Impact of exact segment by segment primary tumor location status on anti-EGFR antibody first-line treatment efficacy in RAS/BRAF wild-type and BRAF mutant metastatic colorectal cancer. A pooled analysis of AIO studies FIRE-1, CIOX, FIRE-3, XELAVIRI, and VOLFI.
Authors: Alig Annabel Helga Sophie , Heinemann Volker , Geissler Michael , Weikersthal Ludwig Fischer von , Decker Thomas , Heinrich Kathrin , Held Swantje , Weiss Lena , Fischer Laura Elisabeth , Moosmann Nicolas , Stahler Arndt , Jelas Ivan , Kurreck Annika , Striefler Jana Kaethe , Einem Jobst Christian von , Reinacher-Schick Anke Claudia , Tannapfel Andrea , Giessen-Jung Clemens , Stintzing Sebastian , Modest Dominik Paul 
Published: February 2021

Abstract
BackgroundPrimary tumor location (left vs. right) has prognostic and predictive impact on the therapeutic management of metastatic colorectal cancer (mCRC) in particular in the context of anti-epithelial growth factor receptor (anti-EGFR) antibodies. This analysis evaluates the relevance of exact segment-by-segment tumor location in patients with metastatic colorectal cancer on outcome and efficacy of anti-EGFR-antibodies.MethodsThis is a retrospective, pooled analysis of five randomized clinical trials (FIRE-1, CIOX, FIRE-3, XELAVIRI and VOLFI) treating metastatic colorectal cancer patients in a first-line setting, published between 2011-2019. Each trial was a multicentre, phase 2 or phase 3 trial in which patients with untreated metastatic colorectal cancer received chemotherapy regimens with or without monoclonal antibodies (anti-VEGF, anti-EGFR). Eligible were patients with histologically confirmed metastatic colorectal cancer in good performance status who were at least 18 years old. Individual data of 1809 patients with available exact primary tumor location were included into this analysis. Prognostic and predictive effects of primary tumor location were evaluated in uni- and multivariate analyses using the Kaplan Meier method, log rank tests, Cox regressions and logistic regressionsResults Exact primary tumor location is an important determinant of overall survival (OS) in mCRC patients (P<0.001). Multivariate analysis of RAS/BRAF wild-type metastatic colorectal cancer indicate that efficacy of anti-EGFR agents in terms of OS increases continuously from primary tumors located in the caecum (HR 2.63), ascending colon (HR 1.24), right flexure/transverse colon (HR 0.99), left flexure/descending colon (HR 0.91) to the sigmoid (HR 0.71) and rectum (HR 0.58), demonstrating significant benefit in sigmoid and rectal metastatic colorectal cancer, as well as clear detriment in caecum mCRC. Patients with BRAF V600E mutant disease arising from left-sided segments of the colorectum benefitted from EGFR-antibody treatment survival: hazard ratio for death in left-sided tumors: 0.42 (95% CI 0.19-0.92).Conclusions Primary tumor location of metastatic colorectal cancer affects prognosis. Anti-EGFR efficacy increases continuously from proximal to distal segments of the colorectum in metastatic colorectal cancer patients with RAS/BRAF wild-type and BRAF mutant tumors. Therefore, patients with BRAF mutant tumors of the distal segments may benefit from first-line Anti-EGFR-based therapy.Trial registrationFIRE1 trial registration ID n/aCIOX trial registration ID NCT00254137FIRE3 trial registration ID NCT00433927XELAVIRI trial registration ID NCT01249638VOLFI trial registration ID NCT01328171