Abstract 770: Exploitation of treatment induced tumor lysis to enhance sensitivity of ctDNA analysis: a first-in-human pilot study
Bibliographic record
Abstract
Abstract Background: Blood based liquid biopsies examining circulating tumour DNA (ctDNA) have increasing applications in non-small cell lung cancer (NSCLC). Limitations in sensitivity, especially in patients with limited disease burden, remains a barrier to ctDNA replacing tissue-based testing. There is a paucity of data regarding the optimal time to measure ctDNA, specifically the dynamics of ctDNA levels in the hours to days following a new and effective treatment. We hypothesize that chemotherapy or radiation will yield an increased abundance of ctDNA in plasma by inducing tumor lysis, allowing for the detection of genetic alterations that were occult in baseline testing. Methods: Two prospective cohorts of twenty patients (pts) with stage III/IV NSCLC were enrolled. Cohort 1 (C1) contained patients starting the first cycle of platinum doublet chemoradiation (C1a, n=10) or the first cycle of platinum doublet cytotoxic chemotherapy ± immunotherapy without concurrent radiation (C1b, n=10). Cohort 2 (C2) contained patients receiving palliative radiation. Consenting patients provided baseline samples, the first ≤ 14 days prior to starting treatment and one immediately prior to treatment. In C1, subsequent samples were collected (A) 2-3, (B) 4-6, (C) 18-72 and (D) 42-96 hours post initiation of chemotherapy. Pts in C2 had samples collected immediately prior to radiotherapy fractions 2, 3, and 4. Samples were analyzed for ctDNA using the 36-gene amplicon-based NGS Inivata InVisionFirst®-Lung assay. Results: Complete results were available for the first 28 of 40 enrolled pts, C1a - 8 pts, C1b - 8 pts, C2 - 12 pts. Detectable ctDNA was present at baseline in 21 pts (75%), 4 additional pts (14.3%) had detectable ctDNA in post treatment samples (C1a - 2pts, C1b - 1pt, C2 - 1pt). Three of the patients with detectable ctDNA at baseline (10.7%) had new genetic alterations detected in post treatment samples. A total of 7/28 pts (25%) had new genetic alterations detected in the post treatment samples. Mutant molecule numbers increased with treatment in 19 of 25 (76%) pts with detectable ctDNA, C1 - 11 of 15 pts (73.3%) and C2 - 8 of 10 pts (80%). ctDNA levels peaked a median of 2.2 hours (interquartile range (IQR): 1.5 - 2.9 hours) after the initiation of chemotherapy and a median of 1 day (IQR: 1-2 days) after radiation was commenced. The percentage increase in ctDNA levels was a median of 39.3% (IQR: -20.5 to +112.8%) in C1, with median increases of 22.0% and 39.3% in C1a and C1b, respectively. C2 had a median increase of 81.9% (IQR: 0 to +161.5%). Conclusion: ctDNA levels increase in the hours to days after starting a new treatment. ctDNA testing in the acute post treatment phase can yield results that were not evident in pretreatment testing. Application of this principle could improve ctDNA utility as an alternate to tissue-based testing and/or improve sensitivity for the detection of treatment-resistant clones. Citation Format: Daniel Breadner, Mark David Vincent, Rohann Correa, Morgan Black, Andrew Warner, Melody Qu, Diane Logan, Michael Sanatani, Jawaid Younus, Brian Yaremko, George Rodrigues, Phillip Blanchette, Joanna Laba, Edward Yu, David Goodale, Lori Lowes, Vasudeva Bhat, Albert Gratton, James Sinfield, Susan Archer, Clive Morris, Emma Green, Greg Jones, Alison Allan, David Palma, Jacques Raphael. Exploitation of treatment induced tumor lysis to enhance sensitivity of ctDNA analysis: a first-in-human pilot study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 770.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".