Feasibility of monitoring response to the PARP inhibitor rucaparib with targeted deep sequencing of circulating tumor DNA (ctDNA) in women with high-grade serous carcinoma on the ARIEL2 trial.
Bibliographic record
Abstract
5549 Background: TP53 mutations are present in > 97% cases of high-grade serous ovarian cancer (HGSOC). Detection of TP53 mutations in ctDNA extracted from plasma has the potential to monitor disease course and treatment response. We have developed targeted amplicon deep sequencing (TADS) to detect low frequency mutations throughout the TP53 gene in ctDNA. Rucaparib is a potent PARP inhibitor in development for treatment of tumors with HR pathway deficiency. We used TADS to assess TP53 mutant allele fraction (MAF) in ctDNA from patients in ARIEL2, a phase II study of rucaparib for treatment of relapsed HGSOC (NCT01891344). Methods: Plasma samples (n = 65) were collected from 18 patients during screening, on day 1 of each cycle, and at the end of rucaparib treatment. DNA extracted from plasma underwent TADS of TP53 (median depth 6916×). FFPE tumor specimens were profiled using an NGS-based assay with a targeted gene panel including TP53. Response was assessed by RECISTv1.1 and GCIG CA-125 criteria. Results: Concordant TP53 mutations were detected in tumor and ctDNA from plasma of all 18 patients. Median TP53 MAF at screening and cycle 1 day 1 was 5.1% (IQR 1.1–17.5, n = 16) and 3.8% (IQR 0.68–10.3, n = 16), respectively. 14 patients were evaluable for response between cycle 1 and 2 (missing sample n = 2; TP53 MAF < 0.5% n = 2). 7/9 patients with > 50% reduction of TP53 MAF in ctDNA at cycle 2 achieved a RECIST PR (see Table); this included 5/6 patients with either a germline or somatic mutation in BRCA1/BRCA2. No patients with < 50% reduction at cycle 2 (n = 5) achieved RECIST response. Conclusions: Noninvasive detection of TP53 mutations by TADS is feasible, using plasma samples collected from women with relapsed platinum-sensitive HGSOC participating in an international multicenter trial. ctDNA is a promising biomarker for monitoring response to the PARP inhibitor rucaparib and will now be explored in all ARIEL2 subjects. Clinical trial information: NCT01891344.% TP53 MAF change C1-C2 Mutation status* RECIST Response −100 gBRCA1 PR −100 WT PR −96 gBRCA2 PR −88 sBRCA2 PR −80 gBRCA1 PR −74 WT PR −74 WT SD −66 WT SD −54 gBRCA1 PR −39 WT PD −18 WT SD −11 WT PD +86 WT PD +188 sBRCA1 SD *g, germline; s, somatic
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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 | 0.003 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".