Although co-targeting MEK and PI3K produced synergistic effects in preclinical studies of both breast cancer and other cancers in vitro [92,127] and in vivo [93,185], the clinical development of such combinations in patients with tumors harboring KRAS, NRAS, or BRAF mutations has been hampered by considerable toxicity and narrow therapeutic index [186,187,188]. This evidence concerns the gene PIK3CA and breast cancer.