Dissecting the genetic variations associated with response to first-line chemotherapy in patients with small cell lung cancer: a retrospective cohort study

Abstract

Background: Chemotherapy has been the standard treatment for small-cell lung cancer (SCLC) for decades. Nonetheless, patients are usually responsive to initial chemotherapy but quickly suffer from relapse, resulting in a poor long-term outcome. Treating advances that greatly ameliorate survival outcomes are historically finite, and credible biomarkers for therapeutic evaluation are deficient. As the genetic biology emerges, investigating biomarkers to optimize individualized treatment for SCLC is necessary.

Methods: Based on following inclusion criteria: (I) patients diagnosed as SCLC by pathology; (II) patients treated with first-line etoposide/cisplatin (EP) chemotherapy; (III) patients who received long-term follow-up and signed informed consent, a total of 24 SCLC patients receiving first-line standard chemotherapy were divided into progressive disease (PD) and partial response (PR) groups. They were regularly followed every 3 months with computed tomography (CT) scan until recurrences determined by CT scan results. Next-generation sequencing (NGS) with a panel of 1,406 cancer-related genes was conducted on the tumor tissue-derived DNA of patients to compare genetic variations, including deletions (indels), single nucleotide variations (SNVs), copy number variations (CNVs), and copy number instability (CNI) between the two groups.

Results: For the clinical characteristics of enrolled SCLC patients, except for significant differences in sex, age, clinical stage, and limited or extensive stage, PD patients showed distinctly shorter overall survival than those with PR (6.5 vs. 14.0 months, respectively, P=0.007). Genetic variations analysis discovered several common genes with CNV mutations between the PR and PD groups, and increased epidermal growth factor receptor (EGFR) gene copy numbers gain was found in PR groups in comparing with PD patients (P=0.006). However, no significant differences in terms of SNVs, indels, genotypes associated with first-line chemotherapy, CNI of tumor tissue-derived DNA, and tumor mutational burden of tumor tissues were observed between two groups. Additionally, the relationship between EGFR gene mutation and clinicopathological features of SCLC indicated that EGFR gene mutation may be an independent indicator for SCLC patients.

Conclusions: Increased EGFR gene CNVs may be an independent indicator influencing the survival time and PR in SCLC patients receiving standard first-line chemotherapy.

Keywords: Epidermal growth factor receptor (EGFR); first-line chemotherapy; genetic variation; small cell lung cancer (SCLC); somatic mutation.

Figure 1

The overall survival of SCLC patients. PD, progressive disease; PR, partial response; SCLC, small cell lung cancer.

Figure 2

Comparison of genetic variations between the PD and PR groups. (A) Tile plots showing copy number variations of 24 genes in the two groups. (B) Tile plots showing known somatic mutations of 16 genes in the two groups. The X-axis represents the number of patients; the y-axis represents mutant genes and the frequency of gene mutations. The top bar (on the right) represents the number of mutations a patient carried. The P value is based on Fisher’s exact test. PD, progressive disease; PR, partial response; SNV, single nucleotide variation.

Figure 3

Analysis of genotypes that influence chemotherapeutic susceptibility in the PD and PR groups. (A-F) The color-coded bar graph shows the genotype distribution of six gene loci with two alleles in the PD and PR groups. The X-axis represents the genotype of chemotherapy-related gene loci; the y-axis represents the number of patients. DYNC2H1_rs716274, GSTP1_rs1695, SLIT1_rs2784917, ERCC1_rs11615 variant genotypes: homozygote (AA), heterozygote (AG), and homozygote (GG); XRCC1_rs25487 genotype: homozygote [1], heterozygote (CT), and homozygote (TT); XPC_rs2228001 genotype: homozygote (GG), heterozygote [2], and homozygote (TT). The P value is based on the nonparametric log-rank test. PD, progressive disease; PR, partial response.

Figure 4

Comparison of tumor mutational burden and copy number instability between the PD and PR groups. (A) The color-coded bar graph of tumor mutational burden values in the two groups. (B) The color-coded bar graph of copy number instability values in the two groups. The P value is based on the nonparametric Wilcoxon rank-sum test. PD, progressive disease; PR, partial response.