Everolimus May Overcome Trastuzumab Resistance in HER2-Positive Breast Cancer Patients
Adding everolimus to trastuzumab in the treatment of HER2-positive metastatic breast cancer helps some women whose disease has been resistant to previous trastuzumab-based therapies, according to a study conducted at The University of Texas MD Anderson Cancer Center and other centers.
In the phase I/II study, 47 women with HER2-positive metastatic breast cancer that had progressed on trastuzumab-based therapy were given trastuzumab every 3 weeks and the mTOR (mammalian target of rapamycin) inhibitor everolimus daily.
The treatment was well tolerated, and side effects, which included fatigue, infection, and mouth sores, were manageable. The combination therapy resulted in partial responses in 15% of the patients and persistent stable disease in 19%.
“Even if HER2-positive metastatic breast cancer initially responds to trastuzumab, the disease usually eventually progresses,” said Phuong Khanh Morrow, M.D., an assistant professor in the Department of Breast Medical Oncology and a co-author of the study’s report, which was recently published in the Journal of Clinical Oncology.
Resistance to the monoclonal antibody trastuzumab has been linked to the activation of the PI3K (phosphoinositol 3-kinase) signaling pathway. PTEN (phosphatase and tensin homolog), a tumor-suppressing protein, can negate the activity of PI3K, thus inhibiting the activation of the mTOR pathway. However, in the absence of PTEN, PI3K activity leads to the activation of the mTOR pathway, which causes trastuzumab resistance.
On the basis of preclinical data developed at MD Anderson, Dr. Morrow and her colleagues hypothesized that mTOR inhibition with everolimus would abrogate trastuzumab resistance in patients whose tumors had PTEN loss and/or mutations in the PI3KCA gene.
The study’s results showed that patients whose tumors had PTEN loss had lower rates of overall survival than did patients whose tumors had normal PTEN levels but that PTEN levels did not affect progression-free survival rates. PIK3CA mutations did not significantly affect progression-free survival or overall survival. Dr. Morrow and her colleagues believe that these findings suggest that the addition of everolimus may slow tumor progression through the inhibition of mTOR.
“This is a great example of translational research—applying a novel concept from bench to bedside to benefit our patients,” said Francisco J. Esteva, M.D., Ph.D., a professor in the Department of Breast Medical Oncology and the senior author of the study’s report.
For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.
Other articles in OncoLog, September 2011 issue: