Feasibility and challenges of a biopsy-driven and biomarker discovery clinical trial in metastatic colorectal cancer to identify signatures of clinical resistance.
Bibliographic record
Abstract
e14108 Background: Biopsy-driven clinical trials are essential to develop personalized therapeutics, since many critical questions are best addressed in the tumor tissue being treated. In the metastatic setting, intrinsic resistance occurs even with the most advanced therapeutic agents, and even in responders, acquired resistance is inevitable. We have designed a prospective study to identify biomarkers of clinical resistance to standard first-line therapy (FOLFOX, XELOX or FOLFIRI in combination with bevacizumab in patients with metastatic CRC (NCT00984048). Methods: Eligible patients have confirmed metastatic CRC, measurable disease, and consent to three needle-core biopsies (NCBs) of a non-resectable liver metastasis before treatment and at resistance. This study is approved at several Quebec hospitals, demonstrating that Research Ethics Boards recognize the value of biopsy-driven studies without therapeutic benefit. Results: Forty patients agreed to partake in this multi-center trial and to provide NCBs. Of these, 5% were non-neoplastic, and 5% had neuroendocrine origins. Using standard operating procedures developed for this trial, we were able to both preserve morphology and obtain high-quality genomic material. We demonstrate that this material is suitable for DNA analysis (array comparative genomic, methylation profiling) and RNA analysis (gene expression profiling, splicing isoforms variants and micro RNA profiling). In parallel, we have generated resistant CRC cell lines resistant to the combination therapy to further study biomarkers of resistance. Challenges in obtaining a biopsy at time of progression include death, patient refusal, heterogeneity of tumors, metastasis at a different organ site, and time constraints for re-biopsy. No significant adverse events were reported related to the biopsy procedure. Conclusions: We conclude that obtaining serial liver NCBs are challenging, but safe and feasible in metastatic CRC patients with unresectable liver disease. This study will provide insight on the relevance of metastatic tissue in assessing signatures of clinical resistance.
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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 | 0.036 | 0.011 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.003 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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".