Genetics in Medicine

Optimization of polygenic risk scores in BRCA1/2 pathogenic variant heterozygotes in epithelial ovarian cancer

A third of familial epithelial ovarian cancer (EOC) is explained by BRCA1/2 pathogenic variants. Polygenic risk scores (PRSs) for BRCA1/2 heterozygotes associated with EOC have been created, but impact of combination with clinical and hormonal risk factors is unclear. We genotyped 300 cases and 355 controls and constructed modified PRSs based on those validated by Barnes et al. Model discrimination and EOC risk was assessed by area under the curve (AUC) values and difference between lowest and highest quintile odds ratios (ORs). We investigated model optimization using logistic regression to combine models with clinical and hormonal data. Unadjusted AUC values ranged from 0.526 to 0.551 with 2.2- to 2.3-fold increase in OR between lowest and highest quintiles (BRCA1 heterozygotes) and 0.574 to 0.585 AUC values with a 6.3- to 7.7-fold increase (BRCA2 heterozygotes). The optimized model (parity, age at menarche, menopause, and first full-term pregnancy) estimated AUC values of 0.872 to 0.876 and 21- to 23-fold increase in OR (BRCA1 heterozygotes) and AUC values of 0.857 to 0.867 and 40- to 41-fold increase (BRCA2 heterozygotes). The combination of PRS with age, family history, and hormonal factors significantly improved the EOC risk discrimination ability. However, the contribution of the PRS was small. Larger prospective studies are needed to assess if combined-PRS models could provide information to inform risk-reducing decisions.

Breast cancer after ovarian cancer in BRCA1 and BRCA2 pathogenic variant heterozygotes: Lower rates for 5 years post chemotherapy

The identification of germline BRCA1/BRCA2 pathogenic variants (PV) infer high remaining lifetime breast/ovarian cancer risks, but there is paucity of studies assessing breast cancer risk after ovarian cancer diagnosis. We reviewed the history of breast cancer in 895 PV heterozygotes (BRCA1 = 541). Cumulative annual breast cancer incidence was assessed at 2, 5, 10, and >10 years after ovarian cancer diagnosis date. Breast cancer annual rates were evaluated in 701 assessable women with no breast cancer at ovarian diagnosis (BRCA1 = 425). Incidence was lower at 2 years (1.18%) and 2 to 5 years (1.13%) but rose thereafter for BRCA1 with incidence post 10 years in excess of 4% annually. Breast cancer pathology in BRCA1 PV heterozygotes showed less high-grade triple-negative breast cancer and more lower-grade hormone-receptor-positive cancer than women with no prior ovarian cancer. In the prospective cohort from ovarian cancer diagnosis, <4% of all deaths were caused by breast cancer, although 50% of deaths in women with breast cancer after ovarian cancer diagnosis were due to breast cancer. Women can be reassured that incidence of breast cancer after ovarian cancer diagnosis is relatively low. It appears likely that this effect is due to platinum-based chemotherapy. Nonetheless women need to be aware that incidence increases thereafter, especially after 10 years.

Cancer risks for other sites in addition to breast in CHEK2 c.1100delC families

Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure

Targeted BRCA1/2 population screening among Ashkenazi Jewish individuals using a web-enabled medical model: An observational cohort study

This study aimed to evaluate uptake and follow-up using internet-assisted population genetic testing (GT) for BRCA1/2 Ashkenazi Jewish founder pathogenic variants (AJPVs). Across 4 cities in the United States, from December 2017 to March 2020, individuals aged ≥25 years with ≥1 Ashkenazi Jewish grandparent were offered enrollment. Participants consented and enrolled online with chatbot and video education, underwent BRCA1/2 AJPV GT, and chose to receive results from their primary care provider (PCP) or study staff. Surveys were conducted at baseline, at 12 weeks, and annually for 5 years. A total of 5193 participants enrolled and 4109 (79.1%) were tested (median age = 54, female = 77.1%). Upon enrollment, 35.1% of participants selected a PCP to disclose results, and 40.5% of PCPs agreed. Of those tested, 138 (3.4%) were AJPV heterozygotes of whom 21 (15.2%) had no significant family history of cancer, whereas 86 (62.3%) had a known familial pathogenic variant. At 12 weeks, 85.5% of participants with AJPVs planned increased cancer screening; only 3.7% with negative results and a significant family history reported further testing. Although continued follow-up is needed, internet-enabled outreach can expand access to targeted GT using a medical model. Observed challenges for population genetic screening efforts include recruitment barriers, improving PCP engagement, and increasing uptake of additional testing when indicated.

Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

RAD51C, RAD51D, and BRIP1 germline pathogenic variants (GPVs) are associated with increased lifetime risks of tubo-ovarian cancer. Resources for managing RAD51C, RAD51D, and BRIP1 heterozygotes in clinical practice are limited. An international workgroup developed a Clinical Practice Resource to guide management of RAD51C, RAD51D, and BRIP1 heterozygotes using peer-reviewed publications and expert opinion. RAD51C, RAD51D, and BRIP1 are moderate (intermediate) penetrance ovarian cancer predisposition genes. Ovarian cancer risks for individuals with RAD51C, RAD51D, and BRIP1 GPVs may be influenced by family history and other modifiers. RAD51C and RAD51D GPVs are also associated with moderate risk of breast cancer, predominantly triple-negative subtype. RAD51C, RAD51D, and BRIP1 heterozygotes should be offered risk-reducing salpingo-oophorectomy close to the age of menopause based on age-specific risks and shared decision making. For RAD51C and RAD51D heterozygotes, enhanced breast surveillance may be indicated according to their personalized risk estimate and country-specific guidelines. Generally, risk-reducing mastectomy is not recommended. For RAD51C, RAD51D, and BRIP1 heterozygotes who develop cancer, there is insufficient evidence to guide any specific targeted treatment. Systematic prospective data collection is needed to establish the outcomes of RAD51C, RAD51D, and BRIP1 associated cancers and particularly response to cancer treatment and survival.

BRCA genetic testing utilization and expenditures among privately insured adults in the United States, 2013 to 2022

Recent clinical guidelines have broadened the criteria for BRCA counseling and testing for women and men, including indications based on family history, personal history, and current diagnosis of breast, ovarian, pancreatic, and prostate cancer. Using claims data from 2013 to 2022, we identified BRCA testing using procedure codes to evaluate annual utilization, median expenditures per enrollee, and the percentage of 0 out-of-pocket expenditures by sex among enrollees aged 18 to 64 years who were continuously enrolled within calendar years. We examined BRCA utilization by metropolitan status and indications. Annual BRCA testing utilization among women (and men) increased 10.2% (44.5%) per year during 2014 to 2015 and 1.7% (10.0%) per year during 2016 to 2019, decreased 34.4% (44.8%) in 2020, and rebounded 8.5% (22.3%) per year during 2021 to 2022, remaining below prepandemic levels in 2022. Median expenditures for comprehensive BRCA testing per enrollee decreased by 68% from 2013 to 2022, most of whom had 0 out-of-pocket expenditures. Most BRCA testing was done based on family health history of breast, ovarian, or prostate cancer and among women aged 18 to 50 years. Health care providers who are knowledgeable about evolving indications for germline BRCA testing can help ensure that eligible individuals have access to germline BRCA testing as preventive service.

Nonadherence to guidelines for genetic testing in families with ovarian cancer shows racial bias

The National Comprehensive Cancer Network (NCCN) recommends germline genetic testing for individuals at risk for hereditary ovarian cancer. We sought to determine the proportion and characteristics of individuals meeting testing criteria in a multicenter biobank who were appropriately offered testing. In this retrospective cohort study, we identified Mass General Brigham Biobank participants meeting genetic testing criteria per NCCN guidelines. Logistic regression was used to analyze sociodemographic factors associated with which participants were offered testing, completed testing, and had a family history that matched their self-report documented in the electronic medical record. Most eligible participants (909/1441, 63.1%) were not offered genetic testing. Participants who were Black or Hispanic had a lower likelihood of being offered testing. Compared with self-report, 988 (68.6%) participants had a family history of ovarian cancer documented in their electronic medical record. Older age, Hispanic ethnicity, and public insurance use were associated with decreased likelihoods of accurate family history documentation. Correct documentation was associated with an increased likelihood of being offered testing. The majority of participants in this study did not receive NCCN-compliant care. Germline genetic testing for hereditary ovarian cancer screening is underutilized and access to this testing is currently inequitable.

Using cancer phenotype sex-specificity to enable unbiased penetrance estimation of SMARCA4 pathogenic variants for small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an extremely rare, highly aggressive cancer (mean age of onset, 24 years). Nearly all cases are associated with somatic or germline pathogenic variants (GPVs) in SMARCA4. Early bilateral oophorectomy is recommended for unaffected females with a SMARCA4 GPV. However, the penetrance of SMARCA4 GPVs for SCCOHT is highly uncertain and subject to ascertainment bias. Leveraging the early-onset, sex-specific, highly morbid nature of SCCOHT, we hypothesized that the penetrance for SCCOHT could be quantified from the deficit in SMARCA4 GPVs in females compared with males in UK Biobank, a population cohort for which recruitment was restricted to those age 40 to 69. We also analyzed pedigrees ascertained internationally by the Montreal-based SCCOHT-SMARCA4 Registry. We observed SMARCA4 GPVs in 8/210,182 (0.0038%) female and 18/179,210 (0.0100%) male participants in UK Biobank (P = .028), representing a male:female odds ratio of 2.64 (95% CI 1.09-7.02), implying a penetrance of 62% for SCCOHT (given the absence of other SMARCA4-related female-specific early morbid diseases). A deficit of GPVs in females in UK Biobank was also demonstrated for BRCA1 and TP53. Our findings support bilateral oophorectomy in early adulthood as a rational choice for at-risk females with SMARCA4 GPVs.

Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.

Recessive FANCM cancer syndrome with high cancer risks, chemotherapy toxicity, chromosome fragility, and gonadal failure

Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome

This study aimed to characterize MSH6/PMS2-associated mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) tumors, given revised guidelines suggesting more modest phenotypes. Patients who consented to Institutional Review Board-approved protocols of tumor/germline sequencing or Lynch syndrome registry at a single institution from February 2005 to January 2021 with germline, heterozygous MSH6/PMS2 pathogenic/likely pathogenic variants were identified. Clinical data were abstracted and correlated with MMR/microsatellite instability status using nonparametric tests. We identified 243 patients (133 sequencing, 110 registry) with germline MSH6/PMS2 pathogenic/likely pathogenic variants; 186 (77%) had >1 cancer. Of 261 pooled tumors, colorectal cancer (CRC) and endometrial cancer (EC) comprised 55% and 43% of cancers in MSH6 and PMS2, respectively; 192 tumors underwent molecular assessments and 122 (64%) were MMR-D/MSI-H (77 in MSH6, 45 in PMS2). MMR-D/MSI-H cancers included CRC (n = 56), EC (n = 35), small bowel cancer (n = 6), ovarian cancer (n = 6), urothelial cancer (n = 5), pancreas/biliary cancer (n = 4), gastric/esophageal cancer (n = 3), nonmelanoma skin tumors (n = 3), prostate cancer (n = 2), breast cancer (n = 1), and central nervous system/brain cancer (n = 1). Among MMR-D/MSI-H CRC and EC, median age of diagnosis was 51.5 (range = 27-80) and 55 (range = 39-74) years, respectively; 9 of 56 (16%) MMR-D/MSI-H CRCs were diagnosed at age <35 years. MSH6/PMS2 heterozygotes remain at risk for a broad spectrum of cancers, with 16% of MMR-D/MSI-H CRCs presenting before upper threshold of initiation of colonoscopy per guidelines.

Universal tumor screening in a population with MSH6- and PMS2-associated Lynch syndrome

Universal screening for Lynch syndrome (LS) on resected colorectal carcinomas (CRCs) and endometrial carcinomas (ECs) was implemented in Iceland in 2017 using immunohistochemistry (IHC) for mismatch repair (MMR) proteins. We examined the efficacy of the universal screening algorithm to detect LS and the diagnostic accuracy of MMR IHC by comparing results with a population-based genotype database. All patients diagnosed with CRC or EC per the Icelandic Cancer Registry from 2017 to 2019 who had tumor MMR IHC performed were included. Pathology reports and patient charts were reviewed. MMR IHC stains were crossmatched with genotyping results obtained from the deCODE database. IHC staining was done on 404 patients with CRC and 74 patients with EC. A total of 61 (15.1%) patients with CRC and 15 (20.3%) patients with EC were MMR-deficient. MMR IHC had 88.9% sensitivity in identifying patients with LS and a positive predictive value of 10.7%. Only 50% of individuals were appropriately referred for genetic testing, leading to underdiagnosis of LS. Universal screening for LS using MMR protein IHC in CRC and EC accurately identified patients appropriate for genetic testing in a population with MSH6 and PMS2 LS predominance. Because of lack of referral to genetic counseling, only 50% of patients with LS were identified through the screening algorithm.

Response to Benusiglio et al.

High detection rate from genetic testing in BRCA-negative women with familial epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is associated with pathogenic variants (PVs) in homologous recombination and/or mismatch repair genes. We aimed to review the testing of women with familial EOC at our center. Women with familial EOC (≥2 EOC in family, including index case) referred to our center between 1993 and 2021 were included. Genetic testing (BRCA/Lynch syndrome screening, exome sequencing, panel testing, 100,000 Genome Project, and NIHR BioResource genome sequencing) and clinical demographic, diagnosis, and survival data were reviewed. Of 277, 128 (46.2%) women were BRCA heterozygotes (BRCA1: 89, BRCA2: 39). The detection rate in BRCA-negative women was 21.8%; the most commonly affected gene was BRIP1 (5.9%). The non-BRCA detection rate was significantly higher in families with 2 affected members with EOC only (22.4%) than the families with ≥3 (11.1%) affected members (odds ratio = 9.9, 95% CI = 1.6-105.2, P = .0075). Overall, 112 different PVs in 12 homologous recombination/mismatch repair genes were detected in 150 of 277 (54.2%) unrelated women. This is the largest report of women with familial EOC undergoing wider testing to date. One-fifth of BRCA-negative women were heterozygous for a PV in a potentially actionable gene. Wider genetic testing of women with familial EOC is essential to optimize their treatment and prevention of disease in family members.

Development and evaluation of polygenic risk scores for prediction of endometrial cancer risk in European women

Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a polygenic risk score (PRS) comprising multiple SNVs may improve endometrial cancer risk prediction for targeted screening and prevention. We developed PRSs from SNVs identified from a systematic review of published studies and suggestive SNVs from the Endometrial Cancer Association Consortium. These were tested in an independent study of 555 surgically-confirmed endometrial cancer cases and 1202 geographically-matched controls from Manchester, United Kingdom and validated in 1676 cases and 116,960 controls from the UK Biobank (UKBB). Age and body mass index predicted endometrial cancer in both data sets (Manchester: area under the receiver operator curve [AUC] = 0.77, 95% CI = 0.74-0.80; UKBB: AUC = 0.74, 95% CI = 0.73-0.75). The AUC for PRS19, PRS24, and PRS72 were 0.58, 0.55, and 0.57 in the Manchester study and 0.56, 0.54, and 0.54 in UKBB, respectively. For PRS19, women in the third tertile had a 2.1-fold increased risk of endometrial cancer compared with those in the first tertile of the Manchester study (odds ratio = 2.08, 95% CI = 1.61-2.68, P An endometrial cancer risk prediction model incorporating a PRS derived from multiple SNVs may help stratify women for screening and prevention strategies.

Clinical outcomes of a genomic screening program for actionable genetic conditions

Three genetic conditions-hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia-have tier 1 evidence for interventions that reduce morbidity and mortality, prompting proposals to screen unselected populations for these conditions. We examined the impact of genomic screening on risk management and early detection in an unselected population. Observational study of electronic health records (EHR) among individuals in whom a pathogenic/likely pathogenic variant in a tier 1 gene was discovered through Geisinger's MyCode project. EHR of all eligible participants was evaluated for a prior genetic diagnosis and, among participants without such a diagnosis, relevant personal/family history, postdisclosure clinical diagnoses, and postdisclosure risk management. Eighty-seven percent of participants (305/351) did not have a prior genetic diagnosis of their tier 1 result. Of these, 65% had EHR evidence of relevant personal and/or family history of disease. Of 255 individuals eligible to have risk management, 70% (n = 179) had a recommended risk management procedure after results disclosure. Thirteen percent of participants (41/305) received a relevant clinical diagnosis after results disclosure. Genomic screening programs can identify previously unrecognized individuals at increased risk of cancer and heart disease and facilitate risk management and early cancer detection.

Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort

Genetic testing of individuals often results in identification of genomic variants of unknown significance (VUS). Multiple lines of evidence are used to help determine the clinical significance of these variants. We analyzed ~138,000 individuals tested by multigene panel testing (MGPT). We used logistic regression to predict carrier status based on personal and family history of cancer. This was applied to 4644 tested individuals carrying 2383 BRCA1/2 variants to calculate likelihood ratios informing pathogenicity for each. Heterogeneity tests were performed for specific classes of variants defined by in silico predictions. Twenty-two variants labeled as VUS had odds of >10:1 in favor of pathogenicity. The heterogeneity analysis found that among variants in functional domains that were predicted to be benign by in silico tools, a significantly higher proportion of variants were estimated to be pathogenic than previously indicated; that missense variants outside of functional domains should be considered benign; and that variants predicted to create de novo donor sites were also largely benign. The evidence presented here supports the use of personal and family history from MGPT in the classification of VUS and will be integrated into ongoing efforts to provide large-scale multifactorial classification.

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10 Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Extended panel testing in ovarian cancer reveals BRIP1 as the third most important predisposition gene

The prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain. An observational study reporting the detection rate of germline PVs in HRR and LS genes in all OC cases tested in the North West Genomic Laboratory Hub between September 1996 and May 2024. Effect sizes are reported using odds ratios (ORs) and 95% confidence intervals (95% CI) for unselected cases tested between April 2021 and May 2024 versus 50,703 controls from the Breast Cancer Risk after Diagnostic Gene Sequencing study. 2934 women were tested for BRCA1/2 and 433 (14.8%) had a PV. In up to 1572 women tested for PVs in non-BRCA1/2 HRR genes, detection rates were PALB2 = 0.8%, BRIP1 = 1.1%, RAD51C = 0.4% and RAD51D = 0.4%. In 940 unselected cases, BRIP1 (OR = 8.7, 95% CI 4.6-15.8) was the third most common OC predisposition gene followed by RAD51C (OR = 8.3, 95% CI 3.1-23.1), RAD51D (OR = 6.5, 95% CI 2.1-19.7), and PALB2 (OR = 3.9, 95% CI 1.5-10.3). No PVs in LS genes were detected in unselected cases. Panel testing in OC resulted in a detection rate of 2% to 3% for germline PVs in non-BRCA1/2 HRR genes, with the largest contributor being BRIP1. Screening for LS in unselected cases of OC is unnecessary.

Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance

BRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for thousands of variants to aid in variant classification. We have collected, curated, and harmonized functional data for 2701 missense variants representing 24.5% of possible missense variants in BRCA1. Results were harmonized across studies by converting data into binary categorical variables (functional impact versus no functional impact). Using a panel of reference variants we identified a subset of assays with high sensitivity and specificity (≥80%) and apply the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to assign evidence criteria for classification. Integration of data from validated assays provided ACMG/AMP evidence criteria in favor of pathogenicity for 297 variants or against pathogenicity for 2058 representing 96.2% of current VUS functionally assessed. We also explore discordant results and identify limitations in the approach. High quality functional data are available for BRCA1 missense variants and provide evidence for classification of 2355 VUS according to their pathogenicity.

Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer

To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. Outcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3,127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial nonmucinous ovarian cancer, and 1,567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. Thirty-five PALB2 and 44 CHEK2_1100delC PGVs were detected in patients (odds ratio [OR] PALB2 breast-ovarian = 5.90 [95% CI: 1.92-18.36], CHEK2 breast-ovarian = 4.46 [95% CI: 1.86-10.46], PALB2 breast = 6.16 [95% CI: 1.98-19.21], CHEK2 breast = 4.89 [95% CI: 2.01-11.34]). Grade 3 ER-positive HER2-negative, grade 3 and triple negative (TN) tumors were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service (respectively: 15/43, 254/1,843, P = 0.0005; 28/37, 562/1,381, P = 0.0001; 12/43, 204/1,639, P < 0.0001). PALB2_PGV likelihood increased with increasing Manchester score (MS) (MS < 15 = 17/1,763, MS 20-39 = 11/520, P = 0.04) but not for CHEK2_1100delC (MS < 15 = 29/1,762, MS 20-39 = 4/520). PALB2 PGVs showed perfect segregation in 20/20 first-degree relatives with breast cancer, compared with 7/13 for CHEK2_1100delC (P = 0.002). PALB2 PGVs and CHEK2_1100delC together account for ~2.5% of familial breast/ovarian cancer risk. PALB2 PGVs are associated with grade 3, TN, and grade 3 ER-positive HER2-negative breast tumors.

Cost-effectiveness of long-term clinical management of BRCA pathogenic variant carriers

Women who inherit a BRCA1 or BRCA2 pathogenic variant are at high risk of developing breast and ovarian cancer. Evidence for the effectiveness and cost-effectiveness of long-term management in clinical practice is lacking. The purpose of this study was to evaluate the real-world cost-effectiveness of BRCA carrier management within a structured clinical program. Lifetime health outcomes and costs of clinical management for female unaffected BRCA carriers aged 20 were measured using a microsimulation model. For the intervention, women could attend a high-risk clinic, undergo risk-reducing surgery, and receive annual breast screening. Input data for the model was from a clinical database of 983 BRCA carriers. The comparator was no risk management. Outcomes were discounted at 5%. The incremental cost-effectiveness ratio for the program was $32,359 to $48,263 per quality-adjusted life-year (QALY). Limiting uptake of risk-reducing salpingo-oophorectomy to <50% of carriers decreased cost-effectiveness by $7000-8000 per QALY. Achieving perfect adherence to guidelines was less cost-effective for BRCA2 due to increased risk-reducing mastectomy costs with smaller incremental health benefit. Long-term management of BRCA carriers within a structured clinical program is cost-effective. Suboptimal adherence to risk management guidelines can substantially affect outcomes and is an important consideration for future studies.