Effects of trastuzumab and trastuzumab-emtansine on QTc intervals

    Authors

    Abstract

    **Introduction**: Trastuzumab and trastuzumab-emtansine are antibody drugs and antibody-conjugate for human epidermal growth factor receptor 2 (HER2)- positive breast cancer. Their possible side effects can be QT prolongation and reduction of left ventricular ejection fraction (LVEF), as previously documented. (1-3) **Methods and Results**: All patients were previously treated with standard regimen: paclitaxel and cisplatinum. After that they received specific antibody drugs. The aim of this study was to test their effect on QTc interval in our patients. A total of 26 patients with preserved LVEF were treated with trastuzumab and before every application, ECG was obtained and analyzed. Later on, 24 patients (aged 57.33 years; 46-69 years) continued the treatment with trastuzumab-emtansine because of metastatic disease. Due to reduction of LVEF two patients could not continue with therapy. The last ECG was obtained 6 months after the last drug application. Statistical analysis was performed using standard t-test. Significant QTc prolongation was noticed after the third application of both drugs, continued during the fourth, fifth and sixth application of both drugs and normalization was noticed after six months without therapy. Results are shown in **tables 1**, **2** and **3**Table 2Table 3. ### TABLE 1: Average duration of QTc intervals. | | **Average duration of QTc intervals (ms)** — **TRASTUZUMAB** | **Average duration of QTc intervals (ms)** — **TRASTUZUMAB+EMTANSIN** | | --- | --- | --- | | Before th.1 | 447.4750 | 448.6250 | | 4 | 469.8750 | 470.1250 | | 5 | 471.0833 | 474.4583 | | 6 | 469.6667 | 471.8750 | | 6 months after administration of the last dose 7 | 451.4583 | 454.4167 | ### TABLE 2: Statistical significance of QTc prolongation compared to initial values (QTc1). | **QTc interval - comparison** | **p-value** **TRASTUZUMAB** | **CI (95%)** **TRASTUZUMAB** | **p-value TRASTUZUMAB+EMTANSINE** | **CI (95%)** **TRASTUZUMAB+EMTANSINE** | | --- | --- | --- | --- | --- | | **QTc1 vs QTc4** | 0.007907 | 6.192 – 38.807 | 0.002223 | 8.143 – 34.857 | | **QTc1 vs QTc5** | 0.002470 | 8.809 – 38.607 | 0.000605 | 11.714 – 39.953 | | **QTc1 vs QTc6** | 0.005007 | 7.072 – 37.511 | 0.000757 | 10.280 – 36.219 | ### TABLE 3: Statistical significance of QTc prolongation compared to the control value 6 months after the last drug application (QTc7). | **QTc interval - comparison** | **p-value** **TRASTUZUMAB** | **CI (95%)** **TRASTUZUMAB** | **p-value** **TRASTUZUMAB+EMTANSINE** | **CI (95%)** **TRASTUZUMAB+EMTANSINE** | | --- | --- | --- | --- | --- | | QTc7 vs QTc4 | 0.022461 | 2.722 – 34.111 | 0.018883 | 2.717 – 28.699 | | QTc7 vs QTc5 | 0.007911 | 5.399 – 33.851 | 0.005280 | 6.267 – 33.816 | | QTc7 vs QTc6 | 0.015374 | 3.648 – 32.768 | 0.007633 | 4.865 – 30.051 | **Conclusion**: Treatment with trastuzumab and also with trastuzumab-emtansine significantly prolonged QTc interval in patients with breast cancer, but the change was reversible after the cessation of treatment.

    Keywords

    trastuzumab, trastuzumab-emntansine, QTc interval, HER2+ breast cancer

    DOI

    https://doi.org/10.15836/ccar2018.466

    Literature

    1. Gupta M, Wang B, Carrothers TJ, LoRusso PM, Chu YW, Shih T, et al. Effects of Trastuzumab Emtansine (T-DM1) on QT Interval and Safety of Pertuzumab Plus T-DM1 in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. Clin Pharmacol Drug Dev. 2013 Jan;2(1):11–24. https://doi.org/10.1002/cpdd.9
    2. Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366–73. https://doi.org/10.1200/JCO.2011.35.0868
    3. Tanriverdi O, Meydan N, Barutca S. Long-term effect of trastuzumab on QT dispersion in adjuvant treatment for patients with Her2 receptor positive breast cancer: a pilot study. Med Oncol. 2012 Dec;29(5):3265–71. https://doi.org/10.1007/s12032-012-0291-z
    Cardiologia Croatica
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    Effects of trastuzumab and trastuzumab-emtansine on QTc intervals

    Extended Abstract
    Issue11-12
    Published
    Pages466-467
    PDF via DOIhttps://doi.org/10.15836/ccar2018.466
    trastuzumab
    trastuzumab-emntansine
    QTc interval
    HER2+ breast cancer

    Authors

    Martina Lovrić Benčić*ORCIDMedicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska
    Lada BradićORCIDMedicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska
    Rea LevickiORCIDOpća županijska bolnica Požega, Požega, Hrvatska
    Juraj JugORCIDMedicinski fakultet Sveučilišta u Zagrebu, Zagreb, Hrvatska
    Marta BegovacMedicinski fakultet Sveučilišta u Zagrebu, Zagreb, Hrvatska
    Marina MihajlovićORCIDMedicinski fakultet Sveučilišta u Zagrebu, Klinički bolnički centar Zagreb, Zagreb, Hrvatska

    *Correspondence email: mlbencic@icloud.com

    Abstract

    **Introduction**: Trastuzumab and trastuzumab-emtansine are antibody drugs and antibody-conjugate for human epidermal growth factor receptor 2 (HER2)- positive breast cancer. Their possible side effects can be QT prolongation and reduction of left ventricular ejection fraction (LVEF), as previously documented. (1-3) **Methods and Results**: All patients were previously treated with standard regimen: paclitaxel and cisplatinum. After that they received specific antibody drugs. The aim of this study was to test their effect on QTc interval in our patients. A total of 26 patients with preserved LVEF were treated with trastuzumab and before every application, ECG was obtained and analyzed. Later on, 24 patients (aged 57.33 years; 46-69 years) continued the treatment with trastuzumab-emtansine because of metastatic disease. Due to reduction of LVEF two patients could not continue with therapy. The last ECG was obtained 6 months after the last drug application. Statistical analysis was performed using standard t-test. Significant QTc prolongation was noticed after the third application of both drugs, continued during the fourth, fifth and sixth application of both drugs and normalization was noticed after six months without therapy. Results are shown in **tables 1**, **2** and **3**Table 2Table 3. ### TABLE 1: Average duration of QTc intervals. | | **Average duration of QTc intervals (ms)** — **TRASTUZUMAB** | **Average duration of QTc intervals (ms)** — **TRASTUZUMAB+EMTANSIN** | | --- | --- | --- | | Before th.1 | 447.4750 | 448.6250 | | 4 | 469.8750 | 470.1250 | | 5 | 471.0833 | 474.4583 | | 6 | 469.6667 | 471.8750 | | 6 months after administration of the last dose 7 | 451.4583 | 454.4167 | ### TABLE 2: Statistical significance of QTc prolongation compared to initial values (QTc1). | **QTc interval - comparison** | **p-value** **TRASTUZUMAB** | **CI (95%)** **TRASTUZUMAB** | **p-value TRASTUZUMAB+EMTANSINE** | **CI (95%)** **TRASTUZUMAB+EMTANSINE** | | --- | --- | --- | --- | --- | | **QTc1 vs QTc4** | 0.007907 | 6.192 – 38.807 | 0.002223 | 8.143 – 34.857 | | **QTc1 vs QTc5** | 0.002470 | 8.809 – 38.607 | 0.000605 | 11.714 – 39.953 | | **QTc1 vs QTc6** | 0.005007 | 7.072 – 37.511 | 0.000757 | 10.280 – 36.219 | ### TABLE 3: Statistical significance of QTc prolongation compared to the control value 6 months after the last drug application (QTc7). | **QTc interval - comparison** | **p-value** **TRASTUZUMAB** | **CI (95%)** **TRASTUZUMAB** | **p-value** **TRASTUZUMAB+EMTANSINE** | **CI (95%)** **TRASTUZUMAB+EMTANSINE** | | --- | --- | --- | --- | --- | | QTc7 vs QTc4 | 0.022461 | 2.722 – 34.111 | 0.018883 | 2.717 – 28.699 | | QTc7 vs QTc5 | 0.007911 | 5.399 – 33.851 | 0.005280 | 6.267 – 33.816 | | QTc7 vs QTc6 | 0.015374 | 3.648 – 32.768 | 0.007633 | 4.865 – 30.051 | **Conclusion**: Treatment with trastuzumab and also with trastuzumab-emtansine significantly prolonged QTc interval in patients with breast cancer, but the change was reversible after the cessation of treatment.

    Literature

    1. 1.
      Gupta M, Wang B, Carrothers TJ, LoRusso PM, Chu YW, Shih T, et al. Effects of Trastuzumab Emtansine (T-DM1) on QT Interval and Safety of Pertuzumab Plus T-DM1 in Patients With Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. Clin Pharmacol Drug Dev. 2013 Jan;2(1):11–24.DOI
    2. 2.
      Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366–73.DOI
    3. 3.
      Tanriverdi O, Meydan N, Barutca S. Long-term effect of trastuzumab on QT dispersion in adjuvant treatment for patients with Her2 receptor positive breast cancer: a pilot study. Med Oncol. 2012 Dec;29(5):3265–71.DOI