Cardiotoxicity Reduced In Early-Stage Breast Cancer With 6-Month Trastuzumab Regimen

Secondary endpoint findings for the Persephone trial show less cardiotoxicity in early-stage HER2-positive breast cancer patients given 6 months of trastuzumab than a 12-month course

medwireNews: Six months of adjuvant trastuzumab results in significantly fewer cardiac side effects in women with HER2-positive, early-stage breast cancer than the standard 12-month course of treatment, suggest preliminary results from the Persephone study.

“This cardiac signal adds importance to the question of the optimum duration of adjuvant trastuzumab treatment”, the phase III study investigators say, adding that if the primary endpoint of disease-free survival after 6 months’ treatment was found to be noninferior to 12 months, “these data would support 6 months as the standard of care.”

In all, 1251 participants were randomly assigned to receive 18 cycles of trastuzumab over 12 months whereas 1249 patients were given nine cycles over 6 months, report Helena Earl, from the University of Cambridge in the UK, and team. Most patients (93%) also received anthracyclines and 49% also received taxane therapy.

The secondary endpoint of clinical cardiac dysfunction was defined as signs or symptoms of congestive heart failure, or new or altered cardiac medication within a year of beginning treatment, they explain in the British Journal of Cancer.

Patients treated with trastuzumab for 12 months were significantly more likely to have cardiotoxicity resulting in a treatment delay (6 vs 4%) or early discontinuation of treatment (8 vs 4%) than those given the 6-month regimen.

Patients on the 12-month regimen were also significantly more likely to experience up to a 50% decrease in their left ventricular ejection fraction (LVEF) between months 7 and 12 of treatment than patients given only 6 months of treatment (8 vs 5%).

The investigators note that LVEF showed a “quadratic change” over time and that patients on the shorter trastuzumab course had a significantly faster recovery.

A landmark analysis demonstrated that patients in the 12-month arm who were free of cardiac events in the first 6 months of treatment were a significant twice as likely to develop cardiac issues in months 7 to 12 than patients in the 6-month arm, at 6% versus 3%.

In addition, cardiac dysfunction was significantly more likely in women of either treatment arm who had a baseline LVEF below 65% (odds ratio [OR]=1.61) or below 55% (OR=5.22) than those with a baseline LVEF of 65% or higher. This was also true for increasing age, with ORs of 1.58, 1.91 and 2.72 for patients aged 50–59, 60–69 and over 70 years compared with patients aged less than 50 years.

Prior need for cardiac medication was another risk factor for cardiac dysfunction (OR=8.46), as was receipt of more than three cycles of anthracyclines, although the latter only reached significance in the 12-month treatment group (OR=1.41).

The authors of an accompanying editorial agree that if the phase III study's primary endpoint of noninferior disease-free survival with a 6-month regimen is met, it would be a "highly important finding".

“This finding would help our patients in that they could end their treatment sooner, would probably need less cardiac monitoring, and would enjoy a less burdensome, less costly and equally effective therapy”, say Michael Ewer, from The University of Texas MD Anderson Cancer Center in Houston, USA, and Steven Ewer, from the University of Wisconsin in Madison, USA.

And they continue: “If 12 months is superior from the oncologic perspective, Earl et al (2016) have reinforced our notion that fears of cardiotoxicity should not undermine optimal oncologic intervention.”


Earl HM, Vallier A-L, Dunn J, et al. Trastuzumab-associated cardiac events in the Persephone trial. Br J Cancer; Advance online publication 22 November 2016. doi: 10.1038/bjc.2016.357

Ewer MS, Ewer SM. Trastuzumab cardiotoxicity: the age-old balance of risk and benefit. Br J Cancer; Advance online publication 22 November 2016. doi: 10.1038/bjc.2016.381

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