Identifying biomarkers to improve the clinical management of patients with hormone receptor-positive/HER2-positive breast cancer.  

Impact

Approximately half of HER2-positive breast cancers also express hormone receptors (HR). However, chemotherapy in combination with anti-HER2 therapy is generally the treatment of choice and hormonal therapy as a secondary choice, irrespective of HR status. Since chemotherapy has several adverse side effects, researchers are looking for ways to decrease its use by identifying biomarkers that can predict which patients will benefit, and those that will benefit from alternative strategies. Recent evidence has indicated that HR, HER2 protein, and the signaling pathway activated by CDK4/6 kinases largely cooperate to facilitate tumor growth—this suggests that CDK4/6 kinase inhibitors may be an effective chemotherapy-free alternative. Dr. Biganzoli and her colleagues have identified a unique pattern of gene expression (gene signature) called RBsig that measures the activity of the CDK4/6 pathway. In laboratory models, they have shown that tumors with RBsig “high” status are relatively resistant to CDK4/6 inhibitors and have better response to chemotherapy whereas, RBsig “low” status predicts a better response to CDK4/6 inhibitors and a poor response to chemotherapy. In collaboration with the International Breast Cancer Study Group, Dr. Biganzoli is leveraging tissue collected from participants in the TOUCH trial (NCT03644186) to correlate RBsig status and treatment response. The results of her studies will inform treatment decisions for patients with HR-positive/HER2-positive breast cancer and ultimately improve outcomes for these patients.   

What’s Next

TOUCH is the first randomized clinical trial to directly compare chemotherapy versus the combination of estrogen with a CDK4/6 inhibitor (palbociclib) in patients with HR-positive/HER2-positive early breast cancer also receiving state-of-the-art anti-HER2 blockade. One hundred forty-four patients across three European countries have been enrolled in this trial. Dr. Biganzoli and her team are performing gene-expression analysis to assess RBsig status in pre-treatment tumor biopsies and correlating treatment response with RBsig high or low status. They will also determine RBsig status in post-treatment surgical specimens to study the changes in RBsig over time in non-responding patients. These studies will create a unique dataset that they will analyze to gain further insights into the biology of HR-positive/HER2-positive tumors, insights that will enhance treatment decision-making to improve outcomes for patients.