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Primary tumour sidedness: a new treatment driver for metastatic colorectal cancer?

In the last months a heated debate surrounded the presentation of results from subgroup analyses of randomized trials in RAS wt metastatic colorectal cancer (mCRC), based on the primary tumour location. Whereas the negative prognostic impact of right sidedness is well established, recent subgroup analyses suggest a potential predictive power of primary tumor location with regard to available targeted agents, and especially to anti-EGFR monoclonal antibodies. Two metanalyses pooled together results from these trials, providing highly consistent findings, and raising the question of how to translate them into the daily clinical practice.

In both metanalyses - Holch et al. included in their work five first-line randomized trials, while Arnold et al. also added the second-line 20050181 trial – a highly significant and clinically relevant benefit from the use of an anti-EGFR monoclonal antibody was reported among patients with left-sided RAS wt mCRC (located within the distal third of the transverse colon or beyond), while minimal or no benefit was evident among patients with right-sided RAS wt primary tumours (up to the proximal two thirds of the transverse colon). The predictive role of tumour sidedness was not significantly different between studies with or without bevacizumab in the control arm or according to the type of anti-EGFR used (cetuximab versus panitumumab). Also, the inclusion of the second-line 2005181 trial did not significantly modify results.

Overall, present data reinforce the adoption of anti-EGFR-containing regimens as first-line treatment for mCRC patients with left-sided primary tumours, while weakening their potential efficacy in right-sided tumours, where the choice of first-line chemotherapy plus bevacizumab should be encouraged in most cases. While modifying clinical decisions based on results from subgroup analyses is highly questionable by a methodological perspective, by a clinical point of view both the consistency of results across different trials and the strong underlying biologic and molecular background are not negligible. In fact, a growing amount of evidence threw light on the molecular make-up of right- and left-sided tumours, clearly showing that a continuum of differences occurs across different segments of the colon, with molecular alterations potentially related to resistance to anti-EGFRs much more represented in right- then left-sided tumours.

In conclusion, sidedness appears as a clinically useful surrogate of a complex landscape of molecular features accounting for resistance or sensitivity to EGFR blockade. While from a research perspective, deepening these molecular mechanisms is awaited, the inclusion of primary tumour location among other drivers for the choice of the first-line treatment may help to personalize treatment of mCRC patients.

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