Genomic markers of panitumumab resistance including ERBB2/HER2 in a phase II study of <i>KRAS</i> wild-type (wt) metastatic colorectal cancer (mCRC).
Bibliographic record
Abstract
646 Background: Epidermal Growth Factor Receptor Inhibitors (EGFRi) are effective agents in the treatment of mCRC but up to one third of KRAS wt tumors do not respond. The primary objective was to identify a gene expression signature associated with primary resistance to panitumumab (Pmab) monotherapy and identify genomic markers associated with resistance. Methods: Patients with previously treated codon 12/13 KRAS wt mCRC were administered Pmab 6mg/kg IV q2weeks in a prospective phase II study. The primary endpoint was tumor response by RECIST and patients with progressive disease 8 weeks after initial Pmab were classified as resistant. Gene expression analysis was performed using a Nanostring-based assay with candidate genes implied in EGFRi resistance expression patterns. Differentially expressed genes were identified by Significance Analysis of Microarrays. Further interrogation of the HER2 signaling pathway was performed by immunohistochemistry and in situ hybridization. Illumina-based targeted resequencing was conducted on 20 cancer-implicated genes. Results: Of 34 patients treated with Pmab, 11 (32%) had progressive disease at 8 weeks and were classified Pmab resistant. A 5-gene expression signature was significantly associated with Pmab resistance (p = 0.001), including ERBB2, MLPH, IRX3, c11orf9, and KLK6. HER2 protein was overexpressed in 4/11 resistant and 0/21 responding cases (p = 0.035). Two (2) resistant tumors had ERBB2 gene amplification only, and one demonstrated both ERBB2 amplification and mutation. A non-codon 12/13 RAS mutation occurred in one treatment-resistant patient and was mutually exclusive with ERBB2 mutation, amplification, or HER2 overexpression. Four BRAF mutations were detected, two occurring in resistant patients. Conclusions: In this prospective study, a 5-gene signature including ERBB2 was associated with primary resistance to single agent Pmab. A subgroup of patients had evidence of aberrant HER2/ERBB2 signaling by protein over-expression and gene amplification. Results suggest a significant portion of KRAS wt tumors unresponsive to EGFRi may be identified by gene signature analysis. Clinical trial information: NCT00853931.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 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".