Analysis of homologous recombination DNA repair gene mutation status in patients with metastatic small cell lung cancer treated with cediranib and olaparib on NCI 9881 study.
Bibliographic record
Abstract
8563 Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of homologous recombination DNA repair (HRR) genes and increases sensitivity of tumors to a poly-(ADP-ribose) polymerase (PARP) inhibitor in vitro and in vivo models of breast and ovarian cancer. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumor with a deleterious mutation in HRR genes. We hypothesized that cediranib induces HRR deficient phenotype by suppressing expression of HRR genes and cediranib and olaparib combination (C+O) results in an objectives response in patients with HRR proficient (HRP) advanced solid tumors. Herein, we report the biomarker data from analyses of targeted sequencing of 84 DNA repair (DR) genes with BROCA-HR assay in patients with metastatic small cell lung cancer (mSCLC). Methods: This multi-institutional phase 2 trial enrolled patients with mSCLC previously treated with a platinum-based chemotherapy. Patients received cediranib 30mg orally (po) daily plus olaparib 200mg po twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. A tumor biopsy was obtained from the patients with safely accessible metastatic tumor. HRR deficiency (HRD) was defined as presence of a deleterious mutation in any of the 10 key HRR-related genes per BROCA-HR assay including: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12 (somatic mutations only), NBN, PALB2, RAD51C, or RAD51D. Otherwise, the tumors were defined as HRR proficiency (HRP). Results: A total of 25 patients with SCLC received the study treatment. Fourteen patients had available tumor biopsy samples and/or germline available for BROCA-HR. One patient (7%) was determined to have a HRD tumor by a presence of PALB2 mutation. This patient had stable disease as a best overall response but came off study due to unequivocal clinical progression. Thirteen patients (93%) had a HRP tumor. Six of these (46%) patients had PR. Median PFS in patients with HPR tumors was 122 days. The most common gene alterations detected by BROCA-HR assay was TP53 (93%) and RB1 (79%). Other DR gene alterations noted from our study samples were MRE11, CKD12 PALB2, ERCC4, FANCB, and BAP1. Conclusions: HRD was infrequent in our mSCLC samples. C+O resulted in objective responses in 46% of mSCLC patients with HRP tumors. Mutations in TP53 and RB1 were the most common gene alterations. Further investigation in warranted to confirm this observation. Clinical trial information: NCT02498613.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.000 | 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".