Cardiotoxicity and Cardiovascular Biomarkers in Patients With Breast Cancer: Data From the GeparOcto-GBG 84 Trial

Alexandra Maria Rüger, Andreas Schneeweiss, Sabine Seiler, Hans Tesch, Marion van Mackelenbergh, Frederik Marmé, Kristina Lübbe, Bruno Sinn, Thomas Karn, Elmar Stickeler, Volkmar Müller, Christian Schem, Carsten Denkert, Peter A Fasching, Valentina Nekljudova, Tania Garfias-Macedo, Gerd Hasenfuß, Wilhelm Haverkamp, Sibylle Loibl, Stephan von Haehling, Alexandra Maria Rüger, Andreas Schneeweiss, Sabine Seiler, Hans Tesch, Marion van Mackelenbergh, Frederik Marmé, Kristina Lübbe, Bruno Sinn, Thomas Karn, Elmar Stickeler, Volkmar Müller, Christian Schem, Carsten Denkert, Peter A Fasching, Valentina Nekljudova, Tania Garfias-Macedo, Gerd Hasenfuß, Wilhelm Haverkamp, Sibylle Loibl, Stephan von Haehling

Abstract

Background Patients with breast cancer can be affected by cardiotoxic reactions through cancer therapies. Cardiac biomarkers, like NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T, might have predictive value. Methods and Results Echocardiography, ECG, hemodynamic parameters, NT-proBNP and high-sensitivity cardiac troponin T were assessed in 853 patients with early-stage breast cancer randomized in the German Breast Group GeparOcto-GBG 84 phase III trial. Patients received neo-adjuvant dose-dense, dose-intensified epirubicin, paclitaxel, and cyclophosphamide (iddEPC group, n=424) or paclitaxel, non-pegylated doxorubicin, and in triple negative breast cancer, (paclitaxel, non-pegylated doxorubicin, carboplatin group, n=429) treatment for 18 weeks. Patients positive for human epidermal growth receptor 2 (n=354, 41.5%) received monoclonal antibodies on top of allocated therapy; 119 (12.9%) of all patients showed a cardiotoxic reaction during therapy (15 [1.8%] using a more strict definition). Presence of cardiotoxic reactions was irrespective of treatment allocation (P=0.31). Small but significant increases in NT-proBNP developed early in patients with a cardiotoxic reaction as compared with those without in whom NT-proBNP rose only towards the end of therapy (P=0.04). High-sensitivity cardiac troponin T rose early in both groups. Logistic regression showed that NT-proBNP (odds ratio [OR], 1.03; 95% CI, 1.008-1.055; P=0.01) and hemoglobin (OR, 1.31; 95% CI, 1.05-1.63; P=0.02) measured at 6 weeks after treatment initiation were significantly associated with cardiotoxic reactions. Conclusions NT-proBNP and hemoglobin are significantly associated with cardiotoxic reactions in patients with early-stage breast cancer undergoing dose-dense and dose-intensified chemotherapy, but high-sensitivity cardiac troponin T is not. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT02125344.

Keywords: biomarker; breast cancer; cardiotoxicity; cardio‐oncology; left ventricular ejection fraction.

Conflict of interest statement

Denkert holds stock interests with Sividon Diagnostics and patents of VMScope and received honoraria from Celgene, Teva, Novartis, Pfizer, MSD, Amgen, and Roche. Tesch received honoraria from Novartis and Roche. Loibl received research funding from Pfizer, Sanofi, Amgen, Roche, Novartis, Celgene, Teva, Astra Zeneca, Myriad, AbbVie, Vifor, and Sividon Diagnostics. von Haehling received honoraria from BRAHMS, Roche, and Vifor. Schem received honoraria from Astra Zeneca and Roche. Fasching received honoraria from Amgen, Novartis, Pfizer, Celgene, Roche, Teva, and Astra Zeneca. Schneeweiss received honoraria from Roche, Astra Zeneca, Celgene, Pfizer, Amgen, and Novartis. Marmé received honoraria from AstraZeneca, Amgen, CureVec, Celgene, Clovis Oncology, Eisai, Genomic Health, Novartis, MSD, Pfizer, Roche, and Tesaro. van Mackelenbergh received honoraria from AstraZeneca, Amgen, Lily, Genomic Health, and Novartis. Rüger is also employed by Vifor. Lübbe received honoraria from Lily, Roche, Novartis, Genomic Health, and Pfizer. Müller received honoraria from Amgen, Astra Zeneca, Daiichi‐Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics, Genomic Health, Hexal, Roche, Pierre Fabre, ClinSol, Lilly, Tesaro, Nektar, and Genentech. Seiler received honoraria from Amgen, Hexal, Roche, Novartis, and Mundipharma. The remaining authors have no disclosures to report.

Figures

Figure 1. Study design GeparOcto‐GBG 84 trial…
Figure 1. Study design GeparOcto‐GBG 84 trial (phase III).
HER2 indicates human epidermal growth receptor 2; iddEPC, neo‐adjuvant dose‐dense, dose‐intensified epirubicin, paclitaxel, and cyclophosphamide; NPLD, non‐pegylated doxorubicin; R, randomization; and PM(Cb), paclitaxel, non‐pegylated doxorubicin, carboplatin.
Figure 2. Consort statement GeparOcto‐GBG 84 trial…
Figure 2. Consort statement GeparOcto‐GBG 84 trial (phase III).
iddEPC indicates neo‐adjuvant dose‐dense, dose‐intensified epirubicin, paclitaxel, and cyclophosphamide; and PM(Cb), paclitaxel, non‐pegylated doxorubicin, carboplatin.
Figure 3. NT‐proBNP during therapy.
Figure 3. NT‐proBNP during therapy.
A, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) (cardiotoxicity vs non‐cardiotoxicity), (B) NT‐proBNP (neo‐adjuvant dose‐dense, dose‐intensified epirubicin, paclitaxel, and cyclophosphamide vs paclitaxel, non‐pegylated doxorubicin, carboplatin). NT‐proBNP as assessed by all (red), cardiotoxicity (blue bar) vs non‐cardiotoxicity (grey bar) and between all (red), epirubicin, paclitaxel, cyclophosphamide (light blue bar) and paclitaxel, non‐pegylated doxorubicin, carboplatin (light grey bar) group. Analysis is shown as mean±SD and independent samples t‐test shown by P values. The time points of assessment are baseline, after 6 weeks, and at the end of therapy. iddEPC indicates neo‐adjuvant dose‐dense, dose‐intensified epirubicin, paclitaxel, and cyclophosphamide; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; and PM(Cb), paclitaxel, non‐pegylated doxorubicin, carboplatin.
Figure 4. High‐sensitivity cardiac troponin T during…
Figure 4. High‐sensitivity cardiac troponin T during therapy.
A, High‐sensitivity cardiac troponin T (hsTrop T) (cardiotoxicity vs non‐cardiotoxicity); (B) High‐sensitivity cardiac troponin T (neo‐adjuvant dose‐dense, dose‐intensified epirubicin, paclitaxel, and cyclophosphamide vs paclitaxel, non‐pegylated doxorubicin, carboplatin). High‐sensitivity cardiac troponin T as assessed by all (red), cardiotoxicity (blue bar) vs non‐cardiotoxicity (grey bar) and between all (red), EPC (light blue bar) and PM(Cb) (light grey bar) group. Analysis is shown as mean±SD and independent samples t‐test shown by P values. The time points of assessment are baseline, after 6 weeks, and at the end of therapy. iddEPC indicates neo‐adjuvant dose‐dense, dose‐intensified epirubicin, paclitaxel, and cyclophosphamide; hsTrop T, high‐sensitivity cardiac troponin T; and PM(Cb), paclitaxel, non‐pegylated doxorubicin, carboplatin.
Figure 5. Hemoglobin during therapy.
Figure 5. Hemoglobin during therapy.
A, Hemoglobin (cardiotoxicity vs non‐cardiotoxicity); (B) Hemoglobin (neo‐adjuvant dose‐dense, dose‐intensified epirubicin, paclitaxel, and cyclophosphamide vs paclitaxel, non‐pegylated doxorubicin, carboplatin). Hemoglobin as assessed by all (red), cardiotoxicity (blue bar) vs non‐cardiotoxicity (grey bar) and between all (red), EPC (light blue bar) and PM(Cb) (light grey bar) group. Analysis is shown as mean±SD and independent samples t‐test shown by P values. The time points of assessment are baseline, after 6 weeks, and at the end of therapy. iddEPC indicates neo‐adjuvant dose‐dense, dose‐intensified epirubicin, paclitaxel, and cyclophosphamide; and PM(Cb), paclitaxel, non‐pegylated doxorubicin, carboplatin.

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