An increase in serum choline levels to predict progression-free survival (PFS) in patients (pts) with advanced cancers receiving pembrolizumab.
Bibliographic record
Abstract
3102 Background: Recent work from our laboratory demonstrated that T cell-derived acetylcholine induces vasodilation and increases T cell migration to infected tissues in response to viral infection (Cox et al. Science 2019). Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study is the first reported attempt to correlate serum choline levels in patients (pts) with advanced solid tumors receiving pembrolizumab with treatment outcomes. Methods: Blood samples were collected pre-treatment in 106 pts treated with pembrolizumab 200 mg IV Q3W in the investigator-initiated INSPIRE study (NCT02644369). Of these, 81 pts had on-treatment blood samples collected at week 7 (pre-cycle 3). Serum choline was analyzed with an HPLC-tandem mass spectrometry assay. PD-L1 staining was performed in baseline tumor tissues using 22C3 antibody and scored using modified proportion score. Tumor mutational burden (TMB) was calculated based on number of nonsynonymous mutations detected using whole exome sequencing. Multivariable Cox models were used to assess the impact of choline on PFS and OS, while adjusting for cohort, PD-L1 expression and TMB. Results: This pan-cancer group of 106 pts (median age 55, 62% females) comprised of 5 cohorts: squamous cell carcinoma of the head and neck = 19 pts, triple negative breast cancer = 22, high grade serous ovarian cancer = 21, melanoma = 19, mixed solid tumors = 32. With a median follow-up of 11 months, the median PFS = 1.9 months and median OS = 13.9 months for the entire cohort. In univariable analysis adjusted by cohort, baseline serum choline levels in 106 pts did not correlate with PFS or OS. However, an increase in serum choline level at week 7 compared to pre-treatment (D choline) in 81 pts was significantly associated with a better PFS (aHR 0.49, 95% CI 0.28-0.85, p = 0.01), and a trend towards a better OS (aHR 0.57, 95% CI 0.32-1.03, p = 0.064). In multivariable analysis, D choline remains significantly associated with an improved PFS (p = 0.0087) after adjustment for cohort, PD-L1 and TMB. Conclusions: This is the first exploratory report of serum choline levels in pan-cancer pts receiving pembrolizumab. The association between improved PFS and D choline suggests a possible role for the cholingeric system in the regulation of antitumor immunity. Further nonclinical and clinical studies are required to validate this finding.
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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 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".