TY - JOUR
T1 - Prognostic and Predictive Impact of Primary Tumor Sidedness for Previously Untreated Advanced Colorectal Cancer
AU - Yin, Jun
AU - Cohen, Romain
AU - Jin, Zhaohui
AU - Liu, Heshan
AU - Pederson, Levi
AU - Adams, Richard
AU - Grothey, Axel
AU - Maughan, Timothy S
AU - Venook, Alan
AU - Van Cutsem, Eric
AU - Punt, Cornelis
AU - Koopman, Miriam
AU - Falcone, Alfredo
AU - Tebbutt, Niall C
AU - Seymour, Matthew T
AU - Bokemeyer, Carsten
AU - Rubio, Eduardo Diaz
AU - Kaplan, Richard
AU - Heinemann, Volker
AU - Chibaudel, Benoist
AU - Yoshino, Takayuki
AU - Zalcberg, John
AU - Andre, Thierry
AU - De Gramont, Aimery
AU - Shi, Qian
AU - Lenz, Heinz-Josef
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press. All rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85117715942&partnerID=8YFLogxK
U2 - 10.1093/jnci/djab112
DO - 10.1093/jnci/djab112
M3 - Article
C2 - 34061178
SN - 0027-8874
VL - 113
SP - 1705
EP - 1713
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 12
ER -