Breast cancer trials that focus on giving treatment before surgery broaden understanding of the disease and may lead to better adjuvant trials
“When we give therapy before removing the tumor, we have easy access to good-quality tumor material that can be interrogated with molecular methods, and that information is then correlated with clinical response,” says Carlos L. Arteaga, MD, director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center (Nashville, TN). “What we learn about treated tumor cells could potentially lead to the discovery of mechanisms of drug resistance and/or new therapeutic targets, and we're starting with the patient and the actual tumor in question.”
Providing therapy before surgery to shrink tumors, known as neoadjuvant systemic therapy or preoperative therapy, is increasingly common in breast cancer treatment. Because studies have shown that the order of therapy does not affect overall survival, and because neoadjuvant therapy allows quick tracking of a tumor's response to therapy, investigators are seeking to optimize this approach in trials.
“Neoadjuvant trials allow for better patient selection, leading to smaller trials; they improve our ability to study tumor subsets, biomarkers, and dual-targeted therapies; and they are faster, offering results in months rather than in years,” says Lisa A. Carey, MD, medical director of the University of North Carolina Breast Center.
“In an age when we have a lot of good ideas, neoadjuvant trials may help us triage among them,” she adds. “For example, in HER2-positive tumors, which patients benefit the most from dual targeting? Might some patients forego chemotherapy?”
Broadening the Scope
Instead of looking at overall or disease-free survival, neoadjuvant trials typically rely on a surrogate endpoint called pathologic complete response (pCR), generally defined in breast cancer as the disappearance of tumor cells in the breast and regional lymph nodes. Many patients don't respond to therapy, and in these cases better predictive factors are needed. But patients who achieve a pCR tend to have good long-term outcomes.
Results of these trials may help to improve the design of adjuvant trials as well, researchers say. For example, the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) and the Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation (NeoSphere) trials have already begun to give hints as to the outcomes of corresponding adjuvant trials.
Specifically, NeoALTTO demonstrated that combining the 2 anti-HER2 drugs lapatinib and trastuzumab was better than using a single agent in early breast cancer (Lancet 2012; 379:596–8). More than half of the patients in the combination arm achieved pCR, meaning tissue samples showed no residual cancer cells.
A larger adjuvant companion study—Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO)—is in progress, and if long-term results continue to match NeoALTTO, it may change clinical trial practice by showing that smaller neoadjuvant trials can offer proof of principle before studies in larger populations.
The contrast-enhanced MRI used in I-SPY 2 includes automated functional measures of tumor volume before, during, and after chemotherapy. Here, MRI scans (top row) show a decrease in tumor volume. The signal enhance-ment ratio (SER) map for each scan (bottom row) shows changes in tumor kinetics with highest SER (red) tumor disappearing and tumor with per-sistent kinetics (blue) remaining over time. [Photo courtesy of Nola Hylton and Laura Esserman, University of California, San Francisco]
The contrast-enhanced MRI used in I-SPY 2 includes automated functional measures of tumor volume before, during, and after chemotherapy. Here, MRI scans (top row) show a decrease in tumor volume. The signal enhance-ment ratio (SER) map for each scan (bottom row) shows changes in tumor kinetics with highest SER (red) tumor disappearing and tumor with per-sistent kinetics (blue) remaining over time. [Photo courtesy of Nola Hylton and Laura Esserman, University of California, San Francisco]
Picking the Right Patients
Laura Esserman, MD, MBA, director of the Carol Franc Buck Breast Care Center at the University of California, San Francisco, points out that patient selection is key for these trials.
“Women with low-risk cancers are not going to benefit in most cases,” says Esserman, co-principal investigator for the neoadjuvant Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2 (I-SPY 2) trial. “But, as a surgeon, I know that for women with certain high-risk tumors, surgery alone is not going to cure their cancers. We believe understanding how each tumor responds to therapy early is going to give us the best chance at offering that patient a cure both now and in the future.”
The I-SPY 1 trial showed that biomarkers can predict response to therapy and outcomes (Breast Cancer Res Treat, 2011 Dec 25 online ahead of print). The I-SPY 2 trial goes a step further—cycling up to a dozen promising investigational drugs for various subset populations using an “adaptive” design model. “We've worked closely with the U.S. Food and Drug Administration, receiving a master Investigational New Drug approval so that we can seamlessly graduate, drop, or add drugs without writing a new protocol,” notes Esserman.
Clinical investigators emphasize that the decision to enroll patients in a neoadjuvant trial or to opt for clinical neoadjuvant therapy should be based on each patient's tumor profile and personal preferences. Additionally, neoadjuvant therapy should reflect what that patient would receive in an adjuvant setting, even if investigational agents are added.
Extended studies are required to answer questions about pros and cons of neoadjuvant trials. For now, researchers seek to move the field forward and benefit patients.
“Waiting until cancers metastasize to test some drugs doesn't make sense,” declares Esserman. “If we can show that giving a drug like Herceptin early is likely to offer a cure for some women, we've got to take that step to test drugs when they have the greatest chance of working and changing the outcome.”
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