A major clinical trial to determine the best treatment for early-stage breast cancer testing positive for the HER2 protein is now enrolling women in North America, researchers from the Mayo Clinic and NCI announced last week at the NCI Science Writers' Seminar in New York City. The international trial, known as the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) study, will recruit 8,000 women with HER2-positive breast cancer in 50 countries across 6 continents and may set the standard of care for women with this aggressive type of breast cancer.

About 20 to 25 percent of breast cancers are studded with the HER2 protein, also known as human epidermal growth factor receptor 2. HER2 is involved in transmitting growth signals from external growth factors to a cell's nucleus. In some types of cancer, this growth signaling pathway leads to increased tumor cell proliferation, suppression of programmed cell death (apoptosis), enhanced motility, and increased tumor angiogenesis. HER2-positive breast cancer tends to be more aggressive, less responsive to standard treatments, and more likely to recur than breast cancer that does not contain HER2.

Patients with HER2-positive breast cancer may benefit from treatments that target this protein, and two targeted drugs, trastuzumab (Herceptin) and lapatinib (Tykerb), have been approved by the Food and Drug Administration to treat patients with HER2-positive tumors. While both of these agents target HER2, they do so in different ways. Trastuzumab, which is approved as a first-line treatment for metastatic disease or adjuvantly for early-stage breast cancer, is a monoclonal antibody that attaches to HER2-positive cancer cells and prevents the protein from receiving growth signals. It may also help a patient's immune system mount a response against the tumor. Lapatinib belongs to a class of drugs called small molecule inhibitors; its small size allows it to permeate the cancer cell and interrupt the HER2 signaling pathway from inside. Currently, lapatinib is only approved for the treatment of metastatic HER2-positve breast cancer. This study will be the first major trial of adjuvant lapatinib for early-stage breast cancer.

Approval of trastuzumab for treatment of early-stage, HER2-positive breast cancer in 2006 greatly improved outcomes for women with this disease, and researchers hope that the ALTTO trial will further extend the benefits of adjuvant therapy targeting HER2. In this trial, women who have undergone surgery to remove their tumors will be randomly assigned to receive lapatinib or trastuzumab alone, lapatinib administered after trastuzumab, or the two drugs administered together.

"The primary questions this trial is intended to answer are: Does lapatinib work better than trastuzumab or are they equivalent in terms of disease-free survival? Or might the combination of the two be better than either single drug alone?" says Dr. Edith Perez of the Mayo Clinic in Jacksonville, FL, and the North American coordinator for the trial. "We know that trastuzumab is a fantastic drug, but we're still not curing all women with this type of cancer. This trial is an important step toward curing more patients with breast cancer."

In addition to the targeted therapies being tested, all patients must have completed at least four cycles of anthracycline-based chemotherapy before randomization; patients for whom chemotherapy with a taxane is indicated will be treated with the drug paclitaxel (Taxol) along with their assigned targeted therapy.

"Adjuvant chemotherapy is very important for the treatment of HER2-positive breast cancer and is a required part of this study," says Dr. Perez.

The ALTTO trial is the first global initiative in which two large, academic breast cancer research networks covering different parts of the world - The Breast Cancer Intergroup of North America (TBCI), based in the U.S., and the Breast International Group (BIG) in Brussels, Belgium - have jointly developed a study in which all care and data collection are standardized, regardless of where patients are treated.

"We hope that this model of international collaboration is one which we can build upon in the future," says Dr. Jo Anne Zujewski, a senior investigator in the Clinical Investigations Branch in NCI's Cancer Therapy Evaluation Program.

—Daryl McGrath