Table 1.

Studies of biomarkers of cardiotoxicity in patients with HER2-positive breast cancer

Study	Patients	Markers	Primary outcome	Findings
Cardinale et al. [50]	251 patients treated with trastuzumab 78% received prior anthracyclines 51% with metastatic disease	Tn-I	↓ LVEF > 10% from baseline to < 50%	Cardiotoxicity occurred in 42 (17%) patients. Cardiotoxicity was more frequent in patients with an elevated TnI >0.08 ng/ml (62 versus 5%, p < 0.001).
El Sherbeny et al. [36]	61 patients treated with AC followed by paclitaxel + trastuzumab	GLS NT-proBNP	↓ LVEF >10% to < 55% with or without signs and symptoms of heart failure.	GLS (absolute) <18% measured at month 3 of trastuzumab predicts development of cardiotoxicity NT-proBNP was not predictive of cardiotoxicity
Ky et al. [52]	78 patients treated with an anthracycline-based regimen followed by a taxane and trastuzumab	hsTn-I MPO CRP GDF-15 PlGF sFlt-1 gal-3	↓ LVEF ≥5% to <55% with CHF symptoms Asymptomatic ↓ LVEF ≥10% to <55%	Increases in hsTn-I and MPO from baseline to month 3 (postanthracyclines) are associated with cardiotoxicity (hazard ratio 1.38 per SD increase in TnI, P = 0.02; hazard ratio 1.34 per SD increase in MPO, P = 0.048)
Morris et al. [53]	95 patients treated with ddAC followed by weekly paclitaxel with trastuzumab + lapatinib	Tn-I CRP	Change in LVEF	Tn-I elevations preceded maximal LVEF decline but did not correlate with development of CHF No correlation between CRP levels and LVEF decline or CHF
Negishi et al. [41]	81 patients treated with trastuzumab 46% received an anthracycline-based regimen	GLS	↓ LVEF ≥ 10% from baseline	A decrease in GLS of 11% measured at 6 months is predictive of subsequent reductions in LVEF at 12 months.
Sawaya et al. [40]	81 patients treated with anthracyclines, taxanes, and trastuzumab	GLS hsTn-I NT-proBNP ST-2	↓ LVEF ≥5% to < 55% with CHF symptoms Asymptomatic ↓ LVEF ≥10% to < 55%	GLS (absolute) < 19% measured after completing anthracycline chemotherapy is predictive of cardiotoxicity during trastuzumab. Elevated usTn-I ≥ 30 pg/ml measured after completing anthracycline chemotherapy is predictive of cardiotoxicity during trastuzumab.
Zardavas et al. [54■]	452 patients treated with adjuvant chemotherapy followed by trastuzumab in the HERA trial 94% received an anthracycline-based regimen	Tn-I Tn-T NT-proBNP	NYHA class III-IV CHF ↓ LVEF >10% from baseline to <50% Death from cardiac cause	Elevated baseline troponin I (>40 ng/l) and T (> 14 ng/l) are associated with risk of significant LVEF decline (hazard ratio = 4.52; P<0.001 and hazard ratio 3.57; P<0.001, respectively)

AC, doxorubicin + cyclophosphamide; CRP, C-reactive protein; ddAC, dose dense doxorubicin + cyclophosphamide; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; gal-3, galectin 3; GDF-15, growth differentiation factor-15; GLS, global longitudinal strain; hsTnI, high-sensitivity troponin I; MPO, myeloperoxidase; NT-proBNP, n-terminal pro-B type natriuretic peptide; NYHA, New York Heart Association; Pl-GF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase receptor-1; ST2, interleukin family member; Tn-I, cardiac troponin-I.