170 - KRAS Variant-Specific Chemoradiation Response and Tumor Microenvironment Characterization in Locally Advanced Rectal Cancer: An Integrated Transcriptomic Profiling

11:35am - 11:45am ET

Room 162

Presenter(s)

Jeril Lasington, MD, MS, MBBS - New York Medical College at St.Mary's and St. Clare's, Denville, NJ

J. Lasington¹, L. S. Mathew Lasington², and S. Umamaheshwaran³; ¹New York Medical College at St. Mary's and St. Clare's, Denville, NJ, ²Rutger's University, East Hanover, NJ, ³Personio, Manhattan, NY

Purpose/Objective(s): Neoadjuvant chemoradiation (CRT) achieves pCR in only 15-20% of locally advanced rectal cancer (LARC). While KRAS mutations occur in ~40% of rectal cancers, the impact of specific KRAS variants on CRT response is poorly characterized. We performed integrated transcriptomic and molecular profiling to identify variant-specific associations with pCR and the biological pathways distinguishing responders from non-responders.

Materials/Methods: We analyzed 203 LARC patients from the GSE87211 cohort, all receiving neoadjuvant CRT (5-fluorouracil ± oxaliplatin ± cetuximab with RT). KRAS variant annotation was available for all patients. Gene expression profiling was performed on pre-treatment biopsies (Agilent microarrays, 34,127 probes). Pathway-level transcriptomic scores were constructed across seven domains: hypoxia, immune microenvironment, DNA repair, RAS-MAPK, proliferation, stemness, and WNT using z-score normalization. Primary endpoint was pCR (ypT0). Mann-Whitney U tests, Fisher's exact test, Kaplan-Meier with log-rank, and multivariate Cox regression were used.

Results: Overall pCR was 17.2% (35/203). KRAS G12V demonstrated 0% pCR (0/13) vs 20.2% WT (22/109), 11.1% G12D (3/27), and 10.5% G13D (2/19). Downstaging was lowest in G12V (30.8% vs 53.2% WT). Immune pathway scores were significantly elevated in pCR patients (p=0.021), driven by CD8A (+0.48, p=0.008), IFNG (+0.77, p=0.008), LAG3 (+0.38, p=0.012), and CXCL9 (+0.69, p=0.029). pCR tumors showed lower hypoxia gene expression: VEGFA (-0.34, p=0.011), EPAS1 (-0.22, p=0.008), SLC2A1 (-0.43, p=0.028). pCR was associated with improved DFS (p=0.0006); KRAS-mutant patients had worse OS (p=0.034).

Conclusion: KRAS G12V was associated with complete CRT resistance (0% pCR). Tumors achieving pCR showed an immune-activated, hypoxia-low profile with upregulated CD8A/IFNG and downregulated VEGFA/SLC2A1. G12V patients may benefit from intensified TNT or immunotherapy-radiation combinations. Prospective KRAS variant-stratified CRT response validation is warranted.

Abstract 170 – Table 1

KRAS Variant-Specific pCR Rates and Differentially Expressed Genes in pCR vs Non-pCR Tumors (N=203)

Category	Variable	WT	G12D	G13D	G12V	pCR	Non-pCR	log2FC	p-value
*pCR Rate*	*n/N (%)*	*22/109*	*3/27*	*2/19*	*0/13*	-	-	-	-
	*Rate*	*20.2%*	*11.1%*	*10.5%*	0%	-	-	-	*OR=1.97*
*Downstaging*	*Rate*	*53.2%*	*51.9%*	*57.9%*	*30.8%*	-	-	-	-
*Immune ?*	*CD8A*	-	-	-	-	?	*ref*	*+0.48*	*0.008*
	*IFNG*	-	-	-	-	?	*ref*	*+0.77*	*0.008*
	*LAG3*	-	-	-	-	?	*ref*	*+0.38*	*0.012*
	*CXCL9*	-	-	-	-	?	*ref*	*+0.69*	*0.029*
*Hypoxia ?*	*VEGFA*	-	-	-	-	?	*ref*	*-0.34*	*0.011*
	*SLC2A1*	-	-	-	-	?	*ref*	*-0.43*	*0.028*