A Conversation With
A Conversation with...Dr. Edith Perez
Dr. Edith Perez is a professor of medicine at the Mayo Clinic in Jacksonville, FL, and the co-principal investigator and North American coordinator for the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) clinical trial, an international phase III clinical trial that aims to define the optimal treatment for early stage HER2-positive breast cancer.
What are the primary goals of the ALTTO study?
Our goal is to optimize adjuvant anti-HER2 therapy in patients with early stage HER2-positive breast cancer. Translational research goals include enhancing our understanding of the biology of HER2-positive disease and identifying molecular markers of sensitivity and/or resistance to trastuzumab and lapatinib.
Why test lapatinib as adjuvant therapy when trastuzumab is already approved in the United States for that purpose?
Lapatinib has been approved in the U.S. and other countries for metastatic HER2-positive breast cancer. ALTTO is the definitive trial to determine whether lapatinib merits not only regulatory approval but also routine use in clinical practice in the adjuvant setting. Adding trastuzumab to standard adjuvant treatments for breast cancer has resulted in dramatically improved disease-free and overall survival in most trials, but it does not always prevent recurrence or cure all patients. We need to work together to determine whether we can improve on what we have accomplished so far in targeting HER2.
What is the role of adjuvant chemotherapy in this study?
Based on improved survival data, chemotherapy is standard for breast cancer patients at high risk of recurrence after surgery. Previous research has shown that the activity of anti-HER2 agents alone is modest and that their benefit is improved when administered with chemotherapy. So at this time, optimization of anti-HER2 adjuvant therapy requires the integration of HER2-targeted agents with other effective treatments such as chemotherapy.
ALTTO currently requires anthracycline therapy prior to enrollment because these agents have clearly demonstrated improved survival in patients with breast cancer, and they were used by more than 10,000 patients in the pivotal adjuvant trastuzumab trials (N9831, B-31, HERA, BCIRG-006, PACS-04, and FinHER).
In the interest of broadening chemotherapy regimens to include a non-anthracycline option, we are conducting a pilot study to determine the safety of a regimen of non-anthracycline chemotherapy, trastuzumab, and lapatinib (NCCTG-N083E). We anticipate modifying the ALTTO protocol to allow a non-anthracycline pretreatment regimen before the end of this year, if we can document safety.
What data collection challenges have the ALTTO investigators faced?
The study currently requires submission of tumor blocks so that we can conduct subsequent translational studies. This has been a challenge here in North America, and some sites are not offering this important trial to patients because of institutional rules “prohibiting” submission of tumor blocks in the context of clinical trials. We are particularly concerned about this trend, as speeding up incorporation of new agents and bringing about cures for breast cancer patients depends on good science, collaboration, and biological understanding of this disease. We will continue working with investigators, patients, the College of American Pathologists, and NCI to further address this barrier.
In terms of other data issues, our case report forms are comprehensive, but not substantially different from other adjuvant trials. We collect relevant safety and efficacy parameters, and we propose to follow patients for longer than 10 years from enrollment in order to gather short- and long-term data.
Is ALTTO predominantly a European trial?
No, ALTTO is a global trial. We actually began proposing incorporation of adjuvant lapatinib in trials back in 2004, even before we had data from the pivotal trastuzumab studies. This was based on the prediction that trastuzumab would improve adjuvant outcomes, early preclinical data with lapatinib, and our prediction that it would be the most rational next step in adjuvant anti-HER2 trials. We then collaborated with investigators around the world, NCI, and industry to develop a single global study. The idea was, and is, to avoid duplication of efforts and to work together to advance the care of patients with early HER2-positive breast cancer. Because of regulatory issues and the IRB processes in the United States and Canada, the trial was activated first in Europe, but it is now active not only in North America and Europe but also on four other continents (50 countries total), making this a truly global collaboration.