Trastuzumab-Associated Cardiac Events Reversible, Outweighed by Benefits

Edward H. Romond, MD

Cardiac events associated with trastuzumab (Herceptin) are mostly reversible and outweighed by significant extensions in overall survival (OS) and progression-free survival (PFS) for patients with HER2-positive breast cancer, according to analyses from several clinical trials exploring the drug.

In the large HERA trial, which was published in the Journal of Clinical Oncology, the cardiac events associated with adjuvant trastuzumab remained low and manageable at an 8-year median follow-up.¹ Moreover, a retrospective review of trastuzumab’s safety and efficacy, published in The Cochrane Library,² demonstrated that the drug’s benefits significantly outweighed its harm across a variety of clinical settings.

The HERA trial enrolled 5102 patients with locally determined HER2-positive invasive early breast cancer. Following surgery and adjuvant chemotherapy and/or radiotherapy, patients were randomized to 1 year of trastuzumab, 2 years of trastuzumab, or observation. The patients’ cardiac function was closely monitored and only patients who had left ventricular ejection fraction (LVEF) ≥ 55% at study entry were eligible to enroll.

Results from the study established 1-year of adjuvant trastuzumab as a standard of care for patients with HER2-positive breast cancer. At the 8-year follow-up, disease-free survival and OS were similar between the 1- and 2-year treatment arms. However, cardiac adverse events leading to treatment discontinuation occurred in 9.4% of patients in the 2-year arm compared with 5.2% in the 1-year arm.

Severe congestive heart failure (CHF), and confirmed significant LVEF decrease remained low in all three arms. Severe CHF occurred in 0.8% of patients in both treatment arms compared with none for observation. Confirmed significant LVEF decrease was significantly higher in the 2-year and 1-year trastuzumab arms in comparison to the observation arm (7.2%, 4.1%, and 0.9%, respectively).

In patients with confirmed LVEF decrease, acute recovery was reached for 87.5% of patients receiving trastuzumab for 2 years compared with 81.2% of patients in the 1-year trastuzumab arm.

“In the adjuvant setting, we have further support that patients with higher-risk HER2-positive breast cancer and importantly also good baseline myocardial function, can be treated safely and with excellent long-term benefit using an anthracycline and taxane-based trastuzumab regimen,” Edward H. Romond, MD, professor of medicine at University of Kentucky said in a podcast about the follow-up study.

Adding to these findings, a review from 7 clinical trials that explored the safety and efficacy of trastuzumab across a variety of clinical settings showed that the benefits of the drug outweighed the harm.

“This review suggests that, for women with advanced breast cancer, trastuzumab has been linked to significant life expectancy gains," Lorenzo Moja, MD, one of the authors of the review, based at the Department of Biomedical Sciences for Health at the University of Milan, Italy, said in a statement. "We found that women survived longer and their cancer did not progress as quickly when they received trastuzumab.”

The seven studies analyzed included data from 1497 patients with HER2-positive breast cancer. In the studies, patients were treated with trastuzumab in combination with chemotherapy, as a first- or later-line therapy. However, the author's noted that the majority of evidence supported the benefits of trastuzumab in the frontline setting, whereas data was limited following progression.

OS and PFS significantly favored the trastuzumab-containing regimens, with a hazard ratio (HR) for OS of 0.82 (95% CI, 0.71-0.94; P = .004) and an HR for PFS of 0.61 (95% CI, 0.54-0.70; P<.00001). However, treatment with trastuzumab was also associated with an increased the risk of cardiac toxicities. The risk ratio (RR) for CHF was 3.49 (90% CI, 1.88-6.47; P = .0009) and the RR for LVEF decline was 2.65 (90% CI, 1.48-4.74; P = 0.006).

Trastuzumab in combination with an anthracycline-containing regimen was associated with the highest risk of cardiac toxicity compared with taxane-based chemotherapies, the authors of the study noted.

“Some of the earlier trials combined trastuzumab with a class of drugs called anthracyclines,” Roberto D’Amico, PhD, director of the Italian Cochrane Centre, University of Modena and Reggio Emilia, Italy and co-author of the review said in a statement. “This combination is not recommended in patients with metastatic breast cancer.”

References

1. de Azambuja E, Procter MJ, van Veldhuisen DJ, et al. Trastuzumab-Associated Cardiac Events at 8 Years of Median Follow-Up in the Herceptin Adjuvant Trial (BIG 1-01). J Clin Oncol. 2014;32(20):2159-2165.
2. Balduzzi S, Mantarro S, Guarneri V, et al. Trastuzumab-containing regimens for metastatic breast cancer. Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No.: CD006242. DOI: 10.1002/14651858.CD006242.pub2.