UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes:RAD51C,RAD51D,BRIP1andPALB2

Hanson, Helen; Kulkarni, Anjana; Loong, Lucy; Kavanaugh, Grace; Torr, Bethany; Allen, Sophie; Ahmed, Munaza; Antoniou, Antonis C.; Cleaver, Ruth; Dabir, Tabib; Evans, D. Gareth; Golightly, Ellen; Jewell, Rosalyn; Kohut, Kelly; Manchanda, Ranjit; Murray, Alex; Murray, Jennie; Ong, Kai-Ren; Rosenthal, Alan D.; Woodward, Emma R; Eccles, Diana; Huntley, Catherine; Tischkowitz, Marc; Lalloo, Fiona

doi:10.1136/jmg-2022-108898

Cited by 11 publications

(21 citation statements)

References 78 publications

(153 reference statements)

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“…Medical prevention and BC surveillance stops after RRM. The recommended age of RRSO is 40 to 50 years for RAD51C and RAD51D PV carriers and age 45 to 50 years for BRIP1 PV carriers, with differences across guidelines . Our analysis supports the cost-effectiveness and undertaking of RRSO at age 45 years for RAD51C , RAD51D , and BRIP1 PV carriers to maximize QALYs and cancers prevented.…”

Section: Discussionsupporting

confidence: 64%

“…Earlier guidelines have debated the appropriateness and timing of risk-reducing surgery for non- BRCA CSG carriers. The American College of Medical Genetics and Genomics (ACMG), UK Cancer Genetics Group (CGG), and RCOG recommend considering RRSO for PALB2 at ages 50, 50, and 45 to 50 years, respectively, with limited evidence highlighted by NCCN . RRM should be considered with personalized risk estimates for PALB2 PV carriers .…”

Section: Discussionmentioning

confidence: 99%

“…The American College of Medical Genetics and Genomics (ACMG), UK Cancer Genetics Group (CGG), and RCOG recommend considering RRSO for PALB2 at ages 50, 50, and 45 to 50 years, respectively, with limited evidence highlighted by NCCN . RRM should be considered with personalized risk estimates for PALB2 PV carriers . We found RRM (at age 40 years) and/or RRSO (at age 45 years) were cost-effective compared with BC surveillance and medical prevention for PALB2 PV carriers, and delaying RRSO until age 50 years yielded fewer QALYs and prevented fewer cancers, despite a small increase in NMB.…”

Section: Discussionmentioning

confidence: 99%

“…Although recent guidelines have started to incorporate recommendations for individuals who carry PVs in non- BRCA CSGs, existing guidelines have mainly focused on BRCA1 and BRCA2 , and the optimal timing of management for all CSGs is inadequately addressed. Available modeling studies show RRSO and/or RRM are cost-effective compared with BC surveillance or no surgery for BRCA1 and BRCA2 , while the ages at surgery varied .…”

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer

Wei,

Sun,

Slade

et al. 2024

JAMA Netw Open

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ImportancePathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BRIP1 cancer susceptibility genes (CSGs) confer an increased ovarian cancer (OC) risk, with BRCA1, BRCA2, PALB2, RAD51C, and RAD51D PVs also conferring an elevated breast cancer (BC) risk. Risk-reducing surgery, medical prevention, and BC surveillance offer the opportunity to prevent cancers and deaths, but their cost-effectiveness for individual CSGs remains poorly addressed.ObjectiveTo estimate the cost-effectiveness of prevention strategies for OC and BC among individuals carrying PVs in the previously listed CSGs.Design, Setting, and ParticipantsIn this economic evaluation, a decision-analytic Markov model evaluated the cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) and, where relevant, risk-reducing mastectomy (RRM) compared with nonsurgical interventions (including BC surveillance and medical prevention for increased BC risk) from December 1, 2022, to August 31, 2023. The analysis took a UK payer perspective with a lifetime horizon. The simulated cohort consisted of women aged 30 years who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. Appropriate sensitivity and scenario analyses were performed.ExposuresCSG-specific interventions, including RRSO at age 35 to 50 years with or without BC surveillance and medical prevention (ie, tamoxifen or anastrozole) from age 30 or 40 years, RRM at age 30 to 40 years, both RRSO and RRM, BC surveillance and medical prevention, or no intervention.Main Outcomes and MeasuresThe incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained. OC and BC cases and deaths were estimated.ResultsIn the simulated cohort of women aged 30 years with no cancer, undergoing both RRSO and RRM was most cost-effective for individuals carrying BRCA1 (RRM at age 30 years; RRSO at age 35 years), BRCA2 (RRM at age 35 years; RRSO at age 40 years), and PALB2 (RRM at age 40 years; RRSO at age 45 years) PVs. The corresponding ICERs were −£1942/QALY (−$2680/QALY), −£89/QALY (−$123/QALY), and £2381/QALY ($3286/QALY), respectively. RRSO at age 45 years was cost-effective for RAD51C, RAD51D, and BRIP1 PV carriers compared with nonsurgical strategies. The corresponding ICERs were £962/QALY ($1328/QALY), £771/QALY ($1064/QALY), and £2355/QALY ($3250/QALY), respectively. The most cost-effective preventive strategy per 1000 PV carriers could prevent 923 OC and BC cases and 302 deaths among those carrying BRCA1; 686 OC and BC cases and 170 deaths for BRCA2; 464 OC and BC cases and 130 deaths for PALB2; 102 OC cases and 64 deaths for RAD51C; 118 OC cases and 76 deaths for RAD51D; and 55 OC cases and 37 deaths for BRIP1. Probabilistic sensitivity analysis indicated both RRSO and RRM were most cost-effective in 96.5%, 89.2%, and 84.8% of simulations for BRCA1, BRCA2, and PALB2 PVs, respectively, while RRSO was cost-effective in approximately 100% of simulations for RAD51C, RAD51D, and BRIP1 PVs.Conclusions and RelevanceIn this cost-effectiveness study, RRSO with or without RRM at varying optimal ages was cost-effective compared with nonsurgical strategies for individuals who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. These findings support personalizing risk-reducing surgery and guideline recommendations for individual CSG-specific OC and BC risk management.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer

Wei,

Sun,

Slade

et al. 2024

JAMA Netw Open

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A comprehensive analysis of Fanconi anemia genes in Chinese patients with high-risk hereditary breast cancer

Zhu

et al. 2023

J Cancer Res Clin Oncol

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Background Four Fanconi anemia (FA) genes (BRCA1, BRCA2, PALB2 and RAD51C) are defined as breast cancer (BC) susceptibility genes. Other FA genes have been inconsistently associated with BC. Thus, the role of other FA genes in BC should be explored in specific populations. Methods Mutations in 16 FA genes were screened with a 98-gene panel sequencing assay in a cohort of 1481 Chinese patients with high-risk hereditary BC. The association between mutations and clinicopathological characteristics as well as prognosis was analyzed. The risk of BC in carriers of FA gene mutations was assessed in the Genome Aggregation Database and the Westlake Biobank for Chinese cohort. Results A total of 2.57% (38/1481) BC patients were identified who had 12 other FA gene germline mutations. Among them, the most frequently mutated gene was FANCA (8/1481, 0.54%). These 38 patients carried 35 distinct pathogenic/likely pathogenic variants, of which 21 were novel. We found one rare FANCB deleterious variant (c.1327-3dupT) in our cohort. There was a statistically significant difference in lymph node status between FA gene mutation carriers and non-carriers (p = 0.041). We observed a trend that mutation carriers had larger tumor sizes, lower estrogen receptor (ER) and progesterone receptor (PR) positivity rates, and lower 3.5-year invasive disease-free survival (iDFS) and distant recurrence-free survival (DRFS) rates than non-carriers (tumor size > 2 cm: 51.43% vs. 45.63%; ER positivity rates: 51.43% vs. 60.81%; PR positivity rates: 48.57% vs. 55.16%; 3.5-year iDFS rates: 58.8% vs. 66.7%; 3.5-year DRFS rates: 58.8% vs. 68.8%). The frequency of the mutations in FANCD2, FANCM and BRIP1 trended to be higher among BC cases than that in controls (p = 0.055, 0.08 and 0.08, respectively). Conclusion This study comprehensively estimated the prevalence, clinicopathological characteristics, prognosis and risk of BC associated with deleterious variants in FA genes in Chinese high-risk hereditary BC patients. It enriches our understanding of the role of FA genes with BC.

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Cascade screening in HBOC and Lynch syndrome: guidelines and procedures in a UK centre

Evans,

Green,

Burghel

et al. 2024

Familial Cancer

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In the 33 years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of healthcare Evidence and these have impacted on the thresholds for testing BRCA1/2 in Hereditary Breast Ovarian Cancer (HBOC) and in determining that all cases of colorectal and endometrial cancer should undergo screening for Lynch syndrome. Gaps for testing other CPGs relevant to HBOC have been filled by the UK Cancer Genetics Group and CanGene-CanVar project (web ref. https://www.cangene-canvaruk.org/). We present time trends (1990–2020) of identification of index cases with germline CPG variants and numbers of subsequent cascade tests, for BRCA1, BRCA2, and the Lynch genes (MLH1, MSH2, MSH6 and PMS2). For BRCA1/2 there was a definite increase in the proportion of index cases with ovarian cancer only and pre-symptomatic index tests both doubling from 16 to 32% and 3.2 to > 8% respectively. A mean of 1.73–1.74 additional family tests were generated for each BRCA1/2 index case within 2 years. Overall close to one positive cascade test was generated per index case resulting in > 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 (p < 0.0001).

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UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes:RAD51C,RAD51D,BRIP1andPALB2

Cited by 11 publications

References 78 publications

Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer

Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer

A comprehensive analysis of Fanconi anemia genes in Chinese patients with high-risk hereditary breast cancer

Cascade screening in HBOC and Lynch syndrome: guidelines and procedures in a UK centre

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