Intratumoral Transcriptome Heterogeneity Is Associated With Patient Prognosis and Sidedness in Patients With Colorectal Cancer Treated With Anti-EGFR Therapy From the CO.20 Trial

Elisa Fontana, Gift Nyamundanda, David Cunningham, Dongsheng Tu, Maggie C U Cheang, Derek J Jonker, Lillian L Siu, Francesco Sclafani, Katherine Eason, Chanthirika Ragulan, Maria Antonietta Bali, Sanna Hulkki-Wilson, Jonathan M Loree, Paul M Waring, Mirella Giordano, Patrick Lawrence, Daniel Nava Rodrigues, Ruwaida Begum, Jeremy D Shapiro, Timothy J PriceChiara Cremolini, Naureen Starling, Filippo Pietrantonio, Livio Trusolino, Christopher J O'Callaghan, Anguraj Sadanandam

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE: Metastatic colorectal cancers (mCRCs) assigned to the transit-amplifying (TA) CRCAssigner subtype are more sensitive to anti-epidermal growth factor receptor (EGFR) therapy. We evaluated the association between the intratumoral presence of TA signature (TA-high/TA-low, dubbed as TA-ness classification) and outcomes in CRCs treated with anti-EGFR therapy.

PATIENTS AND METHODS: The TA-ness classes were defined in a discovery cohort (n = 84) and independently validated in a clinical trial (CO.20; cetuximab monotherapy arm; n = 121) and other samples using an established NanoString-based gene expression assay. Progression-free survival (PFS), overall survival (OS), and disease control rate (DCR) according to TA-ness classification were assessed by univariate and multivariate analyses.

RESULTS: The TA-ness was measured in 772 samples from 712 patients. Patients (treated with anti-EGFR therapy) with TA-high tumors had significantly longer PFS (discovery hazard ratio [HR], 0.40; 95% CI, 0.25 to 0.64; P < .001; validation HR, 0.65; 95% CI, 0.45 to 0.93; P = .018), longer OS (discovery HR, 0.48; 95% CI, 0.29 to 0.78; P = .003; validation HR, 0.67; 95% CI, 0.46 to 0.98; P = .04), and higher DCR (discovery odds ratio [OR]; 14.8; 95% CI, 4.30 to 59.54; P < .001; validation OR, 4.35; 95% CI, 2.00 to 9.09; P < .001). TA-ness classification and its association with anti-EGFR therapy outcomes were further confirmed using publicly available data (n = 80) from metastatic samples (PFS P < .001) and patient-derived xenografts (P = .042). In an exploratory analysis of 55 patients with RAS/BRAF wild-type and left-sided tumors, TA-high class was significantly associated with longer PFS and trend toward higher response rate (PFS HR, 0.53; 95% CI, 0.28 to 1.00; P = .049; OR, 5.88; 95% CI, 0.71 to 4.55; P = .09; response rate 33% in TA-high and 7.7% in TA-low).

CONCLUSION: TA-ness classification is associated with prognosis in patients with mCRC treated with anti-EGFR therapy and may further help understanding the value of sidedness in patients with RAS/BRAF wild-type tumors.

Original languageEnglish
JournalJCO Precision Oncology
Volume4
DOIs
Publication statusPublished - 2020

Fingerprint

Dive into the research topics of 'Intratumoral Transcriptome Heterogeneity Is Associated With Patient Prognosis and Sidedness in Patients With Colorectal Cancer Treated With Anti-EGFR Therapy From the CO.20 Trial'. Together they form a unique fingerprint.

Cite this