Abstract 454P
Background
The CCR5/CCL5 axis plays a key role in CRC. We previously showed that polymorphisms in CCR5/CCL5 are associated with outcome in patients (pts) with metastatic CRC. Here we aimed to characterize the molecular features associated with CCR5/CCL5 expression in CRC and whether CCR5/CCL5 levels could impact treatment outcome.
Methods
7604 CRC tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA and RNA were analyzed. Top quartile transcripts per million (TPMs) for CCR5 & CCL5 expression were considered high (Q4) while bottom quartile low (Q1). Consensus molecular subtypes (CMS) were assessed using RNAseq. Cell infiltration (CI) in the tumor microenvironment (TME) was estimated by QuantiSEQ and MCP counter. X2/Fisher-Exact were used and significance was determined as P-value adjusted for multiple comparison (Q < .05). Real-world overall survival information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined pts.
Results
CCR5 & CCL5 showed a strong positive correlation with CMS1 & 4, and a negative association with CMS2 & 3 (P < .0001, Q1 vs Q4). CCR5 & CCL5 TPMs were associated with higher tumor mutational burden (≥ 10 Mut/Mb), deficiency in mismatch repair (MMR) and PD-L1 (Q < .001); similar patterns were observed in MMR proficient tumors (pMMR). CCR5 & CCL5 TPMs were higher in right- vs left-sided tumors, and negatively associated with APC mutations and FLT1/FLT3 CNA in the pMMR cohort (Q < .01). High CCR5 & CCL5 were associated with higher immune CI, endothelial cells and fibroblasts in the TME in pMMR tumors (Q < .001). High CCR5 & CCL5 expression was associated with poor prognosis (HR 0.83; 95%CI, 0.72-0.96, P = .014 and HR 0.81; 95%CI, 0.70-0.93, P = .004, respectively). CCR5 expression was associated with benefit from bevacizumab-based treatment in right-sided pMMR CRC (HR 0.39; 95%CI, 0.16-0.90, P = .024).
Conclusions
Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features (including CMS), TME cell infiltration, pt outcome, and treatment benefit in CRC. These findings suggest that targeting the CCR5/CCL5 axis may have relevant clinical applications in selected CRC subgroups and chemokines CCL5 & CCL2 may be important targets in TME.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
J. Baca: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. J. Xiu: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. A.F. Shields: Financial Interests, Personal, Speaker’s Bureau: Caris Life Sciences; Financial Interests, Personal, Sponsor/Funding: Caris Life Sciences; Financial Interests, Personal, Advisory Role: Caris Life Sciences; Financial Interests, Personal, Advisory Role: ImaginAb; Financial Interests, Personal, Advisory Role: TransTarget; Financial Interests, Personal, Other: Inovio Pharmaceuticals. R.M. Goldberg: Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Taiho; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Funding: Bristol-Myers Squibb; Financial Interests, Personal, Funding: Caris Life Sciences; Financial Interests, Personal, Advisory Role: Merck KGaA; Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Expert Testimony: Genentech/Roche. A. Seeber: Financial Interests, Personal, Other: Caris Life Sciences. J. Abraham: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. E. Lou: Financial Interests, Personal, Advisory Role: Boston Scientific; Financial Interests, Personal, Advisory Role: Novocure; Financial Interests, Personal, Sponsor/Funding: Novocure; Financial Interests, Personal, Other: GlaxoSmithKline. P.A. Philip: Financial Interests, Personal, Advisory Role: Celgene; Daiichi Sankyo; Ipsen; Merck; Taiho; Syncore; TriSalus Life Sciences; Financial Interests, Personal, Speaker’s Bureau: Bayer; Celgene; Incyte; Ipsen; Novartis; Financial Interests, Personal, Other: AbbVie; Rafael Pharmaceuticals; Array BioPharma; AstraZeneca; Blueprint Medicines. B.A. Weinberg: Financial Interests, Personal, Speaker’s Bureau: Bayer; Lilly; Taiho; Sirtex; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Expert Testimony: AstraZeneca; Financial Interests, Personal, Other: Onclive; Tempus; Rafael Pharmaceuticals. J.L. Marshall: Financial Interests, Personal, Speaker’s Bureau: Merck; Bayer; Taiho; Amgen; Celgene; Genentech/Roche; Financial Interests, Personal, Advisory Role: Merck; Bayer; Taiho; Amgen; Celgene; Caris Life Sciences; Genentech/Roche; Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences; Indivumed. W..M. Korn: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences; Financial Interests, Personal, Stocks/Shares: Caris Life Sciences; Financial Interests, Personal, Advisory Role: Merck Sharp & Dome. H. Lenz: Financial Interests, Personal, Advisory Role: Bayer; Merck Serono; Bristol-Myers Squibb; Roche; GlaxoSmithKline; Financial Interests, Personal, Other: Boehringer Ingelheim; Isofol Medical. All other authors have declared no conflicts of interest.