Abstract AP27: FEASIBILITY OF MONITORING RESPONSE TO THE PARP INHIBITOR RUCAPARIB WITH TARGETED DEEP SEQUENCING OF CIRCULATING TUMOR DNA (CTDNA) IN WOMEN WITH HIGH GRADE OVARIAN CARCINOMA ON THE ARIEL2 TRIAL
Bibliographic record
Abstract
Abstract 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 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 2 study of rucaparib for treatment of relapsed high-grade ovarian cancer (NCT01891344). MATERIAL AND METHODS: Plasma samples (n=65) from 18 patients were collected 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. Investigator-assessed clinical response rates were evaluated by RECIST v1.1 and GCIG CA-125 criteria. RESULTS: Concordant TP53 mutations were detected in tumor and ctDNA from plasma for all 18 patients. Median TP53 MAF at screening and cycle 1 day 1 was 5.1% (interquartile range: 1.1–17.5, n=16) and 3.8% (IQR: 0.68–10.3, n=16), respectively. Fourteen patients were evaluable for response measured by quantification of TP53 MAF 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 confirmed 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 a RECIST response. CONCLUSIONS: Noninvasive detection of TP53 mutations by TADS is feasible, using plasma samples collected from women with relapsed platinum-sensitive high-grade ovarian cancer participating in an international multicenter trial. Circulating tumor DNA is a promising biomarker for monitoring response to the PARP inhibitor rucaparib. We are now testing the pre-specified hypothesis that a >50% reduction in TP53 MAF between baseline and cycle 2 is predictive of response to rucaparib using 560 plasma samples from 139 ARIEL2 subjects. Updated results will be presented at the meeting. Citation Format: Anna Piskorz, Kevin K. Lin, James Morris, Elaina Mann, Amit Oza, Robert L. Coleman, David M. O'Malley, Michael Friedlander, Janiel M. Cragun, Ling Ma, Heidi Giordano, Nitzan Rosenfeld, Mitch Raponi, Iain A. McNeish, Elizabeth Swisher, James D. Brenton. FEASIBILITY OF MONITORING RESPONSE TO THE PARP INHIBITOR RUCAPARIB WITH TARGETED DEEP SEQUENCING OF CIRCULATING TUMOR DNA (CTDNA) IN WOMEN WITH HIGH GRADE OVARIAN CARCINOMA ON THE ARIEL2 TRIAL [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP27.
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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 | 0.004 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".