[cfDNA sequencing reveals response heterogeneity to first-line camrelizumab plus chemotherapy in esophageal squamous cell carcinoma].

Objective

To analyze the heterogeneity of response to first-line camrelizumab combined with chemotherapy in patients with esophageal squamous cell carcinoma (ESCC) by pretreatment circulating cell-free DNA (cfDNA) sequencing.

Methods

A total of 30 patients with human epidermal growth factor receptor 2-negative locally advanced or advanced ESCC who received first-line camrelizumab combined with chemotherapy in the Department of Oncology, Changzhi People's Hospital, from June 2020 to April 2023 were enrolled. Follow-up was conducted until May 30, 2024, with a median follow-up duration of 15.9 months. Differences in cfDNA sequencing profiles between the ORR group (complete response + partial response, n=15), and the Non-ORR group (stable disease + progressive disease, n=15), were analyzed. Base substitution types, functional mutation categories, and mutation frequencies were compared to identify differentially mutated cfDNA genes. The associations between gene mutation status and progression-free survival (PFS) and overall survival (OS) were further evaluated.

Results

In both the Non-ORR and ORR groups, the insert fragment lengths showed a unimodal distribution (160-180 bp), consistent with the typical characteristics of cfDNA. C>T transition was the predominant base substitution type (47.6% in the Non-ORR group and 45.9% in the ORR group). Missense mutation was the most common functional mutation type (80.9% in the Non-ORR group and 81.1% in the ORR group). Six differentially mutated genes were identified between the Non-ORR and ORR groups, including KLF14, ITPR1, NKTR, PRRC2B, MAGI2, and TYW1B. Mutations in KLF14, ITPR1, NKTR and PRRC2B may be associated with lack of objective response (all P＜0.05), whereas MAGI2 mutations may be associated with a better treatment response (P=0.050). Survival analysis showed that, within the sample size and follow-up period of this cohort, the median PFS of patients with TYW1B mutant-type and wild-type was not reached and 9.70 months, respectively, and the median OS was 30.90 and 17.80 months, respectively. TYW1B mutation was associated with better PFS (HR=2.658, P=0.049 7) and better OS (HR=3.029, P=0.033).

Conclusions

After treatment with camrelizumab combined with chemotherapy for ESCC, molecular characteristics differ among patients with different treatment responses. TYW1B mutation is associated with improved PFS and OS. However, these findings require further validation in larger cohorts.