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Objective: Whether or not women who harbor a germline pathogenic variant ('mutation') in the BRCA1 or BRCA2 genes are at elevated risk of developing endometrial cancer is yet to be determined., Methods: We conducted a prospective analysis of 4959 BRCA mutation carriers with no prior history of cancer (except for breast or melanoma) and an intact uterus., Results: After a mean of 6.7 years of follow-up there were 38 incident cases of endometrial cancer diagnosed; 30 among BRCA1 carriers and eight among BRCA2 carriers. The mean age at diagnosis was 58.4 years (range 46.8-76.1). The majority were of the endometrioid subtype (n = 16), followed by mixed endometroid and serous (n = 4), serous (n = 3) or clear cell (n = 1) (missing = 13). The cumulative incidence from age 40 to age 70 was 3.4% for BRCA1 carriers and was 1.6% for BRCA2 mutation carriers. Prior tamoxifen use was associated with a significant two-fold increased risk (HR = 2.24; 95% CI 1.10-4.55). There was no significant association between exogenous hormone use, oophorectomy, smoking or BMI at age 40 and risk (P ≥ 0.32)., Conclusions: Compared to the general population, we observed higher rates of endometrial cancer among young BRCA1 mutation carriers; however, lifetime risks were similar. Women with prior tamoxifen exposure were at a significantly increased risk. These findings were based. on a small number of incident cases and require confirmation with additional follow-up of our aging cohort., Competing Interests: Declaration of competing interest All the authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Olaparib has significantly improved outcome and patient-centered endpoints in BRCA1/2-mutated patients with recurrent platinum-sensitive ovarian cancer (PSOC). Specific information on efficacy and safety of olaparib for older patients appears of special interest., Methods: 295 patients from the SOLO2 trial randomly assigned to olaparib or placebo were categorized according to age-cutoff at 65 years. Efficacy, tolerability, and quality of life (QoL) of olaparib relative to placebo within in each age group was analyzed., Results: Baseline characteristics were similar in patients ≥65 years (N = 62;21.0%) compared to patients <65 years (N = 233;78.9%). No significant difference in the magnitude of progression-free survival (PFS) benefit from olaparib for older patients (N = 40, hazard ratio [HR] ≥65 0.43, 95%-confidence interval [CI] 0.24-0.81) as compared with younger patients (N = 155, HR <65 0.31 (95%-CI 0.22-0.43) was seen (interaction P = 0.33). The overall survival (OS)benefit seen in younger patients in the olaparib arm was not observed in older patients. Older and younger patients had comparable safety profiles and QoL scores although higher discontinuation rates for toxicity, and higher frequency of AML/MDS were noted in the older subset. TWiST analysis revealed clinically meaningful duration of good QoL on olaparib for both age groups (≥65: 13.5 vs <65: 18.4 months, P = 0.05)., Conclusions: Results of this large phase III cohort of BRCA1/2-mutated PSOC patients treated with olaparib underline impressive efficacy of olaparib maintenance irrespective of age. Although toxicity and tolerability did not raise significant concerns, some caution, close monitoring, and follow-up needs to be exercised for older patients given higher discontinuation rates, frequency of AML/MDS, and no clear effects on OS., Competing Interests: Declaration of Competing Interest Dr. Trillsch reports grants and personal fees from AstraZeneca, Clovis, Eisai, Medac, MSD, PharmaMar, Roche, and Tesaro/GSK, outside the submitted work. Dr. Mahner reports grants and personal fees from AstraZeneca, Clovis, Medac, Novartis, Olympus Europe, PharmaMar, Pfizer, Roche, Sensor Kinesis, Tesaro/GSK, and Teva, outside the submitted work. Dr. Ataseven, Dr. Asher, Dr. Aryal, Dr. Dubot have nothing to disclose. Dr. Clamp reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from AstraZenca, Clovis Oncology, outside the submitted work. Dr. Penson reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from AbbVie, Array BioPharma Inc., AstraZenca, Cancer Panels, Care4ward, Eisai, Genetech, Merck & Co., Roche Pharma, Sutro Biopharma, GSK Inc., Vascular Biogenics Ltd., WebMD, outside the submitted work. Dr. Oza, Dr. Dr. Amit, and Dr. Huzarski have nothing to disclose. Dr. Casado reports grants and personal fees from AstraZenca, Eisai, Lilly, MSD, PharmaMar, Roche, Tesaro, outside the submitted work. Dr. Scambia has nothing to disclose. Dr. Friedlander reports grants and personal fees from AbbVie, AstraZenca, Beigene, MSD, GSK, Takeda, Novartis, Lilly, outside the submitted work. Dr. Colombo reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from AstraZeneca, BIOCAD, Clovis Oncology, Eisai, GlaxoSmithKline, Immonogen, Mersana, MSD, Novartis, Oncxerna, Pfizer, PharmaMar, Roche, Tesaro, outside the submitted work. Dr. Fujiwara reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from MSD, Daiichi Sankyo, Takeda, Genmab, Nano Carrier, Regenerone, Seagen, Zeria, outside the submitted work. Dr. Sonke reports grants from AstraZeneca, during the conduct of the study; grants and personal fees from Biovica, Merck, Novartis, Roche, Seagen, outside the submitted work. Dr. Denys reports grants and personal fees from Pfizer, Roche, PharmaMar, AstraZeneca, Eli Lilly, Novartis, Amgen, Tesaro, GSK, Teva, outside the submitted work. Dr. Lowe reports other from AstraZeneca (full time employee), outside the submitted work. Dr. Lee reports grants from AstraZeneca, during the conduct of the study. Dr. Pujade-Lauraine reports grants and personal fees from AstraZeneca, Merck, GSK, Roche, Incyte, ARCAGY Research, outside the submitted work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To compare the survival experience of women with a BRCA1 mutation who enrolled in an ovarian cancer screening program with that of women who opted for preventive oophorectomy., Methods: We followed 1964 women with a BRCA1 mutation and two ovaries intact in a prospective study. No women had ovarian cancer or had a bilateral oophorectomy prior to study initiation. There were 1814 women in the cohort who had at least one screening ultrasound. They were followed from the date of first ultrasound until the date of preventive oophorectomy, death or last follow-up. There were 659 women in the cohort who had preventive oophorectomy. They were followed from the date of preventive oophorectomy until death or last follow-up., Results: Among the 1196 women who had one or more ultrasound examinations and no oophorectomy, there were 73 incident cancers detected and 27 deaths from ovarian/fallopian cancer. The ten year cumulative risk of death was 2.0%. Among the 659 women who had a preventive oophorectomy there were 12 incident cancers (9 detected at oophorectomy and 3 in the follow up period) and two deaths from ovarian cancer. The ten year cumulative risk of death was 0.5%. The hazard ratio for oophorectomy versus ultrasound was 0.23 (95% CI: 0.05 to 0.97; p = 0.05)., Conclusion: The survival of women diagnosed with ovarian cancer enrolled in an ultrasound screening program is relatively poor and screening is not a viable alternative to preventive oophorectomy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: For women at high risk of developing ovarian cancer, it is important to provide an accurate recommendation for the optimal age for preventive surgery in order to maximize the preventative effect while delaying symptoms associated with early surgical menopause. The goal of the current study was to estimate age-specific incidence rates of ovarian cancer among women with a BRCA1 or BRCA2 mutation., Methods: From our international registry, we identified 5689 women with no previous diagnosis of ovarian or fallopian tube cancer or preventive oophorectomy. Women were followed from the date of completion of the baseline questionnaire until either a diagnosis of ovarian or fallopian tube cancer, prophylactic oophorectomy, death or last follow-up. The annual and cumulative incidence rates of ovarian cancer were estimated., Results: Over a mean follow-up period of 4.7 years (ranges 0-22.6), 195 incident ovarian or fallopian tube cancers were diagnosed (169 [86%] ovarian cancers, 22 [11%] fallopian tube cancers and four [2%] cancers that involved both the ovaries and fallopian tubes). Of these, 45 (23%) cancers were diagnosed at preventive surgery (occult cancers). The cumulative risk of ovarian cancer to age 80 was 49% for BRCA1 and 21% for BRCA2 mutation carriers. The mean age at diagnosis was 51.3 years (ranges 33-84) among women with a BRCA1 mutation and 61.4 years (ranges 44-80) among women with a BRCA2 mutation., Conclusion: Based on a cumulative risk of 0.55% to age 35 for BRCA1 mutation carriers and of 0.56% to age 45 for BRCA2 mutation carriers, we recommend bilateral salpingo-oophorectomy before age 40, but ideally by age 35, for women with a BRCA1 mutation and by age 45 for those with a BRCA2 mutation to maximize prevention and to minimize adverse effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370., Methods: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers)., Results: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations., Conclusions: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., (Copyright © 2015 Elsevier Inc. All rights reserved.)