Abstract
Simple SummarySidedness of primary tumor is a well-established prognostic marker and is predictive for anti-EGFR efficacy in RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. As molecular markers change rather continuously throughout the colon, we ask whether the exact primary tumor location (PTL) is a better prognostic marker than sidedness and predictive for anti-EGFR efficacy in RAS/BRAF wild-type mCRC. We retrospectively analyzed five studies containing various therapy protocols concerning primary tumor location, dividing the colorectal frame into six segments. In our cohort, PTL has a prognostic impact on disease spread and overall survival. Only distal segments benefitted when receiving anti-EGFR containing therapy regarding overall survival. Intermediate segments were indifferent and caecal primaries had a detrimental effect receiving anti-EGFR based therapy. Being a retrospective analysis and challenging the standard of basing anti-EGFR treatment on sidedness in RAS/BRAF wild-type mCRC, future studies are necessary to confirm and further investigate our hypothesis-generating results.Primary tumor sidedness (left vs. right) has prognostic and predictive impact on anti-EGFR agent efficacy and thus management of metastatic colorectal cancer (mCRC). This analysis evaluates the relevance of primary tumor location (PTL) in RAS/BRAF wild-type mCRC patients, when dividing the colorectal frame into six segments. This pooled analysis, performed on a single-patient basis of five randomized first-line therapy trials, evaluates the impact of exact PTL classification on baseline characteristics, prognosis and prediction of anti-EGFR antibody efficacy by chi-square and log-rank tests, the Kaplan–Meier method, Cox and logistic regressions. The PTL was significantly associated with metastatic spread: liver (p = 0.001), lung (p = 0.047), peritoneal (p < 0.001) and lymph nodes (p = 0.048). A multivariate analysis indicated an impact on anti-EGFR agent efficacy in terms of overall survival depending on the exact primary tumor location: from detrimental in caecal (HR 2.63), rather neutral effects in the ascending colon (HR 1.24), right flexure/transverse colon (HR 0.99) and left flexure/descending colon (HR 0.91) to clear benefit in sigmoid (HR 0.71) and rectal (HR 0.58) primaries. Exact primary tumor location affects anti-EGFR antibody efficacy in a rather continuous than a dichotomous fashion in RAS/BRAF wild-type mCRC patients. This perspective might help to support clinical decisions when anti-EGFR antibodies are considered.
Highlights
Primary tumor location (PTL), usually defined as left vs. right sidedness with a cut-off at the splenic flexure, is a prognostic and predictive biomarker in the treatment of metastatic colorectal cancer [1,2,3,4]
The population analyzed in this article comprises 717 patients with known exact primary tumor location and with RAS/BRAF wild-type tumors
The presented analysis based on five randomized trials including data of 717 patients with RAS/BRAF wild-type tumors represents a large and robust basis to evaluate the with RAS/BRAF wild-type tumors represents a large and robust basis to evaluate the impact impact of exact primary tumor location in RAS/BRAF wild-type metastatic colorectal cancer (mCRC) on clinical of exact primary tumor location in RAS/BRAF wild-type mCRC on clinical characteristics, characteristics, predictionantibody of anti-epidermal growth factor receptor (EGFR)
Summary
Primary tumor location (PTL), usually defined as left vs. right sidedness with a cut-off at the splenic flexure, is a prognostic and predictive biomarker in the treatment of metastatic colorectal cancer (mCRC) [1,2,3,4]. Patients presenting with right-sided mCRC have a dismal prognosis compared to patients with left-sided mCRC. The PTL predicts the efficacy of antibodies targeting the epidermal growth factor receptor (EGFR) in RAS wild-type tumors: patients presenting with left-sided mCRC (unlike right-sided mCRC). The role of anti-EGFR antibodies in right-sided RAS wild-type mCRC appears conflicting as objective responses could still be improved [1,2]. Given the lack of survival benefit, the use of anti-EGFR antibodies is reserved to left-sided mCRC with RAS and potentially BRAF wild-type tumors [1,2,5]. Various molecular factors—occurring with differing frequencies throughout the colon and rectum—
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