Abstract
IntroductionPemetrexed combined with platinum complexes can be used as first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC), however, the efficacy and safety is varying from individuals. There is a need to better understand the genetic variations associated with platinum response.Materials and MethodsWe performed next-generation sequencing (NGS) based on BGI Oseq-ctDNA panel to analyze 98 longitudinal plasma samples from 32 lung adenocarcinoma patients during platinum-based chemotherapy, and a bioinformatic pipeline was developed to detect point mutations.ResultsWe found that mutation burden was decreased after chemotherapy, which reflected chemotherapy sensitivity, especially the frequency of C>G and C>A substitutions. Moreover, neoplastic cells carrying a specific set of somatic mutations, such as EGFR(L858R), KRAS (p.G12C) were obviously correlated with platinum treatment. In addition, the MAPK pathway was found to have a pivotal role in NSCLC and platinum based response. Finally, we found that smokers benefit less from platinum-based chemotherapy.ConclusionsCollectively, this work described the dynamic changes of ctDNA mutation status during platinum-based treatment, which may contribute to advanced lung adenocarcinoma patients stratification and precision treatment.
Highlights
Pemetrexed combined with platinum complexes can be used as first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC), the efficacy and safety is varying from individuals
When we explore the different spectra following chemotherapy, we found that C>G mutations were significantly decreased during platinum treatment, no matter total SNVs (p = 0.039; Fig. 2c) or variant allele frequency (VAF) (p < 0.01; Fig. 2c), especially in patients with objective response (PR or SDa) (p = 0.029; Additional file 5: Figure S2C), suggesting a significant correction between C>G mutations and platinum-based response
We found that VAFs of some driver mutations decreased following platinum treatment, and some hotspot mutations, such as epidermal growth factor receptor (EGFR)(L858R), KRAS (p.G12C), were still present post chemotherapy(Fig. 4c)
Summary
Pemetrexed combined with platinum complexes can be used as first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC), the efficacy and safety is varying from individuals. Due to the little information about biomarkers to evaluate the chemotherapy response, it is clinically important to find out novel predictive markers for treatment response and survival after platinum-based chemotherapy in patients with NSCLC. Blood is easier to obtain and less expensive It can deliver a more comprehensive genomic profiling because tumor either in first-site or metastases can shed genomic DNA information to the bloodstream [8, 9]. Liquid biopsy via circulating tumor DNA (ctDNA) in blood provides an attractive alternative for long terms evaluation and prediction for lung cancer patients and ctDNA level may provide a more comprehensive picture of the lung cancer, because markers spreading in the blood may contain cancer-associated materials from many diseases site in the body organs
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