Clinical potential of ctDNA-based TMB in small cell lung cancer recieving chemoradiotherapy.

Abstract

3536 Background: Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis. Chemotherapy and / or radiotherapy is the main choice of SCLC treatment. Circulating tumor DNA (ctDNA) has received substantial attention in recent years owing to the potential of patient stratification and monitoring. Here, we assessed the value of prediction and prognosis using ctDNA in SCLC. Methods: SCLC patients (pts) with limited-stage disease (LD) receiving chemoradiotherapy and extensive-stage disease (ED) receiving chemotherapy were enrolled. Baseline plasma samples were collected for NGS using a 1021-gene-panel. Mutational features and blood-based tumor mutation burden (bTMB) were analyzed using ctDNA. pyClone software was used to cluster the mutations. The mutations in the cluster with the highest cancer cell fraction (CCF) were defined as clonal mutations. Progression-free survival (PFS) was followed. Results: 58 SCLC pts (35 LD and 23 ED) and 58 plasma samples were enrolled. Smoking pts accounted for 84% (49/58). In all samples, recurrent genes were TP53 (86%), RB1 (57%), LRP1B (34%), CREBBP (26%), and MLL3 (22%). The median of bTMB and clone count were 7.9 [0-26] and 7 [0-25]. Significant higher bTMB and clone count were observed in ED pts compared with LD (Mann Whitney test, p = 0.019 and p = 0.041, respectively). Mutated CREBBP (10/23 ED versus 5/35 LD) was enriched in ED (Fisher exact test, p = 0.017 and OR = 0.223). Mutations in NOTCH signaling pathway were enriched in ED (l6/23 ED versus 13/35 LD, p = 0.031, OR = 0.265). In LD group, there were trend toward prolonged PFS in pts with higher bTMB(p = 0.065), and pts with higher clonal bTMB (cbTMB) exhibited significant longer PFS (p = 0.016, HR 0.37, 95% CI [0.12-1.11]). Patients with alteration in PIK3CA showed shorter PFS than wild type (p < 0.001, HR 0.11, 95% CI [0-2.86]). There were no significant difference in median PFS in LD stage pts with any detectable pathway alterations. Whereas, LD pts whose ctDNA contained RTK-RAS signaling pathway alterations exhibited shorter PFS than pts without those alterations (p = 0.135). In ED pts, NOTCH1 gene wild type displayed longer PFS than mutant type (p = 0.036, HR 0.38, 95% CI [0.1-1.53]). There were no difference in PFS between pts with higher and lower bTMB and cbTMB. Conclusions: ctDNA can characterize the mutational feature of SCLC. There are differences in the molecular characteristics between ED and LD pts. Clonal bTMB is a potential prognostic biomarker for LD SCLC chemoradiotherapy. The prognostic marker of ED chemotherapy is different from LD.