Untapped Potential of Poly(ADP-Ribose) Polymerase Inhibitors: Lessons Learned From the Real-World Clinical Homologous Recombination Repair Mutation Testing
Bibliographic record
Abstract
Background: Testing for homologous recombination deficiency (HRD) mutations is pivotal to assess individual risk, to proact preventive measures in healthy carriers and to tailor treatments for cancer patients. Increasing prominence of poly(ADP-ribose) polymerase (PARP) inhibitors with remarkable impact on molecular-selected patient survival across diverse nosologies, ingrains testing for BRCA genes and beyond in clinical practice. Nevertheless, testing strategies remain a question of debate. While several pathogenic BRCA1/2 gene variants have been described as founder pathogenic mutations frequently found in patients from Russia, other homologous recombination repair (HRR) genes have not been sufficiently explored. In this study, we present real-world data of routine HRR gene testing in Russia. Methods: We evaluated clinical and sequencing data from cancer patients who had germline/somatic next-generation sequencing (NGS) HRR gene testing in Russia (BRCA1/2/ATM/CHEK2, or 15 HRR genes). The primary objectives of this study were to evaluate the frequency of BRCA1/2 and non-BRCA gene mutations in real-world unselected patients from Russia, and to determine whether testing beyond BRCA1/2 is feasible. Results: Data of 2,032 patients were collected from February 2021 to February 2023. Most had breast (n = 715, 35.2%), ovarian (n = 259, 12.7%), pancreatic (n = 85, 4.2%), or prostate cancer (n = 58, 2.9%). We observed 586 variants of uncertain significance (VUS) and 372 deleterious variants (DVs) across 487 patients, with 17.6% HRR-mutation positivity. HRR testing identified 120 (11.8%) BRCA1/2-positive, and 172 (16.9%) HRR-positive patients. With 51 DVs identified in 242 formalin-fixed paraffin-embedded (FFPE), testing for variant origin clarification was required in one case (0.4%). Most BRCA1/2 germline variants were DV (121 DVs, 26 VUS); in non-BRCA1/2 genes, VUS were ubiquitous (53 DVs, 132 VUS). In silico prediction identified additional 4.9% HRR and 1.2% BRCA1/2/ATM/CHEK2 mutation patients. Conclusions: Our study represents one of the first reports about the incidence of DV and VUS in HRR genes, including genes beyond BRCA1/2, identified in cancer patients from Russia, assessed by NGS. In silico predictions of the observed HRR gene variants suggest that non-BRCA gene testing is likely to result in higher frequency of patients who are candidates for PARP inhibitor therapy. Continuing sequencing efforts should clarify interpretation of frequently observed non-BRCA VUS. World J Oncol. 2024;15(4):562-578 doi: https://doi.org/10.14740/wjon1820
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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 | 0.018 | 0.030 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 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".