1038 - Distinct Efficacy between Very Early-Onset Locally Advanced Rectal Cancer (VEO-LARC) and Late-Onset LARC Receiving Total Neoadjuvant Therapy with or without Immunotherapy

08:15am - 08:20am ET

Room 162

Presenter(s)

Luoxi He, BS - Fudan University Shanghai Cancer Center, Shanghai, Shanghai

M. Yan¹, Y. Wang¹, R. Wu¹, L. He¹, L. Shen¹, J. Wan¹, H. Zhang¹, Y. Wang¹, Y. Chen¹, M. Zhou¹, Z. Zhang¹, J. Wang¹, S. Cai², Y. Xu², F. Xia¹, and Z. Zhang³; ¹Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China, ²Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China, ³Department of Radiation Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University; Shanghai Clinical Research Center for Radiation Oncology; Shanghai Key Laboratory of Radiation Oncology, Shanghai, China

Purpose/Objective(s):

The incidence of colorectal cancer in young population is rising around the globe. Total neoadjuvant therapy (TNT) is demonstrated to improve tumor response and the combination of TNT and immunotherapy (iTNT) has achieved further improved clinical or pathological complete response (cCR/pCR) rate in locally advanced rectal cancer (LARC). However, little is known about whether younger or older LARC patients exhibit different efficacies under TNT/iTNT regimens. This study provides a comprehensive comparison between very early-onset LARC (VEO-LARC, =40 years) and late-onset LARC (LO-LARC, >40 years) patients receiving TNT/iTNT regimens.

Materials/Methods:

A total of 372 LARC patients who adopted TNT/iTNT regimens at one institution were included. Of these, 198 underwent TNT consisted of long-course chemoradiotherapy followed by consolidative chemotherapy, while 174 underwent iTNT consisted of short-course radiotherapy combined with chemotherapy and PD-1 inhibitor. The 372 patients were stratified into either VEO-LARC (n=40) or LO-LARC (n=332) cohorts based on their age at diagnosis. Patients with a sustaining cCR undergoing watch and wait strategy and those confirmed as pCR after surgery were classified as achieving complete response (CR). DESeq2 package in R was utilized for identifying differentially expressed genes (DEGs), which were defined as |log2(fold change)| > 1 and adjusted P value <0.05. Gene set enrichment analysis (GSEA) was conducted with R package clusterProfiler.

Results:

The median follow-up was 34 months for VEO-LARC and 40 months for LO-LARC. Generally, CR rate in VEO-LARC cohort was significantly lower than that in LO-LARC cohort (20.0% vs 52.7%, P<0.001). Subgroup analyses based on TNT/iTNT regimens showed a significant increase of CR rate in LO-LARC cohort following the addition of immunotherapy (43.8% in TNT vs 62.8% in iTNT, P<0.001), while no differences of CR rate were seen between TNT and iTNT in VEO-LARC population (18.2% vs 22.2%, P=0.751). Though there were no distinctions between the two age cohorts concerning 3-year overall survival (3y-OS, 81.8% vs 89.3%, P=0.304), VEO-LARC exhibited a significantly poorer 3-year disease-free survival (3y-DFS, 46.4% vs 76.1%, P<0.001) than LO-LARC. Through bulk RNA-seq analysis, a total of 942 DEGs were identified, with 581 genes up-regulated and 361 genes down-regulated in VEOCRC. Functional GSEA further indicated a significant enrichment for TNFa signaling via NF?B and inflammatory response in VEOCRC samples.

Conclusion:

VEO-LARC exhibited lower CR rate and less favorable 3y-DFS compared to LO-LARC under TNT, and this efficacy does not show significant improvement even in the latest iTNT regimen. Bulk RNA-seq analysis further revealed distinct biological tumor characteristics of VEOCRC.