Combining two therapies that target the same protein but different cellular pathways in breast cancer may provide a boost in patient treatment, said researchers from Baylor College of Medicine and The Methodist Cancer Center in a report that appears in the current issue of the Journal of Clinical Oncology.

"We found that trastuzumab (Herceptin) and lapatinib (Tykerb) work differently by different pathways," said Dr. Jenny C. Chang, director of The Methodist Cancer Center and senior author of the report. "These drugs are very active. They increase your chances of beating cancer, and he combination of both drugs is likely to work better together."

Combination of drugs

"We are suggesting that we need to consider using a combination of the drugs, particularly when the tumor is resistant to trastuzumab," said Dr. C. Kent Osborne, director of the Dan L Duncan Cancer Center and the Lester and Sue Smith Breast Center at BCM. He said larger studies in patients are needed to determine the value of the combination in treating at least some patients with resistant breast tumors.

In their study, researchers first evaluated the effects of trastuzumab and lapatinib in three breast cancer cell lines that produced high levels of HER2, a protein associated with aggressive breast tumors. In these studies, the researchers found that the cells with low levels of a phosphatase called PTEN (phosphatase and tensin homolog) or mutations that activate another cellular pathway called PI3K were resistant to trastuzumab alone. However, the combination of the two drugs decreased the activity of cell pathways associated with growth.

In the clinical study, 35 patients received trastuzumab alone for the first three weeks and the combination of trastuzumab with a cancer drug called docetaxel for 12 weeks. In a comparison group, 49 patients received lapatinib alone for six weeks followed by trastuzumab and docetaxel for 12 weeks. After the drug treatment, all patients underwent surgery to remove the tumor.

Different responses

In the first group, 11 of 32 patients who completed the treatment had a pathologic complete response while in the second group, 24 of 38 patients who completed treatment had a similar positive outcome. (A pathologic complete response is one in which no living tumor cells are found in samples taken from the removed tumors.)

"We are suggesting this combination be used in patients especially when you see Herceptin (trastuzumab) resistance," said Dr. Bhuvanesh Dave, a first author of the report and a member of the faculty of the Methodist Cancer Center. "It has the potential to give us the least amount of resistance."

The loss of PTEN might be considered a marker for resistance to trastuzumab. Tumors with low PTEN and an activated P13 kinase would be considered candidates for the combined treatment.

"It is important because it shows that these two medicines, although targeting the same receptor, work by distinct mechanisms and that different patients may respond differently to different medicines. This also gives strong rationale for our study of the combination of both agents in patients," said co-author Dr. Mothaffar Rimawi, assistant professor in the Lester and Sue Smith Breast Center at BCM.

Others who took part in the research include Ilenia Migliaccio (a co-first author), M. Carolina Gutierrez, Meng-Fen Wu, Gary C. Chamness, Helen Wong, Susan G. Hilsenbeck, Jian Huang, and Rachel Schiff, all of BCM. Anindita Chakrabarty and Carlos Arteaga of Vanderbilt University in Nashville, Tennessee, are also co-authors.

Funding for this work came from the National Institutes of Health/National Cancer Institute, Breast Cancer Research Foundation, Glaxo Smith Kline and the U.S. Army Medical Research and Materiel Command.