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Approximately 10% of patients diagnosed with cancer have a germline variant in a gene that increases susceptibility to cancer. 1 The most common examples include germline pathogenic variants (mutations) in BRCA1 and BRCA2, which are associated with an increased risk of breast, ovarian, pancreatic, and prostate cancer, and germline pathogenic variants in MLH1, MSH2, MSH6, and PMS2 (Lynch syndrome), which are associated with increased risk of colorectal cancer, endometrial cancer, and other cancer types.More than 100 genes that increase susceptibility to cancer (with varied levels of penetrance and association with cancer susceptibility) have been described. 2 The prevalence of these germline genetic variants varies by cancer type, ranging from 4% to 6% in patients with lung cancer, esophageal cancer, and head and neck cancer to 30% for male patients with breast cancer. 3 In patients diagnosed with cancer, testing for gene variants associated with increased cancer susceptibility is important for at least 2 reasons. First, testing informs the most optimal treatment for a patient with cancer. Second, testing helps identify relatives who may have inherited genes that increase their cancer susceptibility. Identifying these genes could improve outcomes by increasing cancer screening and riskreducing measures such as preventive surgery. With the advent of next-generation sequencing technologies, genetic testing for cancer risk has shifted from sequential, singlegene testing to multiple-panel genetic testing using blood or saliva. These tests require only 2 to 4 weeks for results and are performed by several large commercial laboratories.For patients diagnosed with cancer for whom practice guidelines recommend genetic susceptibility testing, multiplepanel genetic testing is covered by most health insurance entities. Practice guidelines now recommend testing for inherited cancer susceptibility genes for all patients with ovarian, male breast, and pancreatic cancer. 4 For other cancer types, including female breast, prostate, and colorectal, the criteria for testing have expanded, with more practice guidelines now advocating for genetic susceptibility testing for all patients or increasing subsets of patients. [4][5][6] Genetic testing for inherited cancer syndromes has become an integral component of cancer care because it directly affects management and therapy. 1,7 In 2014, the first poly (adenosine diphosphate-ribose) polymerase inhibitor was approved by the US Food and Drug Administration for BRCAassociated ovarian cancer, and more recently approval has been expanded to include treatment for BRCA-associated breast cancer, pancreatic cancer, and prostate cancer. 8 At the time of Related articleOpinion EDITORIAL
Approximately 10% of patients diagnosed with cancer have a germline variant in a gene that increases susceptibility to cancer. 1 The most common examples include germline pathogenic variants (mutations) in BRCA1 and BRCA2, which are associated with an increased risk of breast, ovarian, pancreatic, and prostate cancer, and germline pathogenic variants in MLH1, MSH2, MSH6, and PMS2 (Lynch syndrome), which are associated with increased risk of colorectal cancer, endometrial cancer, and other cancer types.More than 100 genes that increase susceptibility to cancer (with varied levels of penetrance and association with cancer susceptibility) have been described. 2 The prevalence of these germline genetic variants varies by cancer type, ranging from 4% to 6% in patients with lung cancer, esophageal cancer, and head and neck cancer to 30% for male patients with breast cancer. 3 In patients diagnosed with cancer, testing for gene variants associated with increased cancer susceptibility is important for at least 2 reasons. First, testing informs the most optimal treatment for a patient with cancer. Second, testing helps identify relatives who may have inherited genes that increase their cancer susceptibility. Identifying these genes could improve outcomes by increasing cancer screening and riskreducing measures such as preventive surgery. With the advent of next-generation sequencing technologies, genetic testing for cancer risk has shifted from sequential, singlegene testing to multiple-panel genetic testing using blood or saliva. These tests require only 2 to 4 weeks for results and are performed by several large commercial laboratories.For patients diagnosed with cancer for whom practice guidelines recommend genetic susceptibility testing, multiplepanel genetic testing is covered by most health insurance entities. Practice guidelines now recommend testing for inherited cancer susceptibility genes for all patients with ovarian, male breast, and pancreatic cancer. 4 For other cancer types, including female breast, prostate, and colorectal, the criteria for testing have expanded, with more practice guidelines now advocating for genetic susceptibility testing for all patients or increasing subsets of patients. [4][5][6] Genetic testing for inherited cancer syndromes has become an integral component of cancer care because it directly affects management and therapy. 1,7 In 2014, the first poly (adenosine diphosphate-ribose) polymerase inhibitor was approved by the US Food and Drug Administration for BRCAassociated ovarian cancer, and more recently approval has been expanded to include treatment for BRCA-associated breast cancer, pancreatic cancer, and prostate cancer. 8 At the time of Related articleOpinion EDITORIAL
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.
ImportanceAmong women diagnosed with primary breast cancer (BC) at or younger than age 40 years, prior data suggest that their risk of a second primary BC (SPBC) is higher than that of women who are older when they develop a first primary BC.ObjectiveTo estimate cumulative incidence and characterize risk factors of SPBC among young patients with BC.Design, Setting, and ParticipantsParticipants were enrolled in the Young Women’s Breast Cancer Study, a prospective study of 1297 women aged 40 years or younger who were diagnosed with stage 0 to III BC from August 2006 to June 2015. Demographic, genetic testing, treatment, and outcome data were collected by patient surveys and medical record review. A time-to-event analysis was used to account for competing risks when determining cumulative incidence of SPBC, and Fine-Gray subdistribution hazard models were used to evaluate associations between clinical factors and SPBC risk. Data were analyzed from January to May 2023.Main Outcomes and MeasuresThe 5- and 10- year cumulative incidence of SPBC.ResultsIn all, 685 women with stage 0 to III BC (mean [SD] age at primary BC diagnosis, 36 [4] years) who underwent unilateral mastectomy or lumpectomy as the primary surgery for BC were included in the analysis. Over a median (IQR) follow-up of 10.0 (7.4-12.1) years, 17 patients (2.5%) developed an SPBC; 2 of these patients had cancer in the ipsilateral breast after lumpectomy. The median (IQR) time from primary BC diagnosis to SPBC was 4.2 (3.3-5.6) years. Among 577 women who underwent genetic testing, the 10-year risk of SPBC was 2.2% for women who did not carry a pathogenic variant (12 of 544) and 8.9% for carriers of a pathogenic variant (3 of 33). In multivariate analyses, the risk of SPBC was higher among PV carriers vs noncarriers (subdistribution hazard ratio [sHR], 5.27; 95% CI, 1.43-19.43) and women with primary in situ BC vs invasive BC (sHR, 5.61; 95% CI, 1.52-20.70).ConclusionsFindings of this cohort study suggest that young BC survivors without a germline pathogenic variant have a low risk of developing a SPBC in the first 10 years after diagnosis. Findings from germline genetic testing may inform treatment decision-making and follow-up care considerations in this population.
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