Background BRCA2-associated breast and ovarian cancers are sensitive to platinum-based chemotherapy. It is unknown whether BRCA2-associated prostate cancer responds favorably to such treatment. Methods Retrospective analysis of a single-institution cohort of men with castration-resistant metastatic prostate cancer was performed to determine the association between carrier status of pathogenic BRCA2 germline variants and prostate-specific antigen response to carboplatin-based chemotherapy. From 2001-2015, 8,081 adult men with prostate cancer seen in consultation and/or treated at Dana-Farber Cancer Institute provided blood samples and consented to analysis of biological material and clinical records. A subgroup of 141 received at least two doses of carboplatin and docetaxel for castration-resistant disease (94% were also taxane refractory). These subjects were categorized according to absence or presence of pathogenic germline mutations in BRCA2, based on DNA sequencing from whole blood. Primary outcome was response rate to carboplatin/docetaxel chemotherapy as defined by decline in prostate-specific antigen exceeding 50% within 12 weeks of initiating this regimen. Association between BRCA2 mutation status and response to carboplatin-based chemotherapy was tested, using Fisher’s exact test, with a two-sided p-value of <0.05 as threshold for significance. Results Pathogenic germline BRCA2 variants were observed in 8/141 (5.7%; 95% CI=2.5%-10.9%) participants. Six of eight (75%) BRCA2 carriers experienced prostate-specific antigen decline >50% within 12 weeks, compared to 23 of 133 (17%) non-carriers (absolute difference 58%; 95% CI=27%-88%; P<0.001). Prostate cancer cell lines functionally corroborate these clinical findings. Conclusions BRCA2-associated castration-resistant prostate cancer is associated with higher likelihood of response to carboplatin-based chemotherapy than non-BRCA2 associated prostate cancer.
Next-generation sequencing technology affords an unprecedented opportunity to analyze multiple breast cancer susceptibility genes simultaneously. With the incarnation of gene panels that combine testing for moderate- and high-penetrance genes, this technology has given birth to a paradigm shift in clinical genetic test offerings. A transformation in genetic counseling for cancer susceptibility will necessarily follow, with a shift from the traditional approach of single-gene testing to considerations of testing by multi-gene panels. At the same time, however, the opportunity to identify rare lesions underlying hereditary susceptibility has introduced new challenges. Available cancer risk estimates for genes included in panel tests may not be supported by evidence, and there is increased risk of identifying variants of uncertain significance (VUS). Management of individuals with rare pathogenic mutations may be unclear. We provide a summary of available evidence for breast cancer risks conferred by pathogenic mutations in genes commonly included in breast cancer susceptibility panels, as well as a review of limitations and counseling points.
The development of novel interpretive and decision-support tools that draw from scientific and clinical evidence will be crucial for the success of cancer precision medicine in WES studies.Genet Med advance online publication 26 January 2017.
Purpose Compared to breast cancer risk genes such as BRCA2, ATM, PALB2, and NBN, no defined phenotype is currently associated with biallelic pathogenic variants (PVs) in CHEK2. This study compared the prevalence of breast and other cancers in women with monoallelic and biallelic CHEK2 PVs. Methods CHEK2 PV carriers were identified through commercial hereditary cancer panel testing (09/2013–07/2019). We compared cancer histories of 6473 monoallelic carriers to 31 biallelic carriers. Breast cancer risks were estimated using multivariate logistic regression and are reported as odds ratios (OR) with 95% confidence intervals (CI). Results Breast cancer frequency was higher among biallelic CHEK2 PV carriers (80.6%, 25/31) than monoallelic carriers (41.2%, 2668/6473; p < 0.0001). Biallelic carriers were more likely to be diagnosed at or before age 50 (61.3%, 19/31) and to have a second breast cancer diagnosis (22.6%, 7/31) compared to monoallelic carriers (23.9%, 1548/6473; p < 0.0001 and 8.1%, 523/6473; p = 0.0107, respectively). Proportionally more biallelic carriers also had any cancer diagnosis and > 1 primary diagnosis. Compared to women with no PVs, biallelic PV carriers had a higher risk of developing ductal invasive breast cancer (OR 8.69, 95% CI 3.69–20.47) and ductal carcinoma in situ (OR 4.98, 95% CI 2.00–12.35) than monoallelic carriers (OR 2.02, 95% CI 1.90–2.15 and OR 1.82, 95% CI 1.66–2.00, respectively). Conclusions These data suggest that biallelic CHEK2 PV carriers have a higher risk for breast cancer, are more likely to be diagnosed younger, and to have multiple primary breast cancers compared to monoallelic carriers. Biallelic carriers also appear to have a higher risk of cancer overall. Therefore, more aggressive management may be appropriate for women with biallelic PVs in CHEK2 compared with current recommendations for monoallelic carriers.
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