Troponin 1 elevation identifies cardiotoxicity

Supplementary editorial provided by OncologySTAT

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Troponin I elevation identified patients at risk for cardiotoxicity associated with trastuzumab therapy.

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Trastuzumab targets human epidermal growth factor receptor 2 (HER2), which is overexpressed in up to 30% of all breast cancers. However, cardiotoxicity, mainly asymptomatic left ventricular ejection fraction (LVEF) reduction or overt heart failure (HF), occurs in up to 34% of patients treated with trastuzumab, particularly when it is used with anthracyclines. Anthracyclines may also cause cardiotoxicity, but the pathologic changes and outcomes differ from those caused by trastuzumab. Unlike anthracycline-induced cardiotoxicity, trastuzumab-induced cardiotoxicity is not dose dependent and does not result in ultrastructural changes; in addition, cardiac function may recover after discontinuation of trastuzumab and initiation of HF therapy.

Tropinin I (TNI) is a well-established marker of myocardial injury resulting from other forms of chemotherapy, but it has not been investigated in trastuzumab-treated patients. This study demonstrated that TNI identifies patients at risk for cardiotoxicity and is a marker for response to HF treatment.

This prospective study enrolled patients with breast cancer who were treated with trastuzumab but did not at baseline have ischemic or valvular heart disease, LVEF <55%, severe hypertension, or abnormal renal or hepatic function. Patients underwent LVEF measurement before trastuzumab therapy, every 3 months during trastuzumab, and during the first year after drug discontinuation, and every 6 months thereafter. In patients exhibiting cardiotoxicity, trastuzumab was discontinued, HF therapy was initiated, and LVEF was measured every month for the first 3 months of HF therapy. TNI was assayed before and after each trastuzumab cycle and at each cardiologic check after completion of therapy. Elevated TNI (TNI+) was defined as TNI >0.08 ng/mL.

A total of 251 women were enrolled, of whom 123 (49%) received trastuzumab as adjuvant therapy and 128 (51%) received trastuzumab as treatment for metastatic disease. Median treatment time was 12 months (range, 1 to 24 months) for adjuvant therapy and 16 months (range, 1 to 72 months) for metastatic disease. In total, 62 patients died from cancer, and 4 patients were lost to follow-up.

Trastuzumab-induced cardiotoxicity occurred in 42 patients (17%), including 14 patients (11%) in the adjuvant group and 28 patients (22%) in the metastatic group (P =.005). Cardiotoxicity was associated with lower baseline LVEF, TNI+, metastatic disease, previous treatment with high-dose chemotherapy, and previous treatment with taxanes or anthracyclines. The relationship between the risk of cardiotoxicity and prior anthracycline use was dose related. Incidence of cardiotoxicity was lower in patients treated with trastuzumab alone than in those treated with trastuzumab in combination with other drugs.

Among the 36 patients (14%) who were TNI+, 7 patients were TNI+ at baseline, possibly as a consequence of previous chemotherapy. In most cases, TNI elevation appeared soon after the first trastuzumab cycle. TNI+ normalized within 3 months. Trastuzumab-induced cardiotoxicity occurred 1 to 8 months after TNI+ was first detected. On multivariate analysis, TNI+ was the strongest independent predictor of cardiotoxicity (hazard ratio [HR], 17.6; 95% CI, 8.85-35.0; P < .001). TNI+ was also a predictor of duration of positivity (HR, 16.5; 95% CI, 8.1-33.6; P < .001).

LVEF recovered in 25 patients (60%) after trastuzumab withdrawal and initiation of HF therapy. The relative risk for LVEF recovery in patients without TNI+ was 3.0 (95% CI, 1.85.1; P < .001). The positive predictive value for lack of LVEF recovery in TNI+ patients was 65%, and the negative predictive value was 100%.

There were 22 major adverse cardiac events. The incidence of these events was higher in patients with TNI+ (50% vs 2%; P < .001). Trastuzumab was reintroduced in 7 patients with trastuzumab-induced cardiotoxicity; 2 patients were TNI+ and developed LVEF <50%, following which trastuzumab was permanently discontinued.

In this study, TNI+ was the strongest independent predictor of cardiotoxicity, thus enabling identification of patients at greatest risk. Assessment of TNI also identified patients in whom trastuzumab-induced cardiac dysfunction may be irreversible even with adequate HF treatment.