Right or left primary site of colorectal cancer: outcomes from the molecular analysis of the AGITG MAX Trial

Abstract

Background: For metastatic colorectal cancer, previous reports have described differences in biology and outcome, including response to biologic agents, based on whether the primary tumor is right- or left-sided. We explored the molecular markers from the AGITG MAX trial. Patients and Methods: The AGITG MAX trial was a randomized study comparing capecitabine versus capecitabine + bevacizumab versus capecitabine + bevacizumab + mitomycin C as first-line therapy in advanced colorectal cancer. Patients were classified as having right-sided (caecum to transverse colon) or left-sided (descending colon to rectum) disease according to anatomic location. Baseline characteristics and previously described molecular profiles were compared by side of primary tumor. Survival outcomes were analyzed by the Kaplan-Meier approach and proportional hazards regression modeling. Results: Among the 471 patients, the location of primary tumor was known in 440 patients (93%). Molecular profile was known in 298 patients (63%). Twenty-eight percent had right-sided primary tumors. Major differences between right and left are as follows: female 49% versus 33% (P < .01), BRAF mutant 16% versus 3.5% (P ≤ .001), and phosphatase and tensin homolog (PTEN) loss 27.6% versus 53% (P = .01). There were no differences in RAS mutation, PIK3CA mutation, or high versus low expression of assessed angiogenic markers. Right-sided primary lesion predicted a poor outcome for median overall survival: right-sided disease 13.2 months versus left-sided disease 20 months (P = .001; hazard ratio [HR] = 0.67; 95% confidence interval [CI], 0.53-0.85), but not for progression-free survival (HR 0.96; 95% CI, 0.78-1.20). The relative treatment effect did not differ significantly according to location of primary tumor: right primary tumor HR (bevacizumab containing arm vs. capecitabine monotherapy arm) was 0.82 (95% CI, 0.54-1.22), and left primary HR (bevacizumab containing arm vs. capecitabine monotherapy arm) was 0.51 (95% CI, 0.4-0.63) (interaction P = .10). Conclusion: There are more negative prognostic factors in patients with right-sided primary tumors, in particular high BRAF mutations, and these patients have inferior overall survival compared to those with a left-sided primary tumor. There was no suggestion that side of primary site had any impact on bevacizumab effect on progression-free survival.