Archived Comments for:
Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer
Filippo Montemurro, Fondazione del Piemonte per l'Oncologia/Candiolo Cancer Center, Division of Investigative Clinical Oncology
12 January 2015
Ihave read with great interest this article by Edith Perez and Colleagues reporting a correlation between trastuzumab-emtansine (T-DM1) efficacy and human epidermal receptor 2 (HER2) mRNA expression in the TDM4450g, phase II randomized clinical trial. [1] While acknowledging that these results are merely hypothesis generating, I believe that some findings of this analysis deserve further reasoning. Upon central histopathological review, the proportion of patients whose tumor turned out to have a normal HER2 status was evenly distributed in the two arms of the trial (about 14%, table 1). However, and not surprisingly, these HER2-normal tumors clustered entirely in the low HER2 mRNA group (table 2), where they accounted for slightly less than one third of the cases. At the same time, the proportion of tumors with hormone receptor expression was higher in the low HER2 mRNA group (62.1% vs 46.6%). These data indicate that, beyond the number of HER2 receptors on the cell surface suitable for T-DM1 binding, mRNA HER2 levels are related to different intrinsic biology and, possibly, reliance not only on HER2 but also upon other regulatory pathways like the hormone-receptor signalling. [2] In other terms, the efficacy of T-DM1 over docetaxel and trastuzumab was (DH), was compared in two biologically different groups of patients, one of which enriched in true HER2-positive tumors, and the other being a mix of HER2-negative and HER2-positive tumors at the lower end of the spectrum to define HER2-positivity. Therefore, I believe that the extremely interesting finding of this analysis is the comparable activity of T-DM1 and DH in the low mRNA HER2 group. Indeed, a combined rate of response of 11% was reported in the TDM4258 and TDM437g phase II trials in 36 heavily pre-treated women whose tumor turned out to be HER2-normal by central re-analysis. [3,4] Should an activity of T-DM1 comparable to that of conventional chemotherapy be confirmed in tumors with low HER2-expression, even in those not fulfilling the conventional criteria for HER2 positivity, this would translate in an increased number of patients benefitting from this agent which, by virtue of its mechanism of action, is excellently tolerated.
References
1. EA Perez, SA Hurvitz, LC Amler, KE Mundt, V Ng, E Guardino, L Gianni: Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Breast Cancer Res 2014, 16: R50.
2. F Montemurro, CS Di, G Arpino: Human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive breast cancer: new insights into molecular interactions and clinical implications. Ann Oncol 2013, 24: 2715-2724.
3. HA Burris, III, HS Rugo, SJ Vukelja, CL Vogel, RA Borson, S Limentani, E Tan-Chiu, IE Krop, RA Michaelson, S Girish etal.: Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 2011, 29: 398-405.
4. IE Krop, M Beeram, S Modi, SF Jones, SN Holden, W Yu, S Girish, J Tibbitts, JH Yi, MX Sliwkowski etal.: Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 2010, 28: 2698-2704.
Competing interests
In the past five years I have been member of the Speaker’s Bureau for Glaxo SmithKline S.p.A. and Hoffmann la Roche S.p.A.
HER2 expression and efficacy of T-DM1
12 January 2015
Ihave read with great interest this article by Edith Perez and Colleagues reporting a correlation between trastuzumab-emtansine (T-DM1) efficacy and human epidermal receptor 2 (HER2) mRNA expression in the TDM4450g, phase II randomized clinical trial. [1] While acknowledging that these results are merely hypothesis generating, I believe that some findings of this analysis deserve further reasoning. Upon central histopathological review, the proportion of patients whose tumor turned out to have a normal HER2 status was evenly distributed in the two arms of the trial (about 14%, table 1). However, and not surprisingly, these HER2-normal tumors clustered entirely in the low HER2 mRNA group (table 2), where they accounted for slightly less than one third of the cases. At the same time, the proportion of tumors with hormone receptor expression was higher in the low HER2 mRNA group (62.1% vs 46.6%). These data indicate that, beyond the number of HER2 receptors on the cell surface suitable for T-DM1 binding, mRNA HER2 levels are related to different intrinsic biology and, possibly, reliance not only on HER2 but also upon other regulatory pathways like the hormone-receptor signalling. [2] In other terms, the efficacy of T-DM1 over docetaxel and trastuzumab was (DH), was compared in two biologically different groups of patients, one of which enriched in true HER2-positive tumors, and the other being a mix of HER2-negative and HER2-positive tumors at the lower end of the spectrum to define HER2-positivity. Therefore, I believe that the extremely interesting finding of this analysis is the comparable activity of T-DM1 and DH in the low mRNA HER2 group. Indeed, a combined rate of response of 11% was reported in the TDM4258 and TDM437g phase II trials in 36 heavily pre-treated women whose tumor turned out to be HER2-normal by central re-analysis. [3,4] Should an activity of T-DM1 comparable to that of conventional chemotherapy be confirmed in tumors with low HER2-expression, even in those not fulfilling the conventional criteria for HER2 positivity, this would translate in an increased number of patients benefitting from this agent which, by virtue of its mechanism of action, is excellently tolerated.
References
1. EA Perez, SA Hurvitz, LC Amler, KE Mundt, V Ng, E Guardino, L Gianni: Relationship between HER2 expression and efficacy with first-line trastuzumab emtansine compared with trastuzumab plus docetaxel in TDM4450g: a randomized phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Breast Cancer Res 2014, 16: R50.
2. F Montemurro, CS Di, G Arpino: Human epidermal growth factor receptor 2
(HER2)-positive and hormone receptor-positive breast cancer: new insights into molecular
interactions and clinical implications. Ann Oncol 2013, 24: 2715-2724.
3. HA Burris, III, HS Rugo, SJ Vukelja, CL Vogel, RA Borson, S Limentani, E Tan-Chiu, IE Krop, RA Michaelson, S Girish et al.: Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast
cancer after prior HER2-directed therapy. J Clin Oncol 2011, 29: 398-405.
4. IE Krop, M Beeram, S Modi, SF Jones, SN Holden, W Yu, S Girish, J Tibbitts, JH Yi, MX Sliwkowski et al.: Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 2010, 28: 2698-2704.
Competing interests
In the past five years I have been member of the Speaker’s Bureau for Glaxo SmithKline S.p.A. and Hoffmann la Roche S.p.A.