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Study of targeted therapies for breast cancer established model for global clinical trials

  • Posted: February 29, 2008
  • Updated: June 1, 2014

Two targeted medications designed to treat an aggressive form of breast cancer were tested in a study that involved 8,000 participants in 44 countries. While the purpose of this trial was to enable researchers to determine whether dual targeted treatment of early stage HER2-positive breast cancer was better than using a single agent against HER2-positive disease, results of this trial did not show a benefit for women taking the drug combination of trastuzumab or lapatinib. The trial however, did provide a new model for global cancer research and collaboration.

ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) was one of the first global initiatives in which two large academic breast cancer research networks, covering different parts of the world, jointly developed a study in which all care and data collection were standardized, regardless of where patients received treatment. The networks were the North American Breast Cancer Groups (NABCG), based in the United States, and the Breast International Group (BIG) in Brussels, Belgium. The National Cancer Institute (NCI), part of the National Institutes of Health, supported this research.

ALTTO was a randomized, phase III study, which is considered a gold standard method for proving drug effectiveness. It answered several questions regarding use of two widely used cancer agents: were two agents more effective than one agent, was one agent safer, and what benefit would be derived by patients who took these drugs -- either together or separately?

The two agents tested in ALTTO were drugs designed to treat HER2-positive tumors, which comprise a particularly aggressive form of cancer that affects approximately 20 percent to 25 percent of breast cancer patients. Both agents, trastuzumab (Herceptin) and lapatinib (Tykerb), were already approved by the U.S. Food and Drug Administration for use as treatment of HER2-positive breast cancer. HER2-positive breast cancer is caused by an excess number of HER2 genes or by over-production of its protein product, the HER2 cell surface receptor. Trastuzumab is a large monoclonal antibody that, once injected into patients, attaches to the portion of the HER2 protein that sits on the outer surface of the cancer cell, whereas lapatinib acts by entering a cancer cell and binding to the part of the HER2 protein that lies beneath the surface of the cell’s outer membrane.

The clinical result of ALTTO was disappointing, particularly in light of the promise of the NeoALLTO trial where patients treated with the combination of lapatinib and/or trastuzumab had shown improved response rates, however, because of ALTTO, all women with early stage HER2-positive breast cancer now know the degree of benefit for these drugs. These results were available sooner, and with fewer patients, because of this international collaboration.

In addition, ALTTO was one of the first trials of its scope in translational research -- taking science from bench to bedside. In ALTTO, biological material was collected from thousands of patients in order to determine a tumor profile that responds best to the drugs. This type of research has the potential to produce data that could lead to individualized patient care and, possibly, to development of a next generation of targeted agents, noted the investigators. Based on the findings from this trial, scientists may be able to sooner determine why 550 patients of the 8,000 in the trial relapsed.

Edith Perez, M.D., an oncologist at Mayo Clinic in Jacksonville, Florida, and Martine J. Piccart, M.D., Ph.D., professor of oncology at the Université Libre de Bruxelles, Belgium, and lead investigator for BIG, led the development team of the ALTTO trial and acted as the study's co-principal investigators. On behalf of BIG and NABCSG, these two lead investigators have been working toward collaborative clinical studies for a number of years. The ALTTO study, they said, represented a new paradigm that blended the high standards of both systems in order to test the latest breast cancer treatments as efficiently as possible in thousands of women worldwide.

"The NCI greatly appreciates the work that NABCG and BIG are doing to help advance our understanding of the complex mechanisms that underlie different types of breast cancer," said Jo Anne Zujewski, M.D., a senior investigator in the clinical investigations branch at NCI." This model of international collaboration is one which we can build upon in the future.”

GlaxoSmithKline provided the study drug, as well as additional financial support for the ALTTO trial. All drugs carry potential side effects, and more information of side effects for lapatinib and trastuzumab can be found in the Q&A at: NCI and GSK also provided comment and input on the design of the study.

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For a Q&A on this trial, please go to

For Spanish translations of the press release and Q&A, please go to

For more info on BIG, please go to Exit Disclaimer.

For more info on Mayo, please go to Exit Disclaimer or contact the Mayo Clinic Cancer Center Clinical Trials Referral Office at 507-538-7623.