Homologous recombination and DNA repair mutations in patients treated with carboplatin and nab-paclitaxel for metastatic non-small cell lung cancer

Abstract

Objectives: Chemotherapy remains a cornerstone treatment in non-small cell lung cancer either in combination with checkpoint inhibitors or as subsequent therapy. Identifying molecular predictors of response allows for optimal treatment selection. We performed genomic analysis on tumor samples of patients treated with carboplatin and nab-paclitaxel as part of a phase II trial to evaluate the prognostic and predictive value of mutations in DNA repair pathway in patients treated with this regimen.

Materials and methods: Next-generation sequencing libraries were produced using a capture-based targeted panel covering the coding exons of 278 genes on patients treated on clinical trial NCT00729612. Overall survival (OS) and progression-free survival (PFS) were assessed as part of the clinical outcomes and correlated with mutation analysis.

Results: Of 63 patients enrolled, 25 patients had sufficient and acceptable DNA isolated from archival tumor samples for targeted sequencing. The most commonly altered pathways included DNA repair (DR) including Fanconi anemia and homologous recombination, JAK-STAT signaling, IGF-1, mTOR, and MAPK-ERK. Four patients with mutations in homologous recombination mutations had a shorter PFS (hazard ratio [HR] = 4.54, 95% CI 1.2, 17.1, p = 0.026) and OS (HR = 6.3, 95% CI 1.8, 21.3, p = 0.003).

Conclusion: In this analysis of patients with predominantly squamous cell non-small cell lung cancer treated with carboplatin and nab-paclitaxel in a phase II trial, patients with mutations in homologous recombination pathways had shorter overall and progression-free survival. Validation on additional datasets of patients treated with platinum-based chemotherapy and immunotherapy combinations is warranted.

Keywords: Biomarker; Chemotherapy; DNA repair; Homologous recombination; Non-small cell lung cancer.

Copyright © 2019 Elsevier B.V. All rights reserved.

Figures

Fig. 1.

Waterfall plot: Maximum percent change from baseline in the sum of the diameters of target lesions in 18 evaluable patients with squamous cell histology, with patients’ tumors harboring DNA repair mutations present indicated in red. Patients whose tumors possess DNA repair mutations appeared to have less clinical benefit from carboplatin and nab-paclitaxel, although this did not meet statistical significance. Red bars indicate DNA repair mutations are present, asterisk indicates homologous repair mutations.

Fig. 2.

Kaplan Meier curves for progression free survival (A, B) and overall survival (C, D) within the 25 patient GEP. No statistically significant difference in PFS (A) or OS (C) was observed in patients with tumors possessing mutations in DNA repair pathways. However, patients whose tumors have mutations in the homologous recombination repair pathway had a shorter PFS (B, HR = 4.54, 95% CI 1.2, 17.1, p = 0.026; log-rank p = 0.014), and OS (D, HR = 6.3, 95% CI 1.8, 21.3, p = 0.003; log-rank p = 0.0008).

Fig. 3.

Kaplan Meier curves for progression free survival (A, B) and overall survival (C, D) for only those patients within the GEP with squamous cell histology. No statistically significant difference in PFS (A) or OS (C) was observed in patients with tumors possessing mutations in DNA repair pathways. However, patients whose tumors have mutations in the homologous recombination repair pathway had a shorter OS (D, HR 4.2, 95% CI 1.1, 16.1, p = 0.035; log-rank p = 0.022) although the association with PFS was weaker (B, HR 4.2, 95% CI 1.0, 17.9, p = 0.05, log-rank p = 0.031).