Germline DNA repair mutations in metastatic castration-resistant prostate cancer: Therapy response and applicability of circulating tumor DNA.
Bibliographic record
Abstract
140 Background: Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to Androgen Receptor (AR) targeted therapy. The aim of this study was to determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies, and secondly to establish whether biallelic DNA-repair gene loss is detectable in matched circulating tumor DNA (ctDNA). Methods: We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In affected patients, matched plasma ctDNA was also sequenced. Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis. Results: 24/319 (7.5%) patients had deleterious germline mutations, with BRCA2 (n = 16), PALB2 (n = 2) and CDK12 (n = 2) being the most frequent. Patients (n = 22) with mutations in genes linked to homologous recombination were heterogeneous at initial presentation but after starting ADT progressed to mCRPC with a median time of 12.3 months (95% CI 5.1-18.4). The median time to progression on first and second line AR-targeted therapy in the mCRPC setting was 3.2 months (95% CI 1.9-4.4) and 1.0 month (95% CI 0.8-1.1), respectively. For patients receiving chemotherapy as their initial therapy for mCRPC (n = 8) the median PFS was 7.5 months (95% CI 6.5-8.2). 10/11 evaluable patients with germline BRCA2 mutations had somatic deletion of the intact allele in ctDNA. Conclusions: mCRPC patients with germline DNA repair defects exhibit transient responses to AR-targeted therapy. Biallelic gene loss was robustly detected in ctDNA suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy.
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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 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".