Red-blood-cell-boosting drugs used to treat anemia may undermine breast cancer treatment with Herceptin, a targeted therapy that blocks the cancer-promoting HER2 protein, researchers from The University of Texas MD Anderson Cancer Center report in the Nov. 16 edition of Cancer Cell.
"Our research indicates when the two drugs were used at the same time, Herceptin was less effective," said study senior author Zhen Fan, M.D., associate professor in MD Anderson's Department of Experimental Therapeutics.
Natural erythropoietin (EPO) controls the body's red blood cell production. Manufactured versions called erythropoietin-stimulating agents or recombinant erythropoietin treat anemia caused by kidney failure and cancer treatment.
"Recombinant erythropoietin is a great drug, and it's saved many lives," Fan said. "Some studies, however, have shown that the drug has effects on cancer cells. We wanted to see if recombinant erythropoietin thwarts Herceptin, based on our understanding of how the two drugs work."
The researchers tested their hypothesis using breast cancer mouse models, then followed up with laboratory experiments on cancer cell lines to work out the molecular details. A retrospective case control study of 111 breast cancer patients supported their findings from the mouse studies.
Human epidermal growth factor receptor-2 (HER2) is overexpressed in 25-30 percent of breast cancers. The drug trastuzumab, known commercially as Herceptin, is an antibody designed to block HER2. Because resistance develops, only about a third of HER2-positive patients respond to the drug.
The presence of functional erythropoietin receptors on HER2-positive breast cancer could be one resistance mechanism, Fan said.
"The whole idea with targeted therapy against the HER2 protein is to shut off the downstream molecular activity launched by HER2," Fan said. "Erythropoietin can activate similar downstream pathways if its receptor is expressed on cancer cells, causing antagonism between the two drugs."
Fan and colleagues demonstrate that when erythropoietin connects with its receptor protein (EpoR), it launches a chain of events that activates Src, a crucial component of a pathway that trastuzumab blocks. It also shuts down a well-known tumor-suppressing gene called PTEN that is believed to be important to trastuzumab's activity against cancer cells.
There is controversy in academic circles about the role and function of EpoR in cancer cells and other types of cells not involved in blood production. It's important to note, Fan said, the team found no evidence that recombinant erythropoietin alone promotes cancer growth.
Tracking down the details
In three HER2-positive breast cancer cell lines, trastuzumab inhibited cell survival and proliferation, while recombinant erythropoietin stimulated cell survival and growth. When the three lines were treated together with trastuzumab and the anemia drug, cell survival increased from 58 percent to 80 percent, 57 percent to 77 percent, and 34 percent to 57.5 percent, respectively.
Two HER2-positive breast cancer cell types were introduced to mice, who then either received mock treatment, trastuzumab only, erythropoietin only or both drugs. Tumors treated with trastuzumab either shrank or stopped growing, with average tumor volume close to zero after 50 days in one cell line and barely registering in another. Growth of tumors treated with erythropoietin closely tracked the control group, increasing rapidly to an average volume of 1,500 cubic millimeters in one line and 600 mm3 in another. Tumors treated with both drugs grew more slowly to about 700 mm3 and 300 mm3.
Improved patient survival in small study
In a retrospective case-control study of patients with HER2-positive breast cancer that had spread, the team compared overall survival and progression-free survival between a group of 37 patients who received trastuzumab plus chemotherapy and recombinant erythropoietin to a matched control group of 74 whose cancer was treated the same way but who received no EPO.
A statistically significant difference in progression-free survival emerged at one year, with 40 percent of the control group having stable disease compared with 19 percent of the erythropoietin group. Overall progression-free survival differences across two years were not statistically significant.
The control group also had better overall survival than the erythropoietin group that was statistically significant in an analysis of multiple variables.
Fan emphasized that clinical findings should be interpreted with caution because the study was small and retrospective. Patients who received erythropoietin might have been sicker than the patients not treated with erythropoietin. Their findings need to be confirmed by larger clinical studies.
"We're expanding this study to include other types of cancer," Fan said. "Of course, different types of cancers are treated with different types of targeted therapies. We need to design our studies using different targeting agents than Herceptin to study whether erythropoietin can antagonize these drugs," Fan said.
Looking forward, Fan said, researchers need to find out why and how some cancer cells express the receptor protein for erythropoietin, and to what extent cancer cells express EpoR. "Recombinant erythropoietin helps to improve a patient's general condition without the need for a blood transfusion," Fan said. "If we can figure out how the expression of the erythropoietin receptor is regulated in cancer cells, we may come up with some new strategies to allow cancer patients to receive the drug for their anemia and fatigue without compromising their treatment with novel targeted therapies, such as anti-HER2 therapy with Herceptin."
The study was funded by a grant from the National Cancer Institute, research awards by the Breast Cancer Research Foundation, and by MD Anderson's Cancer Center Support Grant from from the NCI.
Co-authors with Fan, all from MD Anderson, are first author Ke Liang, Yang Lu, Xinqun Li, M.D., Ph.D., and John Mendelsohn, M.D., all of the department of Experimental Therapeutics; Francisco Esteva, M.D., Ph.D., Giampaolo Bianchini, M.D., Ching-Yi Yang and Gabriel Hortobagyi, M.D., all of the Department of Breast Medical Oncology; Yong Li, Ph.D., Constance Albarracin, M.D., Ph.D., of the Department of Pathology; Katherine Stemke-Hale, Ph.D., and Gordon Mills, M.D., Ph.D., of the Department of Systems Biology; and Chun-Te Chen and Mien-Chie Hung, M.D., Ph.D., of the Department of Molecular and Cellular Oncology.
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