TROPONIN I LEVELS AND TRASTUZUMAB CARDIOTOXICITY

September 9, 2010 — The biomarker troponin I (TNI) can help clinicians identify which breast cancer patients receiving trastuzumab (Herceptin, Genentech/Roche) are at risk for heart damage and which of those patients who are unlikely recover from the damage, say Italian researchers.

The ability to identify these patients is "crucial," in part because various studies have shown that "many" patients who experience toxic effects will not recover, note the study authors, led by Daniela Cardinale, MD, PhD, from the Cardiology Unit at the European Institute of Oncology in Milan, Italy.

In a new study, TNI was the only independent predictor of trastuzumab-induced cardiotoxicity (hazard ratio [HR], 22.9; 95% confidence interval [CI], 11.6 - 45.5; P < .001) and of lack of recovery from that cardiotoxicity (HR, 2.88; 95% CI,1.78 - 4.65; P < .001).

The study appears in the September 1 issue of the Journal of Clinical Oncology.

"We routinely use TNI evaluation in our clinical practice. We measure TNI before beginning both anthracycline-containing regimens and trastuzumab regimens in all patients. It's not an invasive test and it is a cheap way to detect cardiotoxicity early, long before echocardiographic changes. We use a common commercially available test (Siemens Healthcare Diagnostics; Eschborn, Germany)," Dr. Cardinale told Medscape Medical News.

Other research indicates that trastuzumab causes heart damage in as many as one third of treated patients who have received anthracycline treatment, according to Dr. Cardinale and her coauthors.

However, in their study of 251 women with breast cancer, the researchers observed trastuzumab-induced cardiotoxicity in only 42 patients (17%), and it was significantly more frequent in patients with TNI elevation (62% vs 5%; P < .001).

Of the 42 patients, 60% recovered from the cardiotoxicity after trastuzumab withdrawal and initiation of heart failure therapy. None of the patients who recovered had TNI elevation at baseline. However, 7 of 17 (41%) who did not recover had TNI elevation at baseline.

Patients who did not have elevated TNI at baseline were nearly 3 times as likely to recover from trastuzumab-induced cardiotoxicity as those who had elevated TNI (relative risk, 2.88).

Identifying the TNI-positive and TNI-negative patients can greatly aid clinicians, the authors explain.

"The early identification of patients at higher risk of [trastuzumab-induced cardiotoxicity], and of those who may recover from cardiac dysfunction, may allow us to reach 2 important therapeutic goals: first, trastuzumab should not be indiscriminately discontinued in all patients developing [trastuzumab-induced cardiotoxicity], depriving them of the drug's effectiveness; second, a prophylactic therapy should be started in selected high-risk patients."

Dr. Cardinale added: "We hope that this publication will spread this kind of approach among oncologists and cardiologists involved in this clinical setting."

Trastuzumab Not Only to Blame

In the study, the Italian researchers measured TNI in the women before and after each cycle of trastuzumab. TNI elevation was defined as >0.08 ng/mL.

They also measured left-ventricular ejection fraction (LVEF) at baseline, every 3 months during trastuzumab treatment, and every 6 months thereafter. Trastuzumab-induced cardiotoxicity is defined as a LVEF decrease of more than 10 units and below 50%. Recovery was defined as LVEF increase above 50%.

However, an editorial that accompanies the study suggests that the term trastuzumab-induced cardiotoxicity might be misleading

Michael S. Ewer, MD, from the University of Texas MD Anderson Cancer Center in Houston, and Steven M. Ewer, MD, from the University of Wisconsin, Madison, raise questions about the role trastuzumab actually played in the cardiotoxicity reported by Dr. Cardinale's group.

"First, prior anthracycline use was found to be a significant risk factor for the development of [trastuzumab-induced cardiotoxicity]. Second, the cumulative anthracycline dose was significantly higher in those who developed [trastuzumab-induced cardiotoxicity]. Third, elevation of troponin I (with all of its prognostic implications) was observed exclusively in patients with prior anthracycline exposure. Fourth, troponin I elevation was found in 7 patients prior to trastuzumab therapy, despite normal left-ventricular ejection fraction, suggesting ongoing anthracycline-mediated myocyte damage that would have otherwise gone unrecognized," the Drs. Ewer write.

They propose that anthracycline administration causes oxidative damage to cardiac myocytes, which is worsened by trastuzumab.

"As we move forward, we may well discover that trastuzumab aids and abets in the crime of cell death and amplifies the burden of the anthracycline; in this sense, trastuzumab is far from innocent. But when taken by itself and out of the context of the vulnerable and previously damaged anthracycline-exposed myocyte, we may ultimately discover that trastuzumab is not nearly as guilty for the death of the myocyte as has heretofore been suggested," they write.

Dr. Cardinale has disclosed no relevant financial relationships. Dr. Michael Ewer reports serving as a consultant for Roche, MethylGene, and Genentech, and receiving honoraria from Roche and Sanofi-Aventis.

J Clin Oncol. 2010;28:3901-3904, 3910-3916. Abstract, Abstract