An international clinical trial co-led by a VCU Massey Cancer Center researcher is expected to change the way a specific type of breast cancer is treated in some patients. The trial, known as KATHERINE, found that a drug called trastuzumab emtansine reduced the risk of cancer recurring by 50 percent in patients with HER2-positive early stage breast cancer who had residual disease after receiving chemotherapy or other treatments before surgery.

As global co-chair of the trial, Massey physician-scientist Charles Geyer, M.D., a professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine, presented the results at the 2018 San Antonio Breast Cancer Symposium, held Dec. 4-8. Data will be submitted to health authorities around the world, including the U.S. Food and Drug Administration and European Medicines Agency, and the study has been accepted for publication in The New England Journal of Medicine.

“I believe these results will be practice changing,” said Geyer, a medical oncologist specialized in breast cancer and the associate director for clinical research at Massey. “The results should form the foundation of a new standard of care in patients with residual invasive breast cancer following neoadjuvant therapy.”

The trial tested the efficacy and safety of trastuzumab emtansine, a combination of the FDA-approved drug trastuzumab and a chemotherapy drug called DM1. Trastuzumab emtansine is approved by the FDA to treat patients with metastatic HER2-positive breast cancer following previous treatment with trastuzumab and chemotherapy.

The aim of the trial was to see if the combination drug is better than trastuzumab at reducing the risk of cancer recurrence in patients with HER2-positive breast cancer who still had some cancer remaining after treatment done before surgery.

One in six women with breast cancer — about 15 percent of all breast cancers — are diagnosed as HER2-positive. HER2-positive refers to patients whose cancer cells are more aggressive and less responsive to chemotherapy due to the overexpression of a protein called Human Epidermal Growth Factor Receptor 2 (HER2).

Standard treatments for HER2-positive patients include chemotherapy and trastuzumab. After patients complete preoperative chemotherapy, they undergo surgery to remove any remaining tumor in the breast or lymph nodes under the arm. If there is no residual cancer found in the breast or lymph nodes after surgery, patients typically do well with little chance for cancer recurrence. However, if cancer is still present, patients have an increased risk of recurrence.

In KATHERINE, researchers tested two groups — one that received the standard treatment and one that received the investigational treatment — to determine whether the combination drug would reduce the risk of recurrence without an unacceptable increase in toxicities.

“The key to the success of [trastuzumab emtansine] is that the linker — the piece of the molecule that hooks the chemotherapy drug onto the antibody — is designed to come apart only when the molecule gets inside a cell. It doesn’t fall apart in your bloodstream and harm healthy cells,” said Harry Bear, M.D., Ph.D., local principal investigator for the trial at Massey. Bear is also the Dr. Walter Lawrence, Jr., Chair in Surgical Oncology at Massey and a professor of surgery and microbiology and immunology at the VCU School of Medicine.

Results of the trial showed that substituting trastuzumab emtansine in HER2-positive patients significantly reduced the risk of invasive disease recurrence or death.

“We found that [trastuzumab emtansine] improved the three-year invasive disease-free survival rate by 11.3 percentage points,” said Geyer, the Harrigan, Haw, Luck Families Chair in Cancer Research at Massey.

The side effects in the trial were similar to what occurs when trastuzumab emtansine is used for treating patients with metastatic disease. Side effects included drops in platelet count, sensory neuropathy and elevated liver enzymes. Most of these toxicities are resolved following reduction of the dose or discontinuation.

The trial is a study of 1,486 patients with residual HER2-positive breast cancer. The study opened in April 2013 and will continue to collect patient data until April 2023.