Lapatinib Targets Breast Cancer Stem Cells

eric · 04-02-2008, 02:55 AM

Then why isn't it more effective for a larger % of people?

http://www.oncology-times.com/pt/re/...195629!8091!-1

SAN ANTONIO-For the first time, researchers have demonstrated in vivo that a drug, lapatinib, decreases tumorigenic breast-cancer stem cells in the primary breast cancers of women receiving neoadjuvant treatment, slowing tumor growth.
The data from the prospective study suggest that specific signaling inhibitors of the pathways responsible for stem cell self-renewal could provide a therapeutic strategy for eliminating tumorigenic cells in order to achieve long-term eradication of cancer, said Jenny Chang, MD, Medical Director of the Breast Care Center and Associate Professor of Medicine at Baylor University.
Reporting at the San Antonio Breast Cancer Symposium, Dr. Chang said that six weeks of lapatinib treatment cut the number of breast-cancer stem cells by about two-thirds in 30 women studied. Additionally, two-thirds of patients had a pathologic complete response after follow-up treatment with trastuzumab and docetaxel, she said.
Dr. Chang explained that fewer than 10% of breast cancer cells have stem cell properties, but that it is this small number that continually reproduce and fuel tumor growth. The cancer stem cells have the same properties as other stem/progenitor cells, most notably the key features of self-renewal and giving rise to other cell types. Conventional chemotherapy does not eliminate breast-cancer stem cells.
Immunogenic Mice Study

The new human study builds on Dr. Chang's previous work, also reported at the meeting, that showed that a small number of tumorigenic breast-cancer stem cells-known as CD44+/CD24-/low-were able to generate new tumors when injected into immunogenic mice.
For that study, Dr. Chang and colleagues took core biopsy specimens from 35 women with breast cancer, before and after chemotherapy. The number of tumorigenic CD44+/CD24-/low cells significantly increased after chemotherapy, she reported.
Additionally, there was a three-fold increase in mammosphere formation. Mammospheres-clusters of cells that can be seen in suspension cultures-are a surrogate marker for cancer stem cells.
When the post-chemotherapy tissue samples were injected into immunocompromised mice, there was a rapid increase in tumorogenicity, with an increase in new tumor formation, Dr. Chang said. These findings support the hypothesis that chemotherapy fails to eliminate breast-cancer stem cells and leaves behind cells that have the capability of new tumor formation.
Targeting EGFR/HER2

Dr. Chang said that the epidermal growth-factor receptor/human epidermal growth factor 2 (EGFR/HER2) molecular pathways have been shown to be aberrant in cancer stem cells. This suggested that potent inhibitors of EGFR/HER2-such as lapatinib-could be potential breast-cancer stem cell inhibitors.
The new study involved 30 patients with locally advanced HER-2 overexpressing breast cancers. The patients were given lapatinib as a single agent for six weeks, followed by a combination of trastuzumab weekly and docetaxel thrice-weekly for 12 weeks, before primary surgery. At six weeks, 76% of patients had a partial response, 18% had stable disease, and the other 6% had a complete response.
Tumor Regression

Significant tumor regression, with a median decrease of 61% in bidimensional tumor measurements, was observed in the primary tumors after only six weeks of single-agent lapatinib.
Dr. Chang showed the audience before-and-after photos in which one could see large breast tumors shrinking and, in some cases, all but disappearing after lapatinib treatment.
As measured by follow cytometry, single lapatinib treatment decreased the population of tumorigenic CD44+/ CD24-/low breast-cancer cells, from 18% to 6%, she said. Additionally, there was reduced self-renewal capacity as measured by mammosphere assay.