PI3K Activation Might Predict Trastuzumab Resistance

In a Scientific Symposium at ECCO/ESMO, researchers from the Netherlands Cancer Institute, Department of Molecular Carcinogenesis; Academic Medical Center, Department of Pathology; and MD Anderson Cancer Center, Department of Systems Biology, discussed the PI3K pathway as a factor in poor response or resistance to HER2-inhibitors such as trastuzumab (Herceptin). One year of treatment with trastuzumab has become standard adjuvant therapy in patients with HER2-positive early stage breast cancer. Despite these patients’ HER2-positive status, approximately half are nonresponsive to trastuzumab or become resistant to the drug. As part of the drive toward more personalized cancer care, the investigators decided to search for biomarkers that predicted those patients likely to be resistant or refractory to HER2 inhibitors.

First, they used genetic screening in a breast cancer cell line that over expresses HER2. They identified approximately 8000 suspect genes. Of these, they found that “only knock down of PTEN conferred resistance to trastuzumab.” Loss of PTEN expression has received increasing attention recently as a prognostic marker in various solid tumors and hematologic malignancies. In this study, the researchers found decreased PTEN expression resulted in hyperactive signaling via the PI3K pathway. This, combined with earlier in vitro studies associating overexpression due to PIK3CA mutations with resistance to trastuzumab, suggests the PI3K pathway plays a significant role in conferring resistance to trastuzumab.

After cell culture experiments seemed to uphold the theory that PI3K activation was causing trastuzumab resistance, the researchers decided to go forward with a clinical trial. They examined data for 55 women who were treated with adjuvant trastuzumab for metastatic breast cancer and found that those whose genetic profiles showed activation of the PI3K pathway (indicated by PIK3CA mutations or low PTEN expression) had poorer responses to trastuzumab. Taking both indicators together--PIK3CA mutations and low PTEN expression--proved nearly twice as accurate as PTEN loss alone in identifying which women on trastuzumab were at greatest risk for disease progression.

The investigators concluded that patients who are nonresponsive to trastuzumab or are at risk for developing resistance based on PI3K activation may benefit from combination regimens designed to prevent resistance. They are currently looking at a similar cohort of 50 patients who were treated with neoadjuvant trastuzumab to see whether PI3K activation might also constitute a predictive biomarker in the this setting.

ECCO/ESMO Abstract I-57