Abstract A123: Circulating tumor DNA (ctDNA) genomic and epigenomic profiling (GuardantINFINITY) for diagnosis of DNA damage repair (DDR) loss of function (LOF) and response monitoring in the TRESR and ATTACC trials
Bibliographic record
Abstract
Abstract Background First-generation panel-based ctDNA sequencing is widely used to identify actionable genomic alterations, but limited coverage and sensitivity hinder broader clinical utility, especially in cancers driven by DDR LOF. Further, tissue-free, variant-based approaches for response monitoring have several challenges, including the limited number and low variant allele frequencies (VAF) of monitorable variants and contamination from non-tumor-derived sources (eg, clonal hematopoiesis [CH]). Newer panels may address these challenges with broader coverage, optimized bioinformatics, and the integration of epigenetic analysis for molecular response (MR). Methods Blood samples were collected from 2 phase 1 studies (TRESR; NCT04497116 and ATTACC; NCT04972110) of the ataxia telangiectasia and Rad3-related (ATR) inhibitor camonsertib in combination with gemcitabine or PARPi (talazoparib, niraparib, or olaparib). Cell-free DNA and PBMCs were sequenced using the combined genomic (>800 genes) and methylation (15Mb) GuardantINFINITY platform. Results The study included 117 patients (pts) with ovarian (n=29), breast (n=18), pancreatic (n=18), prostate (n=16) and other (n=36) cancers, enrolled with pathogenic alterations in BRCA2 (n=41), ATM (n=32), BRCA1 (n=23), PALB2 (n=8) and other genes (n=13). Enrollment alterations identified by local NGS were confirmed in 83% (94/114) of pts excluding 3 enrolled by protein loss. 50% (5/10) of complex alterations (large deletions or rearrangements) with sufficient circulating tumor fraction (cTF) were confirmed. Among pts with breast, ovarian, prostate, or pancreatic cancers previously treated with PARPi and/or platinum and harboring BRCA1/2 or PALB2 alterations, reversions were detected in 31% (17/54), with 6 pts reverted by 1 or more large intragenic deletions. A CRC pt with a clonal biallelic sATM alteration had 2 missense reversions in cis, an event not previously reported to occur in ATM. In pts with matched PBMCs, confirmed CH alterations were detected in 79% (44/56), including 59% (33/56) with at least 1 CH variant over 1% VAF. 106 pts had evaluable paired samples at baseline and on-treatment (taken between 2-12 weeks on-treatment [median, 3 weeks]). Using mVAF of the Guardant360 74-gene subset or methylation-based cTF, 72% or 86% were monitorable, respectively. In the subset of evaluable pts with matched PBMC sequencing (n=54), after PBMC-informed CH filtering, monitorability was reduced from 69% to 61% between G360 mVAF and G360 mVAF-CH, respectively. PBMC-informed CH filtering improved the correlation between variant-based and methylation-based monitoring (G360 mVAF, R=0.89, p=1.1e-11 vs G360 mVAF-CH, R=0.95, p=3e-15; Pearson correlation). Correlation of ctDNA monitoring metrics with clinical outcomes is ongoing. Conclusions Broad panel coverage enabled accurate diagnosis of complex DDR LOF and detection of reversion alterations. Methylation-based cTF allows monitoring of most pts in this cohort and consistent with previous observations may avoid signal contamination from CH for robust MR analysis. Citation Format: Ezra Rosen, Joseph D Schonhoft, Ian M Silverman, Arielle Yablonovitch, Sunantha Sethuraman, Parham Nejad, Danielle Ulanet, Julia Yang, Insil Kim, Kezhen Fei, Yi Xu, Errin Lagow, Shile Zhang, Mingyang Cai, Maria Koehler, Benedito A Carneiro, Stephanie Lheureux, Michael Cecchini, Benjamin Herzberg, Jorge S Reis-Filho, Victoria Rimkunas, Timothy A Yap. Circulating tumor DNA (ctDNA) genomic and epigenomic profiling (GuardantINFINITY) for diagnosis of DNA damage repair (DDR) loss of function (LOF) and response monitoring in the TRESR and ATTACC trials [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A123.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| 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) | 0.000 | 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 teacher head, 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".