Eighth International Symposium on hereditary breast and ovarian cancer : May 4-7, 2021 - Virtual Edition.
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PROVIDER: S-EPMC8441035 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Nearly 15% of DNA tests for BRCA1/2 results in the identification of an unclassified variant (UV). In DNA diagnostic laboratories in The Netherlands, a 4-group classification system (class I to IV) is in use (Bell et al.). Aim of this study was to investigate whether the UVs in different classes showed a significant difference in their in silico characteristics and would justify current differences in protocols for counselling with respect to communication to the counselees. Methods: Missense UVs in BRCA1/2 identified between 2002 and 2010 (n = 88) were analyzed. In silico analysis of UVs was performed using SIFT– analysis Grantham score and AGVGD for the predicted severity of amino acid substitutions. Each UV was classified to one of the four classes. Results: More than half of the UVs (n = 50) were predicted to be tolerated using SIFT-analysis. Accordingly, all these variants are scored as neutral (C0) by AGVGD. Of the remaining 38 UVs not tolerated using SIFT-analysis, 19 were scored as C0 (neutral), 8 were scored C15–C25 (intermediate) and 11 were scored C35 or higher (likely to be pathogenic). Although class III UVs more frequently show in silico parameter outcomes that are suspicious for a pathogenic effect, the observed differences are not absolute. Seven UVs classified in class II had similar in silico profiles with 7 UVs in class III. Conclusion: This study showed that, in general, in silico analysis is consistently applied and proved to be able to discriminate between the different classes of UVs. However, additional analyses will be required to classify the UVs with more accuracy. In order to reduce psychological distress in families in which a UV is identified, we propose that communication of a UV should not primarily depend on its class, but also on the possibility to perform additional research in the family.
| S-EPMC3320236 | biostudies-literature
Project description:Objectives: It is estimated that 1%–2% of individuals of Ashkenazi Jewish (aj) ancestry carry one of three pathogenic founder mutations in BRCA1 and BRCA2. Targeted testing for these mutations (BRCA1 187delAG and 5385insC, and BRCA2 6174delT) is therefore recommended for all aj breast and ovarian cancer patients, regardless of age of diagnosis or family history. Comprehensive analysis of both genes is recommended for a subset of aj patients in whom founder mutations are not identified, but estimates of the yield from comprehensive analysis in this population vary widely. Methods: We sought to establish the proportion of non-founder mutations in aj patients undergoing clinical testing in our laboratory from January 2006 through August 2013. Analysis included aj patients for whom: 1) comprehensive testing was ordered as the initial test, or 2) founder mutation testing was ordered with instructions to “reflex” to comprehensive analysis if negative. The latter group was limited to cases where the reflex testing was ordered on the original test request form, and not cancelled for any reason other than the detection of a founder mutation. Results: The percentage of non-founder mutations detected in these groups was 13% (104/802) and 7.2% (198/2769) respectively. We detected 189 unique non-founder mutations, 76 in BRCA1 and 113 in BRCA2. BRCA2 4075delGT was detected in 15 patients. The next most common mutations, found in 7 patients each, were BRCA1 5055delG, BRCA2 1982delA, and BRCA2 R3128X. Conclusions: Non-founder mutations make up between 13% and 7.2% of BRCA1 and BRCA2 mutations in patients reporting aj ancestry. These numbers may represent underestimates if some patients were ascertained for testing based on the identification of a founder mutation in a relative. These numbers suggest that the prevalence of non-founder mutations in aj individuals may be comparable to the prevalence of BRCA1/2 mutations in non-aj individuals.
| S-EPMC3997469 | biostudies-literature
Project description: Not available
| S-EPMC8591444 | biostudies-literature
Project description:The comprehensive assessment of inherited mutations in cancer susceptibility genes helps to optimize clinical decision-making. Conventional laboratory methods based on ngs focus on the detection of single nucleotide variants, small insertions/deletions, and certain copy-number changes in accessible regions of a patient’s dna. Other clinically significant alterations are invisible to these approaches, and for this reason their clinical impact is less well studied. We investigated the prevalence of technically challenging mutations in a large (n = 80,000) patient population focusing on 19 genes (including BRCA1 and BRCA2) associated with breast and/or ovarian cancer. Technical methods beyond conventional next-generation sequencing (ngs) were used to detect and confirm the presence of dna alterations in these patients. We found that 8.6% of patients with a potentially actionable result harbored a mutation not easily detected by conventional ngs sequencing or copy number methods. No single class of mutation was responsible for this—rather, a diversity of challenges was present. Most of these mutations were individually extremely rare, although some were recurrent. Many would have clinical relevance in either a germline or somatic context. Laboratory studies generally include few, if any, of these technically challenging variants. To help evaluate and improve methodologies across laboratories, we constructed a synthetic specimen containing 22 challenging variants in 7 cancer genes. This specimen was provided to collaborating laboratories who sequenced it using a total of 10 different ngs tests. Only 10 of the 22 challenging variants were detected by all tests, and just 3 tests detected all 22. Some but not all of these limitations were previously known. In summary, technically challenging pathogenic variants are collectively prevalent in patients, although methods to detect these variants are not yet uniformly implemented. The clinical data and specimen described here are now available and mght help improve the assessment of cancer risk internationally.
| S-EPMC6023566 | biostudies-literature
Project description: Not available
| S-EPMC8556790 | biostudies-literature
Project description:ImportanceThe recently released eighth edition of the American Joint Committee on Cancer TNM staging system for pancreatic cancer seeks to improve prognostic accuracy but lacks international validation.ObjectiveTo validate the eighth edition of the American Joint Committee on Cancer TNM staging system in an international cohort of patients with resected pancreatic ductal adenocarcinoma.Design, setting, and participantsThis international multicenter cohort study took place in 5 tertiary centers in Europe and the United States from 2000 to 2015. Patients who underwent pancreatoduodenectomy for nonmetastatic pancreatic ductal adenocarcinoma were eligible. Data analysis took place from December 2017 to April 2018.ExposuresPatients were retrospectively staged according to the seventh and eighth editions of the TNM staging system.Main outcomes and measuresPrognostic accuracy on survival rates, assessed by Kaplan-Meier and multivariate Cox proportional hazards analyses and concordance statistics.ResultsA total of 1525 consecutive patients were included (median [IQR] age, 66 (58-72) years; 802 (52.6%) male). Distribution among stages via the seventh edition was stage IA in 41 patients (2.7%), stage IB in 42 (2.8%), stage IIA in 200 (13.1%), stage IIB in 1229 (80.6%), and stage III in 12 (0.8%); this changed with use of the eighth edition to stage IA in 118 patients (7.7%), stage IB in 144 (9.4%), stage IIA in 22 (1.4%), stage IIB in 643 (42.2%), and stage III in 598 (39.2%). With the eighth edition, 774 patients (50.8%) migrated to a different stage; 183 (12.0%) were reclassified to a lower stage and 591 (38.8%) to a higher stage. Median overall survival for the entire cohort was 24.4 months (95% CI, 23.4-26.2 months). On Kaplan-Meier analysis, 5-year survival rates changed from 38.2% for patients in stage IA, 34.7% in IB, 35.3% in IIA, 16.5% in IIB, and 0% in stage III (log-rank P < .001) via classification with the seventh edition to 39.2% for patients in stage IA, 33.9% in IB, 27.6% in IIA, 21.0% in IIB, and 10.8% in stage III (log-rank P < .001) with the eighth edition. For patients who were node negative, the T stage was not associated with prognostication of survival in either edition. In the eighth edition, the N stage was associated with 5-year survival rates of 35.6% in N0, 20.8% in N1, and 10.9% in N2 (log-rank P < .001). The C statistic improved from 0.55 (95% CI, 0.53-0.57) for the seventh edition to 0.57 (95% CI, 0.55-0.60) for the eighth edition.Conclusions and relevanceThe eighth edition of the TNM staging system demonstrated a more equal distribution among stages and a modestly increased prognostic accuracy in patients with resected pancreatic ductal adenocarcinoma compared with the seventh edition. The revised T stage remains poorly associated with survival, whereas the revised N stage is highly prognostic.
| S-EPMC6583013 | biostudies-literature
Project description:Importance:The American Joint Committee on Cancer (AJCC) eighth edition staging manual introduced a new prognostic stage for breast cancer incorporating biologic factors in addition to traditional anatomic factors. Objective:To perform a validation study of the AJCC eighth edition prognostic stage in a single-institution cohort and a large population database. Design, Setting, and Participants:Patients with breast cancer treated with surgery as an initial intervention were identified in a prospective institutional database from The University of Texas MD Anderson Cancer Center and the California Cancer Registry. Vital status data were complete through December 31, 2016, in The University of Texas MD Anderson cohort and through December 31, 2014, in the California Cancer Registry cohort. Patients receiving neoadjuvant systemic therapy, those with inflammatory or rare breast cancers, and those with unknown clinicopathologic factors were excluded. Factors evaluated included T, N, and M categories and tumor grade, as well as estrogen receptor, progesterone receptor, and HER2 status. Main Outcomes and Measures:Disease-specific survival was calculated by the Kaplan-Meier method. The Harrell concordance index (C index) was used to quantify models' predictive performance, and the Akaike information criterion (AIC) was used to compare model fits. Results:A total of 3327 patients with stage I to IIIC breast cancer treated between 2007 and 2013 at The University of Texas MD Anderson Cancer Center (median follow-up of 5 years) with complete clinicopathologic data were identified. Compared with the AJCC anatomic stage, the prognostic stage upstaged 29.5% of patients and downstaged 28.1%. The prognostic stage (C index, 0.8357 and AIC, 816.8) provided more accurate stratification with respect to disease-specific survival than the anatomic stage (C index, 0.737 and AIC, 1039.8) (P?<?.001 for the C index). A total of 54?727 patients with stage I to IV breast cancer treated between 2005 and 2009 were identified in the California Cancer Registry (median follow-up of 7 years). The prognostic stage upstaged 31.0% of patients and downstaged 20.6%. The prognostic stage (C index, 0.8426 and AIC, 80?661.68) performed better than the anatomic stage (C index, 0.8097 and AIC, 81?577.89) (P?<?.001 for the C index). Conclusions and Relevance:The prognostic stage provided more accurate prognostic information than the anatomic stage alone in both a single-institution cohort and a large population database, thereby supporting its use in breast cancer staging.
| S-EPMC5838705 | biostudies-literature
Project description: Not available
| S-EPMC8047944 | biostudies-literature
Project description: Not available
| S-EPMC8421196 | biostudies-literature
Project description:BackgroundThe American Joint Committee on Cancer (AJCC) maintains that the eighth edition of its Staging Manual (AJCC8) has improved accuracy compared with the seventh (AJCC7). However, there are concerns that implementation may disrupt analysis of active clinical trials for stage III patients. We used an independent cohort of melanoma patients to test the extent to which AJCC8 has improved prognostic accuracy compared with AJCC7.MethodsWe analyzed a cohort of 1315 prospectively enrolled patients. We assessed primary tumor and nodal classification of stage I-III patients using AJCC7 and AJCC8 to assign disease stages at diagnosis. We compared recurrence-free (RFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. We then compared concordance indices of discriminatory prognostic ability and area under the curve of 5-year survival to predict RFS and OS. All statistical tests were two-sided.ResultsStage IIC patients continued to have worse outcomes than stage IIIA patients, with a 5-year RFS of 26.5% (95% confidence interval [CI]?=?12.8% to 55.1%) vs 56.0% (95% CI?=?37.0% to 84.7%) by AJCC8 (P?=?.002). For stage I, removing mitotic index as a T classification factor decreased its prognostic value, although not statistically significantly (RFS concordance index [C-index]?=?0.63, 95% CI?=?0.56 to 0.69; to 0.56, 95% CI?=?0.49 to 0.63, P?=?.07; OS C-index?=?0.48, 95% CI?=?0.38 to 0.58; to 0.48, 95% CI?=?0.41 to 0.56, P?=?.90). For stage II, prognostication remained constant (RFS C-index?=?0.65, 95% CI?=?0.57 to 0.72; OS C-index?=?0.61, 95% CI?=?0.50 to 0.72), and for stage III, AJCC8 yielded statistically significantly enhanced prognostication for RFS (C-index?=?0.65, 95% CI?=?0.60 to 0.70; to 0.70, 95% CI?=?0.66 to 0.75, P?=?.01).ConclusionsCompared with AJCC7, we demonstrate that AJCC8 enables more accurate prognosis for patients with stage III melanoma. Restaging a large cohort of patients can enhance the analysis of active clinical trials.
| S-EPMC7492758 | biostudies-literature