Cardiotoxicity has been documented as a risk in cancer patients undergoing certain breast cancer therapies, but widely accepted international guidelines do not exist for dealing with those complications.

In a review published by the Journal of the American Heart Association, four medical professionals reviewed studies dealing with these risks and created guidelines of their own in an effort to expand the research and efficacy of human epidermal growth factor receptor-2 (HER2)-targeted therapies in cancer patients.

HER2-positive breast cancers are generally associated with a higher risk of mortality and disease recurrence than other breast cancers, Roberta Florido, MD, and colleagues wrote in the review. The development of trastuzumab, a monoclonal antibody that targets HER2 overproduction, “revolutionized” treatments for HER2-positive cancers, they wrote, improving outcomes in cancer patients and avoiding symptoms like emesis and alopecia, which are generally linked to alternative treatments like chemotherapy.

However, treatments for HER2 breast cancers—trastuzumab in particular—have been increasingly associated with climbing rates of cardiovascular risk since the late 90s.

Trastuzumab was the first monoclonal antibody developed to treat HER2 and was approved by the FDA in 1998. It was initially tested in patients who had failed first- and second-line chemotherapy, Florido and co-authors explained, and first trials resulted in significant improvements in those patients’ health. One 2014 study showed trastuzumab treatment led to 18- and 39-percent improvements in overall and progression-free survival in patients with progressive metastatic breast cancer. Other research followed suit, consistently showcasing the benefits of trastuzumab to cancer patients.

The first data documenting the adverse cardiovascular effects of trastuzumab was published in 2001, Florido and colleagues wrote. In the study, risk of symptomatic or asymptomatic cardiac dysfunction was highest among patients who had been treated with trastuzumab, anthracycline and cyclophosphamide, at 27 percent. Cancer patients who received trastuzumab in conjunction with the chemotherapy agent paclitaxel were at second-highest risk—13 percent—when compared with individuals who received either chemotherapy treatment on its own. In a recent study, the combination of trastuzumab and paclitaxel proved successful in lowering risk of disease recurrence to the extreme in patients with small, node-negative, early-stage breast cancer.

Florido and co-authors found in their research that rates of cardiotoxicity seemed to be much lower in cases where trastuzumab was used with regimens that didn’t include anthracyclines. Because of the results of early studies indicating increased risk for cardiotoxicity where anthracyclines and trastuzumab were involved, subsequent research excluded women with preexisting cardiovascular risk factors to avoid heart failure.

While past use of anthracyclines, especially at high cumulative doses, appeared to be the most telling marker of future cardiovascular dysfunction in breast cancer patients, history of heart failure, systolic dysfunction, coronary artery disease, atrial fibrillation, hypertension, diabetes, obesity, dyslipidemia and renal failure were also significant risk factors, the authors wrote. Age also played a role, with women 60 years old and up showing a higher risk for cardiotoxicity after cancer treatment.

Florido and colleagues outlined recommendations based on their exhaustive research of clinical trials and observational studies, including the suggestion of early initiation of angiotensin-converting enzyme inhibitors and beta-blockers for the prevention of cardiotoxicity in cancer patients. The authors also recommended patients with HER2-positive breast cancer receive baseline assessment of cardiotoxicity before beginning any treatment, including vetting those patients for any previous cardiovascular risks or existing cardiovascular disease.

The authors also recommended individuals have their left ventricular ejection fraction assessed by echocardiography, and that patients make lifestyle changes, like better diets and routine physical activity, before beginning any kind of HER2-targeted treatment. Patients, oncologists and cardiologists should all work together to determine the right course of treatment, they wrote.

“Close collaboration between oncologists and cardiologists is key for successful prevention and management of cardiotoxicity from cancer patients,” the authors concluded. “We suggest that high-risk patients, especially those with preexisting CVD, and patients who develop cardiac dysfunction be referred for consultation with a cardiologist, ideally someone with cardio-oncology expertise. Clinical decision about discontinuation of therapy ought to be informed by both providers and shared with patients in a collaborative process.”