The predictive role of ERBB2 point mutations in metastatic colorectal cancer: A systematic review

[Display omitted] •The predictive role ERBB2 mutations in metastatic colorectal cancer has been only partially assessed so far.•Pathogenic ERBB2 mutations are emerging as a driver of resistance to anti-EGFR agents in mCRC patients.•No anti-HER2 regimen has been proven active so far in specifically targeting ERBB2 mutant mCRC.•ERBB2 mutations emerged as a potential mechanism of acquired resistance to HER2-targeted therapy in ERBB2 amplified mCRC. ERBB2 amplification is a driver oncogenic alteration in many cancers and it has recently been incorporated among therapeutically actionable biomarkers also in metastatic colorectal cancer (mCRC). In contrast, the role of ERBB2 point mutations, which are detectable in up to 3% of CRC patients, remains to be assessed. In this systematic review, we collected preclinical and clinical data addressing the role of ERBB2 point mutations in mCRC patients as a predictive biomarker for anti-EGFR and anti-HER2 targeted agents, and as mechanism of acquired resistance to ERBB2 amplified mCRC treated with any anti-HER2 regimen. In both preclinical and clinical studies, most ERBB2 point mutations were associated with resistance to anti-EGFR agents, particularly L755S and R784G, which occur in the HER2 protein kinase domain. No ERBB2 mutation was associated with tumor response to HER2-targeted agents in mCRC patients, although signals of activity were observed in preclinical models. Eight ongoing clinical trials are underway to test different anti-HER2 treatments in ERBB2 mutant mCRC. Several reports documented the emergence of ERBB2 mutations in the circulating tumor DNA (ctDNA) of ERBB2 amplified mCRC progressing to anti-HER2 agents, thus hinting a role in acquired resistance.