Associations between tumor mutations in cfDNA and survival in non-small cell lung cancer

Anine Larsen Ottestad,Hong Yan Dai,Tarje Onsøien Halvorsen,Elisabeth Fritzke Emdal,Sissel Gyrid Freim Wahl,Bjørn Henning Grønberg

doi:10.1016/j.ctarc.2021.100471

Abstract

IntroductionStudies have indicated that detection of mutated KRAS or EGFR in circulating tumor DNA (ctDNA) from pre-treatment plasma samples is a negative prognostic factor for non-small cell lung cancer (NSCLC) patients. This study aims to investigate whether this is the case also for NSCLC patients with other tumor mutations. MethodsTumor tissue DNA from 107 NSCLC patients was sequenced and corresponding pre-treatment plasma samples were analyzed using a limited target next-generation sequencing approach validated in this study. Patients without detected mutations in tumor samples were excluded from further analyses. ResultsMutations were detected in tumor samples from 71 patients. Median age was 68 years, 51% were female, and 88% were current/former smokers, 91% had adenocarcinoma, 4% had squamous cell carcinoma and 6% had other NSCLC. The distribution between stage I, II, III and IV was 33%, 8%, 30%, and 29%, respectively. Between one and three tumor mutation(s) were detected in ctDNA from corresponding plasma samples. Patients with detected ctDNA had shorter PFS (9.6 vs. 41.3 months, HR: 2.9, 95% CI: 1.6–5.2, p = 0.0003) and OS (13.6 vs. 115.0 months, HR: 4.0, 95% CI: 2.1–7.6, p = 0.00002) than patients without detected ctDNA. ctDNA remained a significant negative prognostic factor for OS (HR: 2.5, 95% CI: 1.1-5.7, p=0.0327), but not PFS, in the multivariable analyses adjusting for baseline patient and disease characteristics including stage of disease. ConclusionsThis study adds further evidence supporting that detectable tumor mutations in cfDNA is associated with a worse prognosis in NSCLC harboring a variety of tumor mutations.

Highlights

Studies have indicated that detection of mutated KRAS or EGFR in circulating tumor DNA from pre-treatment plasma samples is a negative prognostic factor for non-small cell lung cancer (NSCLC) pa tients
We found that detection of circulating tumor DNA (ctDNA) in plasma was significantly associated with shorter progression-free survival (PFS) and overall survival (OS) in the univariable analyses, and ctDNA remained a signifi cant negative prognostic factor for OS in the multivariable analyses
Pavan et al found that TP53 mutations in plasma detected by Next-generation sequencing (NGS), the most commonly detected mutation in ctDNA in our cohort, negatively affected survival both in NSCLC patients who received im mune checkpoint inhibitor therapy and those who did not [13]

Summary

Introduction

Studies have indicated that detection of mutated KRAS or EGFR in circulating tumor DNA (ctDNA) from pre-treatment plasma samples is a negative prognostic factor for non-small cell lung cancer (NSCLC) pa tients. Methods: Tumor tissue DNA from 107 NSCLC patients was sequenced and corresponding pre-treatment plasma samples were analyzed using a limited target next-generation sequencing approach validated in this study. Between one and three tumor mutation(s) were detected in ctDNA from corresponding plasma samples. Studies indicate that detection of ctDNA by identification of tumor mutations in plasma collected before treatment is a negative prognostic factor for patients with lung adenocarcinoma [5,6,7]. CtDNA accounts for a minority of total cell-free DNA (cfDNA) found in plasma and requires sensitive methods for its detection [11].

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