Dr. Jenny Chang, previously with the Smith Breast Center and now director of the Methodist Cancer Center in Houston, will present the results of this clinical study (TBCRC 006) in an oral presentation at the annual ASCO meeting in Chicago in June.
The clinical trial involved 64 women with large tumors that tested positive for HER-2 and some that were also estrogen-receptor positive. Using two drugs – lapatinib and trastuzumab – that target HER-2 in different ways, physicians were able to eradicate tumors in 38 percent of estrogen-receptor negative patients and 21 percent of estrogen receptor-positive patients, said Dr. C. Kent Osborne, director of the Smith Breast Center and a senior author of the report. Estrogen-receptor positive patients were also given an aromatase inhibitor to stop production of estrogen.
Preclinical models developed at BCM
“We have shown in preclinical models that complete blockage of the HER-2 family including HER-1, 2 and 3 with the drugs lapatinib and trastuzumab leads to eradication of HER-2 positive tumors in mice,” said Dr. Mothaffar Rimawi, medical director of the Smith Breast Center and current principal investigator on the study. “These drugs alone only partially inhibit the pathway, quickly resulting in resistance to treatment.” Rimawi developed this model in 2004 as a fellow in the laboratory of Osborne and Dr. Rachel Schiff, associate professor in the Smith Breast Center and a co-author on the paper.
“We conducted two prior clinical studies over the last ten years that show that lapatinib and trastuzumab are effective as single agents but our preclinical data suggested they would likely work better when used together,” said Chang.
The research team at Baylor College of Medicine sought to translate these findings to patients, so they initiated a multicenter clinical trial through the TBCRC.
The same response (eradication of tumors) that Rimawi and his team observed in preclinical models in the laboratory was also seen in many patients in this clinical trial, Osborne said.
The TBCRC 006 trial recruited a total of 64 patients through the Smith Breast Center (at the Baylor Clinic and Ben Taub General Hospital sites), the Vanderbilt University School of Medicine, the University of Alabama at Birmingham, the University of Chicago, and the Mayo Clinic College of Medicine.
The patients had large (average of 6 cm) HER-2 positive tumors in the breast when they were initially diagnosed. They were given a combination of lapatinib (Tykerb®) daily and trastuzumab (Herceptin®) once weekly for 12 weeks before surgery without standard chemotherapy. Lapatinib is a pill that blocks the enzyme activity of HER-2 and its close family member HER-1. Trastuzumab is an antibody administered intravenously that blocks HER-2 in a different way. Some patients’ tumors were also estrogen-receptor positive (grow in the presence of the hormone estrogen). These patients were given an aromatase inhibitor to stop production of estrogen.
“With this combination, we are able to block all of the cancer-promoting signals from the HER family, which we know is crucial for growth of this kind of breast cancer,” said Osborne, also director of the NCI-designated Dan L. Duncan Cancer Center at BCM. “Each of these drugs hits a different receptor, thereby shutting down the pathway responsible for the breast cancer’s growth.”
No patients were given chemotherapy during that 12-week period. Tumor biopsies were gathered at study entry, 2, 8 and 12 weeks (the time of surgery) to study how the drugs were working.
After 12 weeks, 38 percent of the estrogen-receptor negative, HER-2 positive patients had eradication of invasive breast cancer from the breast – “the type of breast cancer that can spread beyond your breast and invade healthy, surrounding tissue, and other organs,” said Rimawi.
A significant benefit was also observed in the estrogen-receptor positive group, Rimawi said. “Twenty-one percent of these patients had complete disappearance of their tumors and another 34 percent had near eradication with only small amounts of tumor left after treatment.”
“We have seen similar results in other recently reported studies using the lapatinib/trastuzumab combination, but this is the first study not to use chemotherapy,” said Osborne. “The side effects of chemotherapy can be significant and eliminating the need for chemotherapy in certain patients would represent a groundbreaking approach to treatment.”
Another strong point of this trial was the representation of minority women in the study group. Of the group, 33 percent were Hispanic and 21 percent were African-American, Rimawi said.
Next steps in research
“Our next step with this research will be to determine the optimal duration of treatment,” said Rimawi. “In an upcoming multicenter TBCRC clinical trial led by us at Baylor College of Medicine, we will compare 12 weeks with 24 weeks of treatment.” Studies are underway now to identify which patients can be safely treated without chemotherapy for this subtype of breast cancer which used to be considered difficult to treat.
For more information on enrolling in that trial, please contact Anne Pavlick at 713-798-7814 or [email protected].
This study was supported by GlaxoSmithKline and the Translational Breast Cancer Research Consortium.