Elevated Troponin Tied to Increased Risk of Trastuzumab-Related Cardiac Dysfunction

By Will Boggs MD

NEW YORK (Reuters Health) - Elevated baseline levels of troponin I and T are associated with an increased risk of trastuzumab-related cardiac dysfunction (TRCD) in women being treated for early-stage HER2-positive breast cancer, researchers report.

"Elevated baseline (after the completion of chemotherapy but prior to adjuvant trastuzumab) troponin I (>40 ng/L) and T (>14 ng/L) were associated with" a significantly higher risk of a drop in left ventricular ejection fraction (LVEF), said Dr. Dimitrios Zardavas from Universite Libre de Bruxelles, Belgium.

"In particular, our study confirms the findings related to troponin I elevation, as reported previously, and shows for the first time to our knowledge that troponin T elevation is associated with an increased risk for trastuzumab-related cardiac dysfunction," he told Reuters Health by email.

Trastuzumab treatment has been associated with cardiac dysfunction that is mostly reversible. LVEF, the standard cardiac monitoring method in routine practice, does not detect early TRCD or predict deterioration of cardiac function in these patients.

Dr. Zardavas and colleagues investigated the potential of troponin I (cTnI), troponin T (cTnT), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) to monitor cardiac safety of women enrolled in the Herceptin Adjuvant (HERA) study.

At baseline, 13.9% of women assigned to trastuzumab had baseline elevations of cTnI and 24.9% had baseline elevations of cTnT, compared with 12.9% and 24.6%, respectively, of women assigned to observation-only, the researchers report in the Journal of Clinical Oncology, online October 24.

"Most of elevated cTnI and cTnT values were already present at baseline and could be interpreted as a manifestation of anthracycline-induced cardiotoxicity, since 94% of the participants had already received anthracyclines, as part of their adjuvant cytotoxic chemotherapy," Dr. Zardavas said.

Elevated baseline cTnI levels were associated with a 3.76-fold increased risk of significant LVEF decline (p<0.001), whereas elevated baseline cTnT levels were associated with a 2.37-fold increased risk of significant LVEF decline (p=0.0041), after adjustment for other factors.

Each 10-ng/dL increase in NT-proBNP was associated with an increase in risk of significant LVEF decline of about 30%, but the variability in NT-proBNP levels was such that they could not be used to distinguish between patients with and without a significant LVEF drop.

Similarly, cTnI and cTnT levels could not reliably predict significant LVEF declines.

"The results of our study do not justify the implementation of the aforementioned cardiac biomarkers for all patients planned to receive trastuzumab-based chemotherapy," Dr. Zardavas said. "However, they deserve to be further explored, ideally in prospectively conducted randomized clinical trials."

"In particular," he said, "multifactorial predictive models incorporating such cardiac biomarkers, along with underlying relevant comorbidity factors (e.g., underlying hypertension requiring medication or obesity), lifestyle habits (e.g., smoking habits), and other possibly relevant parameters should be explored. Identifying patients at risk to develop cardiac dysfunction resulting from anticancer therapy is an important medical need."

Dr. Patrick Dillon from the University of Virginia's division of hematology/oncology in Charlottesville, who was not involved in the study, told Reuters Health by email, "It is reassuring that all but 3 patients who experienced a significant LVEF drop had recovery of the LVEF. It is interesting that troponin I and T both tended to drop for the 2 years following anthracycline, but were relatively unimpacted by 1-2 years of trastuzumab treatment. It is even more interesting, then, that those would turn out to be modestly predictive pretreatment markers for trastuzumab-related LVEF decline."

"It is not clear whether the troponin I and T biomarkers will have predictive value when assessed in patients not previously exposed to anthracyclines," he said. "Also since the biomarkers do not change during trastuzumab treatment, they do not appear to be useful early warning signs for treatment discontinuation. Myocardial strain imaging (not mentioned in this article) may be a useful tool for detecting cardiac changes early enough to prevent frank heart failure."

Dr. Dharamvir Jain from the University of Louisville Health Sciences Center's Multidisciplinary Breast Cancer Program, Kentucky, said, "Trastuzumab therapy, without prior anthracycline administration, results in exceedingly low incidence of cardiac dysfunction. Results of the HERA study are therefore a little intriguing as >90% patients received prior anthracycline and yet resulted in very low incidence of pre-trastuzumab/baseline cardiac dysfunction."

"This may reflect variation in clinical practice pattern among various geographical regions in this multinational study," Dr. Jain, who also was not involved in the study, told Reuters Health by email. "Therefore, the search is on for validated, reliable and reproducible biomarker/s for predicting treatment-related cardiotoxicity."

"We commonly employ clinical examination and LVEF monitoring either by 2D ECHO or by MUGA scan for monitoring cardiac dysfunction," Dr. Jain said. "However, definition of cardiotoxicity should include diastolic dysfunction and strain changes (easily measured by 2D ECHO) which may be affected much earlier as a result of anthracycline-related myocardial damage. Future studies should explore correlating pre-treatment diastolic dysfunction and strain changes with serum biomarkers as baseline prognostic as well as predictor of future symptomatic cardiac dysfunction and/or drop in LVEF."

SOURCE: https://bit.ly/2e5eejb

J Clin Oncol 2016.

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