In CRC, the transit-amplifying (TA) subtype is enriched for tumours sensitive to anti-EGFR agents. At the same time, the presence of TA gene signature in tumours belonging to other subtypes may suggest potential anti-EGFR benefit. Hence, we evaluated the association between the TA signature (presence - class 1; absence - class 2) and outcomes in CRC patients (pts) treated with anti-EGFR therapy.
Formalin-fixed, paraffin-embedded samples from a retrospective discovery cohort (D) and an independent clinical trial cohort (CO.20 study, validation (V)) were classified into the two TA classes using our published nCounter assay (NanoString Technologies). A subset of pts with extended RAS/BRAF wild-type (WT) tumours, cell lines, and pts-derived xenografts (PDXs) were also evaluated. Biomarker portability was evaluated in primary/metastatic samples and different platforms (microarrays).
Up to 295 quality samples were included (D-84; V-121; 30 matched pts and control/treated PDXs). Class 1 pts had significantly longer progression-free survival [PFS; D – adjusted (adj) HR 1.95 (1.15-3.31) p < 0.01; V – adj HR 1.59 (1.07-2.37) p < 0.02] and higher disease control rate (DCR) [D – adj p < 0.0001; V adj p < 0.001]. In D cohort (unselected for RAS/BRAF) classes were significantly associated with sidedness (left 71% class 1; right 58% class 2). In 71 WT pts, class 1 was associated with significantly higher DCR (83% vs. 39%, adj p: 0.003); and trend towards longer PFS and response. This association was more pronounced in a clinically relevant cohort of 51 WT and left-sided pts (class 2 vs. class 1 median PFS: 2 vs. 5.62 months; HR: 1.88 (0.99-3.57) p: 0.049; response rate (class 2 vs. class 1, 8% vs. 33%, odds ratio 0.17(0.02-1.41) p: 0.09, adj (for age, gender) p: 0.14)). WT PDXs and cell lines showed similar response (Wilcoxon test; PDXs p-value: 0.04; cell lines p-value: 0.007). The TA classes were further validated using microarray data from metastatic samples (Khambata-Ford; PFS p < 0.0001).
The detection of TA signature in primary or metastatic samples may further refine the selection of WT CRC pts for anti-EGFR therapy and may explain the differential benefit behind sidedness.
Clinical trial identification
Legal entity responsible for the study
NIHR Biomedical Research Centre at The Royal Marsden and the ICR; Cancer Research UK, MedTech SuperConnector.
D. Cunningham: Research grant / Funding (institution): Amgen; AstraZeneca; Bayer; Celgene; MedImmune; Merck Serono; Merrimack; Sanofi. N. Starling: Research grant / Funding (institution): AstraZeneca; Verastem. A. Sadanandam: Research grant / Funding (institution): Bristol-Myers Squibb; Licensing / Royalties: PCT/IB2013/060416. All other authors have declared no conflicts of interest.