Objective
Unselected population‐based BRCA testing provides the opportunity to apply genomics on a population‐scale to maximise primary prevention for breast‐and‐ovarian cancer. We compare long‐term ...outcomes of population‐based and family‐history (FH)/clinical‐criteria‐based BRCA testing on psychological health and quality of life.
Design
Randomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two‐arms: (i) population‐screening (PS); (ii) FH/clinical‐criteria‐based testing.
Setting
North London Ashkenazi‐Jewish (AJ) population.
Population/Sample
AJ women/men.
Methods
Population‐based RCT (1:1). Participants were recruited through self‐referral, following pre‐test genetic counselling from the North London AJ population.
Inclusion criteria: AJ women/men >18 years old; exclusion‐criteria: prior BRCA testing or first‐degree relatives of BRCA‐carriers.
Interventions: Genetic testing for three Jewish BRCA founder‐mutations: 185delAG (c.68_69delAG), 5382insC (c.5266dupC) and 6174delT (c.5946delT), for (i) all participants in PS arm; (ii) those fulfilling FH/clinical criteria in FH arm. Linear mixed models and appropriate contrast tests were used to analyse the impact of BRCA testing on psychological and quality‐of‐life outcomes over 3 years.
Main outcome measures
Validated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality‐of‐life outcomes at baseline/1‐year/2‐year/3‐year follow up.
Results
In all, 1034 individuals (691 women, 343 men) were randomised to PS (n = 530) or FH (n = 504) arms. There was a statistically significant decrease in anxiety (P = 0.046) and total anxiety‐&‐depression scores (P = 0.0.012) in the PS arm compared with the FH arm over 3 years. No significant difference was observed between the FH and PS arms for depression, health‐anxiety, distress, uncertainty, quality‐of‐life or experience scores associated with BRCA testing. Contrast tests showed a decrease in anxiety (P = 0.018), health‐anxiety (P < 0.0005) and quality‐of‐life (P = 0.004) scores in both PS and FH groups over time. Eighteen of 30 (60%) BRCA carriers identified did not fulfil clinical criteria for BRCA testing. Total BRCA prevalence was 2.9% (95% CI 1.97–4.12%), BRCA1 prevalence was 1.55% (95% CI 0.89–2.5%) and BRCA2 prevalence was 1.35% (95% CI 0.74–2.26%).
Conclusion
Population‐based AJ BRCA testing does not adversely affect long‐term psychological wellbeing or quality‐of‐life, decreases anxiety and could identify up to 150% additional BRCA carriers.
Tweetable
Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life.
Tweetable
Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life.
This paper includes Author Insights, a video available at https://vimeo.com/rcog/authorinsights15905
Three inherited autosomal dominant conditions-BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)-have been termed the Centers for ...Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health
. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics
. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care.
Integration of gene panels in the diagnosis of hereditary breast and ovarian cancer (HBOC) requires a careful evaluation of the risk associated with pathogenic or likely pathogenic variants (PVs) ...detected in each gene. Here we analyzed 34 genes in 5131 suspected HBOC index cases by next-generation sequencing.
Using the Exome Aggregation Consortium data sets plus 571 individuals from the French Exome Project, we simulated the probability that an individual from the Exome Aggregation Consortium carries a PV and compared it to the estimated frequency within the HBOC population.
Odds ratio conferred by PVs within BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, BRIP1, CHEK2, and MSH6 were estimated at 13.22 10.01–17.22, 8.61 6.78–10.82, 8.22 4.91–13.05, 4.54 2.55–7.48, 5.23 1.46–13.17, 3.20 2.14–4.53, 2.49 1.42–3.97, 1.67 1.18–2.27, and 2.50 1.12–4.67, respectively. PVs within RAD51C, RAD51D, and BRIP1 were associated with ovarian cancer family history (OR = 11.36 5.78–19.59, 12.44 2.94–33.30 and 3.82 1.66–7.11). PALB2 PVs were associated with bilateral breast cancer (OR = 16.17 5.48–34.10) and BARD1 PVs with triple-negative breast cancer (OR = 11.27 3.37–25.01). Burden tests performed in both patients and the French Exome Project population confirmed the association of PVs of BRCA1, BRCA2, PALB2, and RAD51C with HBOC.
Our results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of HBOC and suggest that the other genes are involved in an oligogenic determinism.
Breast cancer is a common cancer affecting a large number of patients. Notably, 5–10% of all breast cancer patients are genetically predisposed to cancers. Although the most common breast cancer ...susceptibility genes are
BRCA1
and
BRCA2
, which are also associated with the risk of developing ovarian and pancreatic cancer, advances in next-generation sequencing (NGS) analysis technology enabled the discovery of several non-
BRCA
genes responsible for breast and ovarian cancers. Studies on hereditary breast and ovarian cancer (HBOC) involve not only determining the predisposition to developing cancer, but also considering the current treatment for breast cancer, prevention of next cancer, risk diagnosis, and adoption of protective measures for relatives. We present a comprehensive review of HBOC, which will be a useful resource in the clinical setting. Many hereditary tumors, including HBOC, are syndromes characterized by the development of different types of cancer in succession. Taking advantage of knowing predisposition of susceptibility to cancer, it is important to continue and update cancer management protocols, which includes the adoption of preventive measures, countermeasures, and treatments, to accurately assess and prevent the impact of cancer on the quality of life of the next generation of patients.
In the Phase 3 VELIA trial (NCT02470585), PARP inhibitor (PARPi) veliparib was combined with first-line chemotherapy and continued as maintenance for patients with ovarian carcinoma enrolled ...regardless of chemotherapy response or biomarker status. Here, we report exploratory analyses of the impact of homologous recombination deficient (HRD) or proficient (HRP) status on progression-free survival (PFS) and objective response rates during chemotherapy.
Women with Stage III-IV ovarian carcinoma were randomized to veliparib-throughout, veliparib-combination-only, or placebo. Stratification factors included timing of surgery and germline BRCA mutation status. HRD status was dichotomized at genomic instability score 33. During combination therapy, CA-125 levels were measured at baseline and each cycle; radiographic responses were assessed every 9 weeks.
Of 1140 patients randomized, 742 had BRCA wild type (BRCAwt) tumors (HRP, n = 373; HRD/BRCAwt, n = 329). PFS hazard ratios between veliparib-throughout versus control were similar in both BRCAwt populations (HRD/BRCAwt: 22.9 vs 19.8 months; hazard ratio 0.76; 95% confidence interval CI 0.53–1.09; HRP: 15.0 vs 11.5 months; hazard ratio 0.765; 95% CI 0.56–1.04). By Cycle 3, the proportion with ≥90% CA-125 reduction from baseline was higher in those receiving veliparib (pooled arms) versus control (34% vs 23%; P = 0.0004); particularly in BRCAwt and HRP subgroups. Complete response rates among patients with measurable disease after surgery were 24% with veliparib (pooled arms) and 18% with control.
These results potentially broaden opportunities for PARPi utilization among patients who would not qualify for frontline PARPi maintenance based on other trials.
Display omitted
•The VELIA trial assessed the PARPi veliparib, combined with frontline chemotherapy and continued as maintenance monotherapy.•Within the BRCA wild type population, survival outcomes were improved regardless of homologous recombination status.•During chemotherapy, radiographic and CA-125 responses were numerically higher with veliparib vs control in all subgroups.•PARPi could benefit a broader patient population than those currently eligible based on prior Phase 3 trials.
Genotype-first approach allows to systematically identify carriers of pathogenic variants in BRCA1/2 genes conferring a high risk of familial breast and ovarian cancer. Participants of the Estonian ...biobank have expressed support for the disclosure of clinically significant findings. With an Estonian biobank cohort, we applied a genotype-first approach, contacted carriers, and offered return of results with genetic counseling. We evaluated participants' responses to and the clinical utility of the reporting of actionable genetic findings. Twenty-two of 40 contacted carriers of 17 pathogenic BRCA1/2 variants responded and chose to receive results. Eight of these 22 participants qualified for high-risk assessment based on National Comprehensive Cancer Network criteria. Twenty of 21 counseled participants appreciated being contacted. Relatives of 10 participants underwent cascade screening. Five of 16 eligible female BRCA1/2 variant carriers chose to undergo risk-reducing surgery, and 10 adhered to surveillance recommendations over the 30-month follow-up period. We recommend the return of results to population-based biobank participants; this approach could be viewed as a model for population-wide genetic testing. The genotype-first approach permits the identification of individuals at high risk who would not be identified by application of an approach based on personal and family histories only.
The hereditary breast and ovarian cancer (HBOC) registration system of Japan was established by the Japanese HBOC Consortium. The first trial was registered in 2015 in four institutions to which some ...registration committee members belonged. We analyzed the information of 830 Japanese pedigrees, who underwent BRCA1/2 genetic testing, including mutation carriers with BRCA1 (N = 127) and BRCA2 (N = 115), and their families. The mutation-positive rate was 19.7%. Variants of uncertain significance were found in 6.5% of all individuals subjected to genetic testing for BRCA1/2. Compared to the United States, Japan had a higher mutation-positive rate in most categories, except for the groups with male breast cancer. Among the intrinsic subtypes of BRCA1-associated breast cancers, 75.8% were triple-negative. The incidence rate of contralateral breast cancer in BRCA1/2 mutation carriers was 0.99%/year. Among 240 mutation carriers, 26 and 62 patients underwent risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), respectively; the respective frequencies of occult cancer were 7.1 and 3.2%. Metachronous breast cancer after RRM or peritoneal cancer after RRSO was not observed during the follow-up period. The nationwide registration system began last year and the system enables follow-up analysis in Japan.
The prevalence of germ line mutations in non‐BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is ...conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67–4.94), CDH1 (OR: 17.04, 95%CI: 3.54–82), CHEK2 (OR: 2.93, 95%CI: 2.29–3.75), PALB2 (OR: 9.53, 95%CI: 6.25–14.51), and TP53 (OR: 7.30, 95%CI: 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple‐negative breast cancer (TNBC) and estrogen receptor (ER)‐negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)‐positive tumors.
In this case‐control study of well‐characterized breast cancer patients, we confirm ATM, CHEK2, PALB2, CDH1, and TP53 as BC risk genes, no association was observed for NBN. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC and both, ATM and CHEK2, were negatively associated with TNBC and (ER)‐negative tumor phenotypes. Our study confirmed the benefit of multi‐gene testing for risk assessment in BC families while clinical phenotypes associated with non‐BRCA1/2 gene mutations remain to be determined.
Recently developed clinical guidelines suggest that men in families with specific cancer syndromes, such as hereditary breast and ovarian cancer (HBOC), consider genetic testing, especially in the ...setting of aggressive disease. However, although a family history (FH) of the same disease among close relatives is an established risk factor for prostate cancer (PC), a direct comparison of PC risk for men with each syndrome in a single population is needed.
The Utah Population Database was used to identify 619,630 men, age ≥ 40 years, who were members of a pedigree that included at least 3 consecutive generations. Each man was evaluated for FH of hereditary PC (HPC), HBOC, and Lynch syndrome (LS) and for his own PC status. PC occurrences (N = 36,360) were classified into one or more subtypes: early onset (EO), lethal, and/or clinically significant. Relative risks (RRs) associated with each subtype, adjusted for important covariables, were calculated in STATA using a modified Poisson regression with robust error variances to obtain corresponding RR CIs for each FH definition.
An FH of HPC conveyed the greatest relative risk for all PC subtypes combined (RR, 2.30; 95% CI, 2.22 to 2.40), followed by HBOC and LS (both with 1 < RR < 2 and statistically significant). The strongest risks associated with FH were observed for EO disease in all pedigree types, consistent with the contribution of genetic factors to disease occurrence.
In this large, population-based, family database, the risk of PC varied by cancer FH and was most strongly associated with EO disease. These results are critically valuable in understanding and targeting high-risk populations that would benefit from genetic screening and enhanced surveillance.
PDF
