5073 - Association between transit-amplifying signature and outcomes of patients treated with anti-epidermal growth factor receptor (EGFR) therapy in colorectal cancer

Background

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.

Methods

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).

Results

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).

Conclusions

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

NCT00640471.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

NIHR Biomedical Research Centre at The Royal Marsden and the ICR; Cancer Research UK, MedTech SuperConnector.

Disclosure

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.