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Lani · 06-04-2008, 10:01 AM

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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06-04-2008, 10:01 AM	#2
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	ASCO paper shows this has been done for head and neck cancer with 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. .