Because transactivation of the IGFR pathway is a well-recognized mechanism underlying de novo (i.e., primary) [113] and acquired (i.e., secondary) [114, 115] resistance to anti-HER2 therapies, metformin's ability to simultaneously target HER2, while preventing increased IGF-IR signaling may represent a potential therapeutic tool in breast carcinomas resistant to HER2-directed therapy. This evidence concerns the gene ERBB2 and breast carcinoma.