Association between type and location of germline BRCA1/2 pathogenic or likely pathogenic variants with phenotype and prognosis in young patients with breast cancer: results from an international cohort study
Bibliographic record
Abstract
BACKGROUND: The clinical implications of specific pathogenic and likely pathogenic variant (LP/PV) types and locations in the BRCA1 orBRCA2 tumor-suppressor genes remain to be elucidated. PATIENTS AND METHODS: The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study that included BRCA carriers diagnosed with invasive breast cancer at the age of ≤40 years between January 2000 and December 2020. In this analysis, only patients with detailed available information on LP/PVs in the BRCA genes were included. Clinicopathological features and survival outcomes [disease-free survival (DFS) and overall survival (OS)] were investigated according to LP/PV type [insertion-deletion (indel) versus single-nucleotide variants versus copy number variations; truncating versus non-truncating LP/PVs; frameshift versus nonsense versus splicing versus missense LP/PVs] and location (exon involved and protein domain). RESULTS: Out of 5660 patients from 109 centers worldwide, 3294 were eligible for the present analysis (2080 BRCA1 and 1214 BRCA2). The distribution of LP/PV types showed no meaningful associations with baseline clinicopathological features. BRCA1 protein-truncating variants were associated with worse OS compared with non-truncating variants [hazard ratio (HR) 2.00, 95% confidence interval (CI) 1.17-3.41]. A similar, though non-significant, trend was observed for BRCA2. Missense variants were linked to better OS for both BRCA1 (HR 0.48, 95% CI 0.28-0.84) and BRCA2 carriers (HR 0.17, CI 0.03-0.96). Regarding variant location, BRCA1 LP/PVs outside exons 2, 10, and 19 were associated with improved OS. In BRCA2, LP/PVs located in exons 15-26 and other regions were linked to worse DFS compared with those in exon 10, with no significant differences in OS. CONCLUSIONS: This study advances our understanding of the influence of specific types of BRCA LP/PVs on breast cancer characteristics and outcomes. A deeper understanding of these variant-specific features will drive future research and support the development of tailored clinical strategies based on individual BRCA variant.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".