Discovery of smoking-related biomarkers for advanced treatment in non-small cell lung cancer (NSCLC)

Abstract

Lung cancer is one of the most diagnosed cancers and the leading cause of cancer death globally. Up to 60% of the non-small cell lung cancer lung (NSCLC) cancer patients are diagnosed with distant metastases with a poor five-year survival of only 5%. Despite the remarkable therapeutic benefits from targeted therapy and immune checkpoint inhibitor (ICI), only a subset of patients obtains druggable oncogenic drivers and has durable clinical response. Therefore, it is imperative to identify readily obtainable biomarkers that are available in majority of the patients to make prompt treatment decisions and to benefit more patients.

In chapter 1, we first clarified the dose-dependent association between quantitative smoking history, namely smoking pack-years and smoking-free interval, and oncogenic drivers KRAS and EGFR mutations and their subtypes in 931 advanced NSCLC. Doubling smoking pack-year is associated with increased likelihood of obtaining KRAS mutations while an inverse relationship with EGFR mutations was observed. Doubling smoking-free interval is only significantly associated with increased likelihood of EGFR mutations, suggesting KRAS mutations as an early and permanent event. We further quantified the dose-response relationship between detailed smoking history and TMB - it accumulates with smoking pack-years and declines with smoking-free interval, revealing the potential of smoking history being a surrogate for TMB.

In chapter 2, we evaluated the predictive effect of quantitative smoking pack-years on the efficacy – objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) of ICI monotherapy in 644 metastatic NSCLC adjusting for potential confounders. Smoking pack-year has a significant positive effect on ORR, PFS and OS independent of PD-L1 tumor proportional scores (TPS). To validate the clinical utility of smoking pack-years on ICI efficacy, we constructed and compared five prediction models incorporating baseline characteristics and different predictive biomarkers for all three outcomes. Predictive models incorporating smoking pack-years and PD-L1 TPS yielded additional information compared to the baseline model and achieved similar model performance compared to using TMB and PD-L1 TPS. Smoking pack-years may serve as an independent surrogate to TMB on ICI efficacy in metastatic NSCLC.

In chapter 3, we discovered the most predominant oncogene KRAS mutation in 1948 NSCLC patients with paired germline and somatic mutation. We first comprehensively characterized the overall genomic profiles by KRAS subtypes in 805 NSCLC patients with somatic genome measured by clinically targeted next generation sequencing OncoPanel. Distinct different mutational landscapes including top mutated genes, mutational signatures, co-mutation/mutually exclusive patterns, TMB and copy number alterations were observed among KRAS subtypes. KRASG12C and KRASG12V were enriched in patients who had a history of smoking, while a higher proportion of never smoker patients was observed in KRASG12D. KRASG12C and KRASG12V had significantly higher median TMB and lower level of copy number alterations, suggesting potential explanations of improved clinical outcomes of ICI observed in patients with these alleles. Genome-wide association studies of multiple KRAS mutation outcomes were conducted at single nucleotide polymorphism (SNP), gene and pathway levels in 1699 patients with non-squamous cell carcinoma. Genetic determinants of KRAS mutations might be polygenic, including immune-related gene MILR1, and energy transportation and metabolic pathways. Understanding the genetic underpinnings may help elucidate the mechanism of KRAS lung tumorigenesis, facilitate therapeutic development and offer insight into treatment strategy in certain molecularly defined KRAS non-squamous cell carcinoma.