Prognostic and Predictive Impact of Primary Tumor Sidedness for Previously Untreated Advanced Colorectal Cancer

Jun Yin, Romain Cohen, Zhaohui Jin, Heshan Liu, Levi Pederson, Richard Adams, Axel Grothey, Timothy S. Maughan, Alan Venook, Eric Van Cutsem, Cornelis Punt, Miriam Koopman, Alfredo Falcone, Niall C. Tebbutt, Matthew T. Seymour, Carsten Bokemeyer, Eduardo Diaz Rubio, Richard Kaplan, Volker Heinemann, Benoist ChibaudelTakayuki Yoshino, John Zalcberg, Thierry Andre, Aimery De Gramont, Qian Shi, Heinz Josef Lenz

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1705-1713
Number of pages9
JournalJournal of the National Cancer Institute
Issue number12
StatePublished - Dec 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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