Moreover, the METTEN trial was conducted in patients with the HER2+ subtype of breast cancer, which leaves open the question of whether the circulating levels of MOTS-c and/or the regulatory activity of metformin on MOTS-c might be different in patients with other BC subtypes, such as luminal A, HER2-negative luminal B or triple negative [31]. This evidence concerns the gene ERBB2 and breast cancer.