Coordinated signaling between HER-family receptors and c-Met has been demonstrated to drive breast cancer in some patients. Although combination therapies targeting HER and c-Met can be very effective in some of these patients, no clinical data has supported an approval for this drug combination in breast cancer. In a recent study, researchers examined the ability of a new clinical test to identify potentially responsive patients. The test, called the CELsignia Multi-Pathway Signaling Function Test, uses an impedance biosensor loaded with a patient’s live tumor cells to quantify cell signaling responses in real time. Using this test, the researchers identified patients whose HER2-negative breast tumors had hyperactive coordinated HER1, HER2, HER3/4, and c-Met signaling, despite having normal expression levels of these receptors on their tumor cells. These results indicated that the identified patients might be responsive to HER-/c-Met-targeting combination therapy. Specifically, analyses of the tumor cells’ responses to HER and c-Met agonists and targeted treatments (including combination treatment) suggested hyperactive signaling, and results obtained in mouse xenograft tumor models supported the CELsignia test results. Although the outcomes of clinical tests remain to be determined, these preclinical results demonstrate the potential benefit of the CELsignia test for identifying patients who may respond well to combined c-Met + pan-HER targeted therapies.