Laura Biganzoli, MD

Identifying biomarkers to improve the clinical management of 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 hormone receptor, 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 called RBsig that measures the activity of the CDK4/6 pathway. In laboratory models, they have shown that tumors with high RBsig levels (called RBSig-high) 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.

Progress Thus Far

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. The trial accrued its target of 147 patients in July 2022. Dr. Biganzoli and her team have conducted gene-expression analysis of tissue specimens from all patients enrolled 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 how it changes over time.

What’s Next

Dr. Biganzoli and her colleagues will continue the tumor sequencing analysis. In addition to the pre-treatment tissue samples, they will also analyze the surgical samples obtained after treatment, which represent the “treatment resistant” tumors. Their analysis will yield unique insights into the biology of HR-positive/HER2-positive tumors, including drug resistance, and insights that will enhance treatment decision-making and improve outcomes for patients.