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AlaskaAngel · 02-07-2007, 11:37 AM

Phosphorylated HER-2 tyrosine kinase and Her-2/neu gene amplification as predictive factors of response to trastuzumab in patients with HER-2 overexpressing metastatic breast cancer (MBC).

Giuliani R, Durbecq V, Di Leo A, Paesmans M, Larsimont D, Leroy JY, Borms M, Vindevoghel A, Jerusalem G, D'Hondt V, Dirix L, Canon JL, Richard V, Cocquyt V, Majois F, Reginster M, Demol J, Kains JP, Delree P, Keppens C, Sotiriou C, Piccart MJ, Cardoso F

Translational Research Unit, Jules Bordet Institute, 125, Boulevard de Waterloo, 1000 Brussels, Belgium.AIM:

Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER-2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stressing the need for additional predictive markers. The following markers could be implicated in response to T: (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the activated status of HER-2; (4) the activated status of downstream effectors as mitogen-activated protein kinases (MAPKs), p38 and p27. METHODS: Medical files of patients with MBC treated with T either as a single agent or in combination with chemotherapy (CT) were reviewed. HER family members (EGFR, HER-2, HER-3, HER-4), the phosphorylated forms of EGFR (p-EGFR), HER-2 (p-HER-2) and of the downstream effectors were evaluated in the archival tumours. The correlation between clinical outcome and the expression of these markers was investigated.

RESULTS: (1) Increasing values of Her-2 amplification were associated with a higher probability of achieving an objective response; (2) no statistical significant correlation between the expression of the HER family receptors was found; (3) p-HER-2 was predictive of response in patients treated with T+CT; (4) a statistically significant correlation between p-ERK 1/2, p-p38 and p-HER-2 emerged, pointing to the activated vertical pathway p-HER-2-->p-MAPKs.

CONCLUSIONS: p-HER-2 and the magnitude of Her-2 amplification were predictive of response to T and their role deserves to be analysed in larger and more homogenous T-treated populations such as those from large phase III trials.

Published <?xml:namespace prefix = st1 ns = "urn:schemas-microsoft-com[img] /><st1:date Year=[/img]25 January 2007</st1:date> in Eur J Cancer.

02-07-2007, 11:37 AM	#7
AlaskaAngel Senior Member Join Date: Sep 2005 Location: Alaska Posts: 2,018	Looking for better markers for patients with mets Phosphorylated HER-2 tyrosine kinase and Her-2/neu gene amplification as predictive factors of response to trastuzumab in patients with HER-2 overexpressing metastatic breast cancer (MBC). Giuliani R, Durbecq V, Di Leo A, Paesmans M, Larsimont D, Leroy JY, Borms M, Vindevoghel A, Jerusalem G, D'Hondt V, Dirix L, Canon JL, Richard V, Cocquyt V, Majois F, Reginster M, Demol J, Kains JP, Delree P, Keppens C, Sotiriou C, Piccart MJ, Cardoso F Translational Research Unit, Jules Bordet Institute, 125, Boulevard de Waterloo, 1000 Brussels, Belgium.AIM: Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER-2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stressing the need for additional predictive markers. The following markers could be implicated in response to T: (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the activated status of HER-2; (4) the activated status of downstream effectors as mitogen-activated protein kinases (MAPKs), p38 and p27. METHODS: Medical files of patients with MBC treated with T either as a single agent or in combination with chemotherapy (CT) were reviewed. HER family members (EGFR, HER-2, HER-3, HER-4), the phosphorylated forms of EGFR (p-EGFR), HER-2 (p-HER-2) and of the downstream effectors were evaluated in the archival tumours. The correlation between clinical outcome and the expression of these markers was investigated. RESULTS: (1) Increasing values of Her-2 amplification were associated with a higher probability of achieving an objective response; (2) no statistical significant correlation between the expression of the HER family receptors was found; (3) p-HER-2 was predictive of response in patients treated with T+CT; (4) a statistically significant correlation between p-ERK 1/2, p-p38 and p-HER-2 emerged, pointing to the activated vertical pathway p-HER-2-->p-MAPKs. CONCLUSIONS: p-HER-2 and the magnitude of Her-2 amplification were predictive of response to T and their role deserves to be analysed in larger and more homogenous T-treated populations such as those from large phase III trials. Published <?xml:namespace prefix = st1 ns = "urn:schemas-microsoft-com[img] /><st1:date Year=[/img]25 January 2007</st1:date> in Eur J Cancer.