BCRF-Supported Study Identifies Gene Network to Better Predict Treatment Response for HER2-Positive Breast Cancer

BCRF investigator Dr. Lajos Pusztai and his team have discovered a new way to combat drug resistance in HER2-positive cancer.

A team of Yale researchers has discovered a new complexity in drug resistance that may lead to the development of future therapies for patients with HER2-positive breast cancer.

The study, led by BCRF investigator and Scientific Advisory Board member Dr. Lajos Pusztai, was presented at the 2015 San Antonio Breast Cancer Symposium. His team analyzed DNA from 203 HER2-positive cancer samples from the international NeoALTTO clinical trial to determine whether specific gene mutations could predict response or resistance to HER2-targeted therapies.

“The goal of this study is to eventually develop an assay to better define which patients with HER2-positive breast cancer will do better on trastuzumab (brand named Herceptin ©) or lapatinib (brand name Tykerb ©),” Pusztai said.

HER2-positive breast cancer is an aggressive form of the disease that comprises 20 percent of all breast cancers. In the study, patients with early stage breast cancer were treated pre-operatively with either paclitaxel (Taxol) chemotherapy in combination with one of two HER2 targeted therapies (trastuzumab or lapatinib), or with the drugs alone.

“The key finding is that different cancers acquire resistance to trastuzumab through different mutations in different genes,” Pusztai said. “The silver lining is that these genes participate in biological processes that are all connected through the PIK3CA gene.”

While mutations in the PIK3CA gene were already known to be a marker of decreased sensitivity to trastuzumab, these new results extend this association to a broader network of genes. For instance, investigators also identified a different set of genes whose mutations were associated with greater sensitivity to lapatinib. All of these genes involve the regulation of cell movement.

The findings lead to the conclusion that alterations at the level of pathways may be more informative as predictive markers than single gene mutations, Pusztai said. The next step after this discovery is to validate the findings using a similar data set obtained from clinical trials. This way the team can test their hypothesis to prove whether or not it’s valid.

Pusztai is looking forward to this – and acknowledged his BCRF support that allows him to pursue his work.  

“We couldn’t have done this without BCRF funding,” he said.