for prostate, breast, colorectal, pancreatic, and skin malignant abnormalities using a predefined protocol (Table).
We report patient characteristics and prevalence of tumors identified prior to enrollment and initial screening. Standardized incidence ratios were calculated to compare cancer incidence in our cohort with the age-adjusted cancer incidence in the Israeli Jewish male population as reported in the Israeli-National Cancer Registry.
A total of 117 (60%) BRCA1 and 79 (40%) BRCA2 carriers were included. Median age was 49 (interquartile range [IQR], 41-63) years. Common mutations were 185delAG in BRCA1 (87 of 117 [74%]) and 6174delIT in BRCA2 (67 of 79 [85%]).
Thirty-four (17%) patients were diagnosed with 46 malignant abnormalities; 13 (28%) were identified during screening. Median age at first cancer diagnosis was 54 (IQR, 44-63) years. Seven patients had multiple malignant abnormalities, with a median of 3 per patient (range, 2-4). The most common malignant abnormality was prostatic adenocarcinoma identified in 10 (8.6%) BRCA1 carriers , and 3 (3.8%) BRCA2 carriers (Figure, A). Initial screening identified malignant abnormalities of the prostate (n = 9), pancreas (n = 2), and skin (n = 2), all treated with a curative intent.
Compared with the Jewish-Israeli male population, men with BRCA mutations had a significant increase in overall incidence of malignant disease (standardized incidence ratio, 8; 95% CI, 5.74-10.85; P < .001). BRCA mutations were associated with an elevated incidence of prostate, melanoma, pancreas, and breast cancers; however, the incidence of colon cancer was not higher (Figure, B).
Current recommendations for the screening of BRCA-positive men include annual clinical breast examination starting at age 35 and yearly prostate cancer screening in BRCA2 carriers starting at age 45.5 We devised a screening protocol for male BRCA mutation carriers based on malignant abnormalities previously associated with this group of patients. Twenty-eight percent of malignant abnormalities were identified during screening, all of which were found at early stage and amenable to curative treatment.
In this study, overall cancer incidence among BRCA carriers was higher than that of the general population. Detection rates of prostate cancer were similar to those in the IMPACT study.6 The rate of prostate cancer among BRCA1 carriers was more than twice as high (8.6% vs 3.8%), likely owing to the high prevalence of the Jewish founder mutation 185delAG in this population. Melanoma was the second most common malignant abnormality, related to the high incidence of melanoma in the Israeli population.
We used abdominal ultrasound and CA19-9 testing to screen for pancreatic cancer and identified 2 cases of malignant disease, both received definitive local surgical treatment, emphasizing the profound clinical impact screening may have on patient outcome.
Limitations of the study include initial screening ascertainment bias, and lack of control group to establish the benefit of screening.
Our initial findings suggest that in addition to screening for prostate and breast cancer, as recommended in current guidelines, there may be a role for screening for pancreatic cancer and melanoma, whereas screening for colon cancer may not be justified. Further long-term studies are needed to determine the effect of screening on mortality.
Corresponding Author: David Margel, MD, PhD, Department of Urology, Rabin Medical Center, Petach Tikva 4941492, Israel (firstname.lastname@example.org).
Accepted for Publication: January 22, 2018.
Published Online: April 12, 2018. doi:10.1001/jamaoncol.2018.0271
Author Contributions: Drs Mano and Margel had access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Mano, Kedar, Baniel, Margel.
Acquisition, analysis, or interpretation of data: Mano, Benjaminov, Tamir, Tabachnik, Margel.
Drafting of the manuscript: Mano, Benjaminov, Kedar, Tabachnik, Margel.
Critical revision of the manuscript for important intellectual content: Tamir, Baniel, Margel.
Statistical analysis: Mano.
Obtained funding: Baniel, Margel.
Administrative, technical, or material support: Tamir, Kedar, Baniel.
Study supervision: Baniel, Margel.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was partially supported by the American Society of Clinical Oncology career development award (grant No. 8259); the Israeli Cancer Association; and the German Israeli Foundation (grant No. 2393).
Role of the Funder/Sponsor: The American Society of Clinical Oncology, the Israeli Cancer Association, and the German Israeli Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank Yaara Ber, PhD, Sivan Sela, BSc, and Rachel Ozalvo, MA, all at the Urology research unit at Rabin Medical Center, for their assistance in data collection and analysis. They were not compensated.
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