Abstract 478P
Background
RAS/BRAF wt mCRC pts could potentially benefit from antiEGFR treatment but only 50% of them respond. Data from CRCAssigner (CRCA) and Consensus Molecular Subtypes (CMS) classification identified transit-amplifying (TA)/CMS2 as more sensitive to antiEGFR. We aimed to evaluate different gene-expression–based classifiers for identification of RAS wt pts that may benefit from antiEGFR.
Methods
RNA was extracted from FFPE slides obtained from 74 RAS wt mCRC pts treated with cetuximab (Cmab) or panitumumab (Pmab) from a retrospective multicentre study. Transcriptomic profiling was carried out using a custom NanoString gene panel (NanoCRC) to classify pts into CMS and CRCA subtypes along with TA-ness. Immune gene profiling was performed using HTG EdgeSeq Precision Immuno-Oncology Panel. Single sample Gene Set Enrichment Analysis (ssGSEA) and CIBERSORTx was performed to assess immune cell enrichment. Progression free survival (PFS) and overall survival (OS) was estimated by Kaplan-Meier curves and cox regression model.
Results
We included 74 pts treated with Cmab (74%) or Pmab (26%), 29 right-sided and 51 left-sided. 76.5% pts were stage IV. Tumors (T) were grouped as inflammatory (4, 5.41%), enterocyte (23, 31.1%), goblet-like (12, 16.2%), TA (12, 16.2%) and stem-like (16, 21.6%). We observed a correlation between CRCA and CMS classifiers (p-value < 0.001). In the TA-ness classification, 26 T (38.2%) were TA-high and 42 T (61.8%) were TA-low. Pts classified as CMS3 did not benefit from antiEGFR compared to CMS2 and CMS4 (PFS, HR = 20, p-value = 0.03). CMS2 pts classified as enterocyte or TA were the ones more likely to benefit from Cmab/Pmab. In terms of OS, TA-ness was the only classifier that better discriminated RAS wt mCRC pts who did benefit from Cmab/Pmab (p-value=0.013). We observed a high heterogeneity in the immune landscape, with a trend towards NK cells enrichment in responder pts.
Conclusions
TA-high subtype was associated with better OS in RAS wt mCRC pts treated with Cmab/Pmab suggesting TA-ness classification may be useful for antiEGFR treatment selection. Further analyses from prospective clinical trials are necessary to validate our results.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The Bellvitge Biomedical Research Institute.
Funding
Instituto de Salud Carlos III.
Disclosure
C. Santos: Financial Interests, Personal, Invited Speaker: Pierre-Fabre; Financial Interests, Personal, Expert Testimony: Amgem; Financial Interests, Personal, Expert Testimony: Sanofi. M.E. Elez Fernandez: Financial Interests, Advisory Board: Amgen; Financial Interests, Advisory Board: Array Biopharma; Financial Interests, Advisory Board: Bayer; Financial Interests, Advisory Board: Bristol Myers Squibb; Financial Interests, Advisory Board: Hoffman La Roche; Financial Interests, Advisory Board: Merck Serono; Financial Interests, Advisory Board: Servier; Financial Interests, Advisory Board: Sanofi. D. Paez: Financial Interests, Advisory Role: Amgen; Financial Interests, Speaker’s Bureau: F Hoffmann - La Roche; Financial Interests, Advisory Role: Sanofi; Financial Interests, Advisory Role: Ipsen; Financial Interests, Speaker’s Bureau: Advance Accelerator Applications. L. Layos Romero: Financial Interests, Advisory Role: Celgene; Financial Interests, Advisory Role: Sanofi; Financial Interests, Other, Travel and accommodation: Merck; Financial Interests, Other, Travel and accommodation: Amgen; Financial Interests, Other, Trael and accommodation: Ipsen. R. Salazar: Financial Interests, Invited Speaker: Advanced Accelerator Applications; Financial Interests, Advisory Board: Agendia; Financial Interests, Advisory Board: Amgen; Financial Interests, Invited Speaker: Astellas; Financial Interests, Expert Testimony: AstraZeneca; Financial Interests, Invited Speaker: Bayer; Financial Interests, Invited Speaker: BMS; Financial Interests, Advisory Board: Celgene; Financial Interests, Invited Speaker: Eisai; Financial Interests, Advisory Board: Ferrer; Financial Interests, Invited Speaker: GSK; Financial Interests, Advisory Board: Guardant Health; Financial Interests, Advisory Board: Ipsen; Financial Interests, Invited Speaker: Janssen Oncology; Financial Interests, Advisory Board: Lilly; Financial Interests, Advisory Board: Merck; Financial Interests, Advisory Board: MSD; Financial Interests, Advisory Board: Novartis; Financial Interests, Advisory Board: Pfizer; Financial Interests, Invited Speaker: Pierre Fabre; Financial Interests, Invited Speaker: Roche; Financial Interests, Advisory Board: Roche Dx; Financial Interests, Advisory Board: Roche Farma; Financial Interests, Invited Speaker: Sanofi; Financial Interests, Advisory Board: Tayhoo; Financial Interests, Advisory Board: VCN-BCN; Financial Interests, Ownership Interest: Sace-MEDhealth; Financial Interests, Institutional, Other: Merck KGaA; Financial Interests, Other, Steering committee: Tayhoo; Financial Interests, Institutional, Other, Subinvetigator: Mologen; Financial Interests, Institutional, Other, Invetigator: Novartis Farmaceutica. A. Sadanandam: Financial Interests, Funding: BMS; Financial Interests, Funding: Merck; Financial Interests, Funding: Pierre Fabre; Financial Interests, Other, Patent number PCT/IB2013/060416: N/A. All other authors have declared no conflicts of interest.