Circulating tumor (ct)-DNA alterations in metastatic castration-resistant prostate cancer (mCRPC): Association with outcomes and evolution with therapy.
Bibliographic record
Abstract
149 Background: Cell-free ctDNA may be prognostic and evolve following therapy. We report ctDNA profiling of patients (pts) with mCRPC and their association with clinical outcomes and evolution with therapy. Methods: Pts with mCRPC that underwent baseline ctDNA analysis for potentially actionable alterations using Guardant360 before new systemic therapy were identified. Data were requested for clinical factors, current and prior therapy, TTF (time to failure) and survival. A 70-gene cfDNA next generation sequencing panel from a CLIA-licensed, CAP-accredited laboratory (Guardant Health, Inc.) offers complete exon sequencing for 29 genes, critical exons in 39 genes and amplifications (16 genes), fusions (6 genes) and indels (3 genes) harvested from 10 mL of peripheral blood. Alterations were reported and association of alterations with outcomes and prior therapy was examined. Results: Of 514 with confirmed mCRPC, 482 (94%) had ≥ 1 ctDNA alteration. The median age was 70 years (range 39-91). The most common recurrent somatic mutations were in TP53 (36% of patients), AR (22%), APC (10%), NF1 (9%), EGFR, CTNNB1 and ARID1A (6% each) and BRCA1, BRCA2 and PIK3CA (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%) and BRAF (18%). Clinical outcomes were available for 163 pts, of whom 46 (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations was associated with shorter TTF (HR: 1.05, p = 0.026). AR alterations had a trend for shorter TTF (HR: 1.42, p = 0.053) and survival (HR: 2.51, p = 0.09). Pts who received prior therapy had new alterations in AR (56% vs. 37%, p = 0.028) compared to untreated pts. Serial ctDNA profiling of 64 pts revealed the evolution of alterations in AR, BRCA1 and BRCA2 following therapy. Conclusions: ctDNA was frequently detected in patients with mCRPC, and alterations appear similar to tumor tissue alterations. A higher number of overall gene alterations and AR alterations appeared associated with poor clinical outcomes and new AR and BRCA alterations appeared following therapy. These data suggest that developing salvage agents targeting AR alterations and PARP inhibitors hold promise.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".