Prognostic and predictive impact of primary tumor sidedness for previously untreated advanced colorectal cancer

Yin, Jun, Cohen, Romain, Jin, Zhaohui, Liu, Heshan, Pederson, Levi, Adams, Richard ORCID: https://orcid.org/0000-0003-3915-7243, Grothey, Axel, Maughan, Timothy S, Venook, Alan, Van Cutsem, Eric, Punt, Cornelis, Koopman, Miriam, Falcone, Alfredo, Tebbutt, Niall C, Seymour, Matthew T, Bokemeyer, Carsten, Rubio, Eduardo Diaz, Kaplan, Richard, Heinemann, Volker, Chibaudel, Benoist, Yoshino, Takayuki, Zalcberg, John, Andre, Thierry, De Gramont, Aimery, Shi, Qian and Lenz, Heinz-Josef 2021. Prognostic and predictive impact of primary tumor sidedness for previously untreated advanced colorectal cancer. Journal of the National Cancer Institute 113 (12) , pp. 1705-1713. 10.1093/jnci/djab112

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Abstract

Background Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients. Methods PTS data of 9277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemotherapy, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs chemotherapy alone). All statistical tests were 2-sided. Results Compared with right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 vs 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67 to 0.76; P < .001) and PFS (median = 8.6 vs 7.5 months; HRadj = 0.80, 95% CI = 0.75 to 0.84; P < .001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction < .001); left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53 to 0.66; PFS HRadj =0.68, 95% CI = 0.61 to 0.75) but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75 to 0.97; P = .01; PFS HRadj = 0.77, 95% CI = 0.67 to 0.88; P < .001) but not for right-sidedness. Conclusions The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Centre for Trials Research (CNTRR)
Publisher:	Oxford University Press
ISSN:	0027-8874
Date of Acceptance:	26 May 2021
Last Modified:	10 Nov 2022 09:59
URI:	https://orca.cardiff.ac.uk/id/eprint/145337

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