Interesting research re Her2

[Soccermom]

John Mendelsohn, MD








Professor and President
The University of Texas MD Anderson Cancer Center, Houston, TX


2007-2008 BCRF Project:
Co-Investigator: Zhen Fan, MD, The University of Texas MD Anderson Cancer Center

Recombinant erythropoietin (EPO) is a bioactive protein drug currently used in the clinic for alleviating cancer- or cancer chemotherapy-related anemia and fatigue in cancer patients, including breast cancer patients, owing to its effects on stimulating the production of red blood cells by prolonging the survival of their precursors in the bone marrow.
Controversy has arisen recently as some emerging evidence suggested that certain breast cancer cells also express EPO receptors (the specific cell membrane proteins through which the biologic information of EPO is transmitted into cells). Recombinant EPO may act on breast cancer cells and red blood cell precursors in a similar way. Therefore, recombinant EPO may protect breast cancer cells from various cytotoxic treatments by activating the receptor of EPO in breast cancer cells and, as a result, prolonging breast cancer cell survival.
Over the past year, Drs. Mendelsohn and Fan focused on demonstration of specific cell signaling activated by EPO in breast cancer cells, and evaluated the extent to which EPO plays a negative role in breast cancer responses to trastuzumab treatment. It is expected that successful completion of the planned studies will provide important guidance as to whether recombinant EPO is safe to be used concurrently with trastuzumab for HER2-positive breast cancer patients whose tumors are also positive for the receptor of EPO. This is a very important issue, and the knowledge generated from this research will be of great value to the clinical management of breast cancer and will ultimately benefit patients. Mid-Year Progress Report:
Resistance of some HER2-overexpressing breast cancer patients to Herceptin (an antibody drug approved for treating patients with HER2-positive breast cancer) remains a challenge in clinical practice. BCRF finding enabled the Fan/Mendelsohn research team to address this challenge by exploring whether concurrent administration of erythropoietin (a drug frequently used in the clinics to treat chemotherapy-induced anemia and fatigue in cancer patients) has a role in causing poor responses of some breast cancer patients to Herceptin.
Funding for this project is from the BCRF.

[Lani]

interesting results:

Home > Meetings > ASCO Annual Meeting > ASCO Daily News > Tuesday, June 3, 2008 Section A


Erythropoietin Receptor mRNA is Associated with Poor Local-regional Progression-free Survival for Unresected Head and Neck Cancers

After evaluating the association of erythropoietin receptor mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR), the presence erythropoietin receptor (EpoR) on tumors was found to be associated with an unfavorable outcome, according to data presented by Carl Anthony Blau, MD, of the University of Washington, on behalf of his colleagues (Abstract 11007).

Although anemia is a condition that is independent of malignancy, and patients with cancer who have the syndrome have shown poor prognosis, the use of erythropoietin may further promote cancer progression and reduce survival, as suggested by several recent phase III trials (See Section A of the Monday issue of ASCO Daily News for additional information on erythropoiesis-stimulating agents).

In a phase III study reported by Henke et al (Henke M, et al. J Clin Oncol. 2006;24:4708-4713), 351 patients who received radiation for head and neck cancer were randomly assigned to receive either erythropoietin-beta or placebo. The resulting EpoR mRNA levels in tumors were evaluated through an immunohistochemical methodology using a polyclonal antibody. However, C20 has been found to cross-react with nonerythropoietin receptor proteins (Elliott S, et al. Blood. 2006;107:1892-1895), which has resulted in questions concerning the validity of the C20 Santa Cruz study.

For this report, the investigators obtained 154 formalin-fixed paraffin-embedded tumor blocks from the original Henke study that had been evaluated using C20 immunohistochemistry. The mRNA from the blocks was highly degraded, but the RT-PCR methodology was very reproducible, Dr. Blau said, with 101 samples available for evaluation. A number of transcripts were measured, including EpoR, the protein tyrosine kinase Janus kinase-2 (Jak-2), and heat-shock protein 70 (Hsp70).

Fourteen patients with unresected tumors who were treated with erythropoietin-beta and whose tumors expressed above-median EpoR mRNA levels experienced a reduction in loco-regional progression-free survival compared with the placebo group (p = 0.02). This effect was not observed for the 14 patients with unresected tumors treated with erythropoietin-beta whose disease expressed below-median EpoR mRNA levels (p = 0.80). EpoR mRNA levels had no prognostic effect for patients with completely resected or partially resected tumors. The same pattern was seen for Jak-2; for Hsp70, the effect was reversed. Patients with unresected tumors treated with erythropoietin-beta and whose disease expressed below-median Hsp70 experienced significantly shorter loco-regional disease-free survival (p = 0.01); no difference in loco-regional disease-free survival was seen for patients with unresected tumors in the placebo group who had below-median Hsp70 levels.

Dr. Blau concluded that the data must be interpreted with caution as a result of the limited sample size (28 patients for the erythropoietin receptor analyses, 14 receiving erythropoietin-beta, and 14 receiving placebo), the inability to correct for confounding variables, and lack of an independent cohort of tumors for validation. Dr. Blau indicated that important insights may be obtained from archival tumors, and obtaining them from other studies for further exploration of the potentially adverse effects of erythropoietin on tumor progression is warranted.

David P. Steensma, MD, FACP, of Mayo Clinic Rochester, commented that there are two key questions about the erythropoietin receptor in cancer:
Are enough receptors present on the tumor cells to be meaningful?
If the receptors are present, are they functional? And could they be responsible for poorer outcomes in the recent studies of erythropoietin-stimulating agents?
Although there were controversial factors in the original study, such as patient imbalance for risk factors, failure to complete assigned treatment, and the requirement of a high hemoglobin level, Dr. Steensma opined that these factors were unlikely to have influenced the EpoR results. Moreover, it is highly plausible that EpoR mRNA should be found in tumor cells because it has been detected in a wide range of healthy nonhematopoietic tissues, in a number of cell lines, and in primary tumor cells.

In a study of 1,083 solid tumors, EpoR gene amplification was rare, with 3-fold or less copy number increase. Very low levels of EpoR mRNA expression were detected in both malignant and normal tissues compared with marrow; in cell lines with EpoR mRNA, no EpoR protein was detectable on the cell surface (Sinclair A, et al. Br J Cancer. 2008;98:1059-1067). The technical issues limit interpretation of the existing body of work, said Dr. Steensma.

Dr. Steensma concluded that the reported study is provocative. It provides a potential mechanistic explanation, but the technical issues and the small sample size are problematic. As a result, this work should have no immediate effect on clinical practice. Oncologists should continue to use a conservative strategy, following the ASCO/American Society of Hematology clinical practice guidelines. Any available tissue blocks from the other studies that have reported unfavorable outcomes for patients who receive erythropoiesis-stimulating agents should be studied to confirm or discount the hypotheses offered by the investigators.

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[StephN]

Yes, this IS interesting. Findings may depend on yet another factor that they may find in common with those patients.

Notice that the head and neck patients had UNRESECTED tumors, so more to fight.

In my case I took the Epo during my adjuvent therapy and then the brand new long acting version Darbepoetin (sp?) for my mets the following year.

Seemed to keep me on my treatment so I could beat back my liver mets. Otherwise the big doses of Taxol plus Navelbine were playing havoc with my red count, and white as well.