Background. DICER1 syndrome is an autosomal dominant disorder predisposing to a broad spectrum of malignant and benign neoplasms, caused by germline pathogenic variants (PVs) in the DICER1 gene. We aimed to characterize the clinical features of DICER1 syndrome in a national referral cohort and to estimate neoplasm risk.Materials and Methods. This retrospective study was conducted in a cohort of 945 patients who underwent DICER1 genetic testing at Institut Curie, Paris, using Sanger sequencing from 2012 to 2014 and Next Generation Sequencing from 2015 to 2023.Results. Among 584 index cases evaluated for DICER1 syndrome, 91 (16%) carried a germline DICER1 PV and 31 (5%) harbored only somatic DICER1 PVs. Several tumors that were not previously part of the DICER1 tumor spectrum were identified. ETMR-like brain tumor and testicular Sertoli cell tumor are now recognized as DICER1-related neoplasms, and schwannoma is a strong candidate. The neoplasm risk was estimated in 170 relatives carrying a germline DICER1 PV. The cumulative incidence of malignant neoplasms was 4.8% [95% CI: 2.1% – 9.1%] at 10 years and 15.8% [95% CI: 8.9% – 24.7%] at 50 years. Overall neoplasm risk was significantly higher in females, primarily driven by the higher incidence of multinodular goiter.Conclusion. This large cohort study provides a comprehensive overview of the distribution of neoplasms associated with DICER1 syndrome. Broader genetic testing identified additional DICER1-related neoplasms, and schwannoma emerged as a candidate association. Finally, this study confirms the moderate penetrance of germline DICER1 PVs.

BACKGROUND:Lynch syndrome (LS), caused by pathogenic variants (PVs) in mismatch repair genes, increases the risk of several cancers. Surveillance guidelines vary internationally due to inconsistent risk estimates. This study refines cancer risk estimates by gene, sex, and age to support personalized recommendations. METHODS:This meta-analysis included studies reporting cumulative cancer risks in genetically confirmed LS PV carriers. PubMed was searched until December 31, 2024. Following the MOOSE (Meta-analyses Of Observational Studies in Epidemiology) guideline, data were extracted independently by 2 reviewers and analyzed using fixed (n = 2 estimates) or random-effects models (n > 2 estimates), stratified by gene, sex, cancer site, and study design: LS retrospective family (LSRF), LS prospective cohort (LSPC), and population-based case-control (PBCC) studies. RESULTS:Thirty-three studies were included, mostly LSRF. Meta-analysis of LSRF showed that colorectal cancer risk at 40 years was markedly lower in MSH6 and PMS2 carriers (<2%) than in MLH1 and MSH2 (>4%). For endometrial cancer, risks at 50 years were 8.3% (95% CI = 5.1 to 13.4), 8.7% (95% CI = 3.8 to 18.7), 5.2% (95% CI = 2.3 to 11.2), and 3.0% (95% CI = 1.0 to 8.0) for MLH1, MSH2, MSH6, and PMS2, respectively. For ovarian cancer, risks at 40 years were 1.2% (95% CI = 0.6 to 2.7) and 0.9% (95% CI = 0.5 to 1.8) for MLH1 and MSH2, respectively. Few studies addressed other cancer types, highlighting the need for additional data. CONCLUSIONS:This is the first meta-analysis providing stratified cancer risk estimates by cancer site, gene, and study design. These findings support gene-specific surveillance strategies, such as initiating colonoscopy at 30-35 years for MSH6 and PMS2 carriers, postponing hysterectomy after 50 years for PMS2 carriers, and delaying oophorectomy after 45 years for MLH1 and MSH2 PV carriers.

Background: Women with a familial predisposition to breast cancer (BC) are offered screening at earlier ages and more frequently than women from the general population. Methods: We evaluated the effect of screening mammography in 1552 BC cases with a hereditary predisposition to BC unexplained by BRCA1 or BRCA2 and 1363 unrelated controls. Participants reported their lifetime mammography exposures in a detailed questionnaire. Germline rare deleterious or predicted deleterious variants (D-PDVs) in 113 DNA repair genes were investigated in 82.5% of the women and classified according to the strength of their association with BC. Genes with an odds ratio (OR) < 0.9 was assigned to the Gene Group “Reduced”, those with OR ≥ 0.9 and ≤1.1 to Group “Independent”, and those with OR > 1.1 to Group “Increased”. Results: Overall, having been exposed to mammograms (never vs. ever) was not associated with BC risk. However, an increase in BC risk of 4% (95% CI: 1–6%) per additional exposure was found under the assumption of linearity. When grouped according to D-PDV carrier status, mammograms doubled the BC risk of women carrying a D-PDV in Group “Reduced”, as compared to those carrying a D-PDV in Group “Increased”. Conclusions: Our study is the first to investigate the joint effect of mammogram exposure and variants in DNA repair genes other than BRCA1 and BRCA2 in women at high risk of BC; therefore, further studies are needed to verify our findings. Even though mammographic screening reduces the risk of mortality from BC, the identification of populations that are more or less susceptible to ionizing radiation may be clinically relevant.

INTRODUCTION:Renal cancers are inherited in about 5 % of cases and are associated with several genetic syndromes. Genetic testing is recommended for selected patients suspected of having hereditary syndromes. In the absence of guidelines regarding which genes should be included for carrying out genetic screening of these individuals, discrepancies existed among the next generation sequencing (NGS) multi-gene panels (MGP) used in French laboratories. There was therefore a clear need to standardise practices and offer patients with renal cancer a consensus-based genetic testing in France. METHODS:A working group comprising national experts from the French Genetic and Cancer Group Unicancer (GGC) and from the French network on Hereditary PREDIspositions to Renal Cancer (PREDIR) and encompassing medical geneticists, genetic counsellor, molecular biologists and epidemiologists was established. The objective was to define a list of clinically relevant genes that should be included in a "GGC-PREDIR" approved NGS MGP for patients with renal cancer. A list of 32 genes of interest was compiled following an exhaustive and critical review of the literature. The inclusion or exclusion of each gene was determined based on available data regarding risk, prevalence and analyses published from large studies of patients. RESULTS:The French group of experts defined a list of 12 genes of clinical and genetic counselling relevance comprising BAP1, FH, FLCN, MET, PTEN, SDHA, SDHB, SDHC, SDHD, TSC1, TSC2 and VHL to be included in the national recommended "renal cancer" NGS MGP. For each of these genes, recommendations for renal surveillance are proposed. CONCLUSION:Unlike hereditary predisposition to breast or colon cancer, hereditary renal cancer predispositions are rare syndromes and risk estimates are lacking for most of them. Prospective studies are needed to improve our knowledge. The GGC-PREDIR experts retained 12 genes for inclusion in the NGS MGP for renal cancer patients. However, the panel will be expanded on the basis of regularly updated data from the medical literature.

Background ELP1 pathogenic variants (PV) have been recently identified as the most frequent variants predisposing to Sonic Hedgehog (SHH) medulloblastomas (MB); however, guidelines are still lacking for genetic counseling in this new syndrome.Methods We retrospectively reviewed clinical and genetic data of a French series of 29 ELP1-mutated MB.Results All patients developed SHH-MB, with a biallelic inactivation of PTCH1 found in 24 tumors. Other recurrent alterations encompassed the TP53 pathway and activation of MYCN/MYCL signaling. The median age at diagnosis was 7.3 years (range: 3-14). ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups and similar outcomes (5 y - OS = 86%); no unusual side effect of treatments was noticed. Remarkably, a germline ELP1 PV was identified in all patients with available constitutional DNA (n = 26); moreover, all tested familial trio (n = 11) revealed that the PVs were inherited. Two of the 26 index cases from the French series had a family history of MB; pedigrees from these patients and from 1 additional Dutch family suggested a weak penetrance. Apart from MB, no cancer was associated with ELP1 PVs; second tumors reported in 4 patients occurred within the irradiation fields, in the usual time-lapse for expected radiotherapy-induced neoplasms.Conclusions The low penetrance, the "at risk' age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with SHH-MB, depending on the parents" request.

Abstract BACKGROUND Medulloblastomas (MB) Sonic hedgehog (SHH) subtype are associated with a cancer predisposition syndrome (CPS) in about 15% of cases, the most frequent being related to ELP1 pathogenic variant (PV). The aim of our study is to better evaluate penetrance of this CPS and detail the characteristics of the related tumors. METHODS Twenty-nine ELP1-mutated MB identified in France were retrospectively reviewed. Molecular characteristics of the tumor and clinical features of the patients were collected; whenever possible, the germline DNA from patients and their relatives were sequenced. RESULTS All patients (sex ratio 16/13) presented with SHH-MB, mostly nodular desmoplastic (n=20/28), between 3 and 15 years of age (median 7.3). All mutations are found in the germline when a constitutional DNA sample was available (n=26). Most tumors (93%) showed a biallelic inactivation of PTCH1, other recurrent alterations concerned the TP53 pathway (including 1 somatic TP53 VP) and activation of MYCN/MYCL signaling. We observed that ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups of MB, similar outcomes (5y-OS = 85%) and no unusual side effects of treatments. Three patients developed a second tumor (2 high-grade gliomas and 1 thyroid carcinoma) within the irradiation fields. All germline PV were inherited from one asymptomatic parent (11 trio). No specific morphological features were mentioned. Only two index cases from the 29 French patients had a previous familial history of MB (occurring in a cousin), with many asymptomatic carriers. Except the MB, no other cancer was significantly associated with the ELP1 PV. CONCLUSIONS the low penetrance, the ‘at risk’ age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with MB, depending on the parents’ request.

This article describes some of the key prevention services in the Leon Berard Comprehensive Cancer Center (CLB) Lyon, France, which are based on clinical prevention services, outreach activities, and collaboration with professional and territorial health communities. In addition, research is embedded at all stages of the prevention continuum, from understanding cancer causes through to the implementation of prevention interventions during and after cancer. Health promotion activities in the community and dedicated outpatient primary cancer prevention services for individuals at increased risk have been implemented. The CLB's experience illustrates how prevention can be integrated into the comprehensive mission of cancer centers, and how in turn, the cancer centers may contribute to bridging the current fragmentation between cancer care and the different components of primary, secondary, and tertiary prevention. With increasing cancer incidence, the shift toward integrated prevention-centered cancer care is not only key for improving population health, but this may also provide a response to the shortage of hospital staff and overcrowding in cancer services, as well as offer opportunities to reduce carbon emissions from cancer care.

Background Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by biallelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome. With the increased sensitivity of next-generation sequencing (NGS), mosaicisms in genes linked to genetic diseases are more detectable. This study focuses on exploring SMARCB1 germline alterations, notably mosaicism in blood samples of children with RT and in parents, using a custom NGS panel.Methods A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were reanalyzed with a custom NGS panel with 1500X average depth targeting the SMARCB1 gene to identify intragenic variants not detected with conventional low-sensitivity methods. Follow-up data was obtained for 77 patients.Results Nine previously undetected mosaicism cases were identified, totaling 17/280 patients with a mosaic variant (6.1%) in the cohort, with variant allele frequencies between 0.9% and 33%, thus highlighting the prior underestimation of its prevalence. Follow-up data showed that 4 out of 7 survivors with mosaic variants developed distinct novel tumors, 2 sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism.Conclusions The hitherto underestimated rate of SMARCB1 mosaicism in RT underscores the need for optimized genetic counseling and oncological monitoring. The findings have significant medical implications, considering the dire prognosis of RT. Graphical Abstract

Table S1: Multivariate Model of progression-free survival in the study cohort; Table S2: Multivariate Model of overall survival in the study cohort; Table S3: BRCA2 mutations in the study cohort; Figure S1: Flow diagram for selection of patients in the study cohort; Figure S2: A model for double-strand breaks repair by homologous recombination that depends on the location of mutation in BRCA2 gene.

Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for <i>BRCA1</i> and <i>BRCA2</i> Mutation Carriers: Implications for Risk Prediction

Supplementary Figure 1: Representation of BRCA1 and BRCA2 major functional and risk domains (location of codons)

The use of multigene panel testing for patients with a predisposition to Hereditary Breast and Ovarian Cancer syndrome (HBOC) is increasing as the identification of mutations is useful for diagnosis and disease management. Here, we conducted a retrospective analysis of BRCA1/2 and non-BRCA gene sequencing in 4630 French HBOC suspected patients. Patients were investigated using a germline cancer panel including the 13 genes defined by The French Genetic and Cancer Group (GGC)-Unicancer. In the patients analyzed, 528 pathogenic and likely pathogenic variants (P/LP) were identified, including BRCA1 (n = 203, 38%), BRCA2 (n = 198, 37%), PALB2 (n = 46, 9%), RAD51C (n = 36, 7%), TP53 (n = 16, 3%), and RAD51D (n = 13, 2%). In addition, 35 novel (P/LP) variants, according to our knowledge, were identified, and double mutations in two distinct genes were found in five patients. Interestingly, retesting a subset of BRCA1/2-negative individuals with an expanded panel produced clinically relevant results in 5% of cases. Additionally, combining in silico (splicing impact prediction tools) and in vitro analyses (RT-PCR and Sanger sequencing) highlighted the deleterious impact of four candidate variants on splicing and translation. Our results present an overview of pathogenic variations of HBOC genes in the southeast of France, emphasizing the clinical relevance of cDNA analysis and the importance of retesting BRCA-negative individuals with an expanded panel.

BACKGROUND:Three partially overlapping breast cancer polygenic risk scores (PRS) comprising 77, 179 and 313 SNPs have been proposed for European-ancestry women by the Breast Cancer Association Consortium (BCAC) for improving risk prediction in the general population. However, the effect of these SNPs may vary from one country to another and within a country because of other factors.OBJECTIVE:To assess their associated risk and predictive performance in French women from (1) the CECILE population-based case-control study, (2) BRCA1 or BRCA2 (BRCA1/2) pathogenic variant (PV) carriers from the GEMO study, and (3) familial breast cancer cases with no BRCA1/2 PV and unrelated controls from the GENESIS study.RESULTS:All three PRS were associated with breast cancer in all studies, with odds ratios per standard deviation varying from 1.7 to 2.0 in CECILE and GENESIS, and hazard ratios varying from 1.1 to 1.4 in GEMO. The predictive performance of PRS313 in CECILE was similar to that reported in BCAC but lower than that in GENESIS (area under the receiver operating characteristic curve (AUC) = 0.67 and 0.75, respectively). PRS were less performant in BRCA2 and BRCA1 PV carriers (AUC = 0.58 and 0.54 respectively).CONCLUSION:Our results are in line with previous validation studies in the general population and in BRCA1/2 PV carriers. Additionally, we showed that PRS may be of clinical utility for women with a strong family history of breast cancer and no BRCA1/2 PV, and for those carrying a predicted PV in a moderate-risk gene like ATM, CHEK2 or PALB2.

Background: a specific subset of metastatic triple-negative breast cancers (mTNBC) is characterized by homologous recombination deficiency (HRD), leading to enhanced sensitivity to platinum-based chemotherapy. Apart from mutations in BRCA1/2 genes, the evaluation of other HRD-related alterations has been limited to date. As such, we analyzed data from mTNBC patients enrolled in the ProfiLER-01 study to determine the prevalence of alterations in homologous recombination-related (HRR) genes and their association with platinum sensitivity. Methods: next-generation sequencing and promoter methylation of BRCA1 and RAD51C were performed on tumors from patients with mTNBC, using a panel of 19 HRR genes. Tumors were separated into three groups based on their molecular status: mutations in BRCA1/2, mutations in other HRR genes (BRCA1/2 excluded) or BRCA1/RAD51C promoter methylation and the absence of molecular alterations in HRR genes (groups A, B and C, respectively). Sensitivity to platinum-based chemotherapy was evaluated through the radiological response. Results: mutations in BRCA1/2 were detected in seven (13.5%) patients, while alterations in other HRR genes or hypermethylation in BRCA1 or RAD51C were reported in 16 (30.7%) patients; furthermore, no alteration was found in the majority of patients (n = 29; 55.8%). Among 27 patients who received platinum-based chemotherapy, the disease control rate was 80%, 55% and 18% (groups A, B and C, respectively; p = 0.049). Regarding group B, patients with disease control exhibited mutations in FANCL, FANCA and the RAD51D genes or RAD51C methylation; Conclusion: mutations in HRR genes and epimutations in RAD51C were associated with disease control through platinum-based chemotherapy. As such, apart from well-characterized alterations in BRCA1/2, a more comprehensive evaluation of HRD should be considered in order to enlarge the selection of patients with mTNBC that could benefit from platinum-based chemotherapy.

Background Pathogenic variants (PV) of CTNNA1 are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germline CTNNA1 PV. Methods Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A 'leave-one-out' strategy was used to evaluate estimate uncertainty. Results Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of CTNNA1 PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL. Conclusion This is the largest series of CTNNA1 families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of CTNNA1 in germline testing panels.

Background: Some studies suggested a decreased ovarian reserve among BRCA1/2 pathogenic variant carriers, with conflicting results. Methods: We conducted a retrospective single-center observational study of ovarian reserve and spontaneous fertility comparing BRCA1/2 pathogenic variant carriers to controls (women who attended consultations to discuss fertility preservation before gonadotoxic treatment). Measures of associations between plasma AMH concentration, AFC and BRCA1/2 status were modelled by nonlinear generalized additive regression models and logistic regressions adjusted for age at plasma storage, oral contraceptive use, body mass index, cigarette smoking, and the AMH assay technique. Results: The whole population comprised 119 BRCA1/2 pathogenic variant carriers and 92 controls. A total of 110 women (42 carriers, among whom 30 were cancer-free, and 68 controls) underwent an ovarian reserve evaluation. Spontaneous fertility analysis included all women who previously attempted to become pregnant (134 women).We observed a tendency towards a premature decrease in ovarian reserve in BRCA1/2 pathogenic variant carriers, but no difference in mean AMH or AFC levels was found between BRCA1/2 pathogenic variant carriers and controls. An analysis of the extreme levels of AMH (≤5 pmol/l) and AFC (≤7 follicles) by logistic regression suggested a higher risk of low ovarian reserve among BRCA1/2 pathogenic variant carriers (adjusted odds ratio (OR) = 3.57, 95% CI = 1.00–12.8, p = 0.05; and adjusted OR = 4.99, 95% CI = 1.10–22.62, p = 0.04, respectively). Discussion: Attention should be paid to BRCA1/2 pathogenic variant carriers’ ovarian reserve, considering this potential risk of premature alteration.

INTRODUCTION:Apoptosis deregulation have been associated to tumorigenesis process and was highlighted as a prominent hallmark of cancer. Several mutations have been reported in several forms of Blood cancer. However, it has never been investigated in familial aggregations of hematological malignancies.METHODS:In this study, we performed a mutational analysis by sequencing the entire coding regions in four key apoptotic genes FAS, FASLG, CASP8 and CASP10 in 92 independent families belonging to French and Tunisian populations and diagnosed with several forms of familial hematological malignancies.RESULTS:We report 15 genetic variations among which 7 were previously reported in several form of cancers and have a potential effect on gene expression. Particularly, the CASP8 variants p.Asp302His and p.Lys337Lys were detected in 15% and 10% of our group of patients respectively and were previously reported in association to breast cancer and to breast cancer susceptibility.DISCUSSION:In this study, we do not report the underlining deleterious mutations in familial hematological malignancies, but we describe some variants with potential risk of developing blood cancer. To gain further insights on the association between apoptosis pathway deregulation and familial hematological malignancies, more apoptotic genes should be investigated.

Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs. The classification method was a multifactorial model combining different associations between VUSs and cancer, including cosegregation data. At this time, among the 653 variants selected, 101 (15%) distinct variants shared by 1,624 families were classified as pathogenic/likely pathogenic or benign/likely benign by the COVAR study. Sixty-six of the 101 (65%) variants classified by COVAR would have remained VUSs without cosegregation data. Of note, among the 34 variants classified as pathogenic by COVAR, 16 remained VUSs or likely pathogenic when following the ACMG/AMP variant classification guidelines. Although the initiation and organization of cosegregation analyses require a considerable effort, the growing number of available genetic tests results in an increasing number of families sharing a particular variant, and thereby increases the power of such analyses. Here we demonstrate that variant cosegregation analyses are a powerful tool for the classification of variants in the BRCA1/2 breast-ovarian cancer predisposition genes.

Faithful DNA replication is necessary to maintain genome stability and implicates a complex network with several pathways depending on DNA damage type: homologous repair, nonhomologous end joining, base excision repair, nucleotide excision repair and mismatch repair. Alteration in components of DNA repair machinery led to DNA damage accumulation and potentially carcinogenesis. Preclinical data suggest sensitivity to immune checkpoint inhibitors in tumors with DNA repair deficiency. Here, we review clinical studies that explored the use of immune checkpoint inhibitor in patient harboring tumor with DNA repair deficiency.

BACKGROUND:Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE:This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN:In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS:Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION:For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.