Utilizing comprehensive next-generation sequencing to determine the clinical significance of copy number variation in advanced/metastatic non-small cell lung cancer

Abstract

<p><strong>Background:</strong> Large population-based comprehensive tumor genomic profiling using next-generation sequencing (NGS) technology offers insight into the detection of copy number variation (CNV) in advanced/metastatic solid cancers. However, the significance and role of CNV in advanced-stage non-small cell lung cancer (NSCLC) is limited. In this analysis, we investigated the incidence and impact of CNV on patient outcomes. <strong>Methods:</strong> Patients were recruited as part of an ongoing real-world multicentre prospective NSCLC Precision Oncology Programme in Hong Kong. All patients underwent tissue and liquid NGS using Foundation One CDx and Foundation One Liquid CDx, respectively. Patients were classified into two groups based on CNV status: group 1 (CNV+) was defined as tumors with CNV reported; group 2 (CNV-) was defined as tumors with no CNV reported. The association of clinical factors with CNV was reported using Chi-square tests. The overall survival (OS) was calculated from the date of diagnosis of advanced-stage cancer to the date of death or the last follow-up date. Survival analysis was estimated using the Kaplan-Meier method with the log-rank test. <strong>Results:</strong> 353 patients were included in this analysis. NGS was performed in 216 (61%) tumor tissues, and 137 (39%) liquid specimens. 37% (n = 129) were female, and 50% (n = 175) were ever-smoker. 63% (n = 223) of our patient cohort harbored druggable mutations. The detection rate of CNV was 74% in tissue and 14% in liquid specimens. Patients with brain, liver, or bone metastasis (p = 0.018) and/or TMB-high (TMB-H) (p = 0.0014) were associated with CNV+. Next, we assessed the impact of CNV on treatment outcomes. Among patients who received immunotherapy ± chemotherapy, CNV+ was associated with a median OS of 20.4 months compared to 31.4 months in the CNV- group (HR:2.09, 95% CI: 1.05-4.16, p = 0.034). In contrast, there was no statistically significant difference in OS among the CNV+ and CNV- patient groups treated with chemotherapy alone. Although not significant, there was a trend towards poorer OS to immunotherapy ± chemotherapy in the TMB-H CNV+ cohort (23.6 months versus 31.4 months; p = 0.082). <strong>Conclusions:</strong> We demonstrate the significance of CNV as a prognostic tool for the prediction of survival outcomes among lung cancer patients. Our data suggests that CNV represents a distinct entity in advanced/metastatic NSCLC, associated with poorer survival outcomes to immunotherapy.<br></p>