Real-world data analysis from Dana-Farber Cancer Institute and the Gustav Roussy Cancer Center in Paris has validated predictors of exceptional responses to HER2-targeted therapies in metastatic breast cancer. The findings, derived from the EMBRACE metastatic breast cancer program and the Épidémio-Stratégie Médico-Economique (ESME) database, highlight specific clinical and genetic factors associated with prolonged progression-free survival in a subset of patients. This research may pave the way for personalized treatment strategies and clinical trials aimed at optimizing outcomes for individuals with HER2-positive metastatic breast cancer.
Identifying Exceptional Responders
Stefania Morganti, MD, a clinical research fellow in Dr. Parsons' lab, defined exceptional responders as those who survived without progression on first-line anti-HER2 therapy for at least three years, three times the median duration. Analysis of the EMBRACE database revealed that 28% of patients with HER2-positive metastatic breast cancer were exceptional responders, while a similar analysis of the ESME database, led by Dr. Thomas Grinda, showed 25% of patients being exceptional responders.
"It's impressive, because we think of metastatic disease as incurable, with a dismal prognosis," says Dr. Morganti.
Predictors of Exceptional Response
Both the EMBRACE and ESME database analyses identified consistent predictors of exceptional response. These included:
- Strong HER2 expression on cancer cells
- De novo metastatic disease (disease already spread at diagnosis)
- Treatment with the triplet regimen of trastuzumab, pertuzumab, and chemotherapy
Genetic Markers and Treatment Response
Genetic sequencing data from the EMBRACE repository identified PIK3CA and MYC mutations as potential markers associated with poor response to therapy. While PIK3CA was already known, MYC is a novel finding in this setting. Further research is underway to validate these findings and determine how they might be used to guide treatment decisions.
"The genomics plus the clinical variables could be a strong predictor of who is going to be an exceptional responder," says Dr. Grinda.
Future Directions and Clinical Trials
Building on these findings, Dr. Parsons is planning a clinical trial called SAPPHO to identify conventional responders and examine the effects of intensifying therapy. Additionally, the STOP-HER2 trial will explore the possibility of safely stopping treatment for exceptional responders.
"There is this dogma that we can't cure metastatic disease," says Dr. Parsons. "But if we have these really effective therapies, maybe we can."
