Sidedness and TP53 mutations impact OS in anti-EGFR but not anti-VEGF treated mCRC - An analysis of the KRAS registry of the AGMT (Arbeitsgemeinschaft Medikamentöse Tumortherapie)

Abstract

Background: In metastatic colorectal cancer (mCRC), the localization of the primary tumour has been shown to be of prognostic as well as predictive relevance. Methods: With the aim to investigate clinical and molecular disease characteristics with respect to sidedness in a real-world cohort, we analyzed 161 mCRC patients included in the KRAS Registry of the Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) between January 2006 and October 2013. Results: Right-sided mCRC displayed a worse median overall survival (OS) in comparison to left-sided disease (18.1 months [95%-CI: 14.3-40.7] versus 32.3 months [95%-CI: 25.5-38.6]; HR: 1.63 [95%-CI: 1.13-2.84]; p = 0.013). The choice of the biological agent in front-line therapy had a statistically significant impact on median OS in patients with right-sided tumours (anti-epidermal growth factor receptor (EGFR): 10.6 months [95%-CI: 5.2-NA]; antivascular endothelial growth factor (VEGF): 26.2 months [95%-CI: 17.9-NA]; HR: 2.69 [95%-CI: 1.30-12.28]; p = 0.015) but not in patients with left-sided tumours (anti-EGFR: 37.0 months [95%-CI: 20.2-56.6]; anti-VEGF: 32.3 months [95%- CI: 23.6-41.1]; HR: 0.97 [95%-CI: 0.56-1.66]; p = 0.905). When evaluating molecular characteristics of tumour samples, we found a clinically meaningful trend towards an inferior OS in TP53 mutant mCRC treated with anti- EGFR based therapy compared to anti-VEGF based therapy (17.1 months [95%-CI: 8.7-NA] versus 38.3 months [95%-CI: 23.6-48.0], HR = 1.95 [95%-CI: 0.95-5.88]; p = 0.066), which was not significantly dependent on sidedness. This was not the case in patients with TP53 wild-type tumours. Therefore we evaluated the combined impact of sidedness and TP53 mutation status in the anti-EGFR treated cohort and patients with left-sided/TP53 wild-type mCRC showed the longest median OS (38.9 months) of all groups (right-sided/TP53 mutant: 12.1 months; rightsided/TP53 wild-type: 8.9 months; left-sided/TP53 mutant: 18.4 months; p = 0.020). Conclusions: TP53 mutation and right-sidedness are associated with shorter OS in patients treated with anti- EGFR based therapy but not with anti-VEGF based therapy. The confirmation of the predictive value of TP53 mutation status in a larger cohort is warranted.