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. 2023 Jul 12:13:1116809.
doi: 10.3389/fonc.2023.1116809. eCollection 2023.

Temporal genomic heterogeneity guiding individualized therapy in recurrent non-small cell lung cancer

Qiyu Fang  1   2 , Xiaoying Wan  2 , Angelica D'Aiello  3 , Hui Sun  2 , Weiquing Gu  2 , Yixue Li  4   5 , Caicun Zhou  2 , Boxiong Xie  6 , Qinfang Deng  2 , Haiying Cheng  3 , Songwen Zhou  2
Affiliations

Temporal genomic heterogeneity guiding individualized therapy in recurrent non-small cell lung cancer

Qiyu Fang et al. Front Oncol. .

Abstract

Introduction: Despite the benefit of adjuvant systemic therapy for patients with resected non-small cell lung cancer (NSCLC), the risk of postoperative recurrence remains high. Our objective was to characterize temporal genetic heterogeneity between primary resected and recurrent tumors, and its impact on treatment outcomes.

Methods: In this study, next-generation sequencing (NGS) testing was performed on tissue specimens and circulating tumor DNA (ctDNA) collected at postoperative recurrence, and results were compared to the genotypes of initial surgical specimens.

Results: Of forty-five patients with matched primary and post-operative recurrent tumors, EGFR status switched in 17 patients (37.8%) at post-operative recurrence and 28 patients (62.2%) had no genotype change (17 mutant, 11 wild-type). Based on the changes of EGFR status, patients were divided into 4 groups. Following subsequent treatment with EGFR TKI o chemotherapy: In group A, with sustained sensitive mutation, the percentage achieving partial response (PR) was the highest, at 72.2%, the median progression-free survival (PFS) was 17 months, and the median overall survival (OS) was 44.0 months respectively; In group B, with genotype changed from wild-type to mutant, 50% achieved PR, PFS was 10 months, and OS was 35 months; In group C, in which mutant status shifted to wild-type or new co-mutation emerged, the percentage achieving PR was 30%, PFS was 9 months, and OS was 35 months. In group D, with sustained wild type, the percentage achieving PR was 27.3%, PFS was 8 months, and OS was 22 months.

Discussion: Genotypic shift between paired primary and post-operative recurrent tumors was not infrequent, and this temporal genomic heterogeneity substantially impacted subsequent treatment outcomes.

Keywords: EGFR; NSCLC; dynamic gene sequencing; genotypic switch; temporal heterogeneity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Venn diagram showing EGFR-positive status of 45 cases with surgical and recurrent specimens.
Figure 2
Figure 2
Response outcome between different groups.
Figure 3
Figure 3
Kaplan-Meier curve for recurrent progression-free survival of patients between groups.*Log-rank test: Group A vs. Group B(P=0.008), Group A vs. Group C (P=0.016), Group A vs. Group D(P<0.001), Group B vs. Group C(P=0.620), Group B vs. Group D(P=0.163), Group C vs. Group D(P=0.156).
Figure 4
Figure 4
Kaplan-Meier curve for recurrent overall survival of patients between groups. * Log-rank test: Group A vs. Group B(P=0.171), Group A vs. Group C (P=0.641), Group A vs. Group D(P=0.039), Group B vs. Group C(P=0.715), Group B vs. Group D(P=0.482), Group C vs. Group D(P=0.182).
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