Trastuzumab-associated cardiac events in the Persephone trial

Background: We report cardiac events in the Persephone trial which compares 6–12 months of adjuvant trastuzumab in women with confirmed HER2-positive, early-stage breast cancer. Methods: Clinical cardiac events were defined as any of the following: symptoms and/or signs of congestive heart failure (CHF) and new or altered CHF medication. In addition, left ventricular ejection fraction (LVEF) was measured at baseline and then 3 monthly for 12 months. Results: A total of 2500 patients, aged 22–82, were included: 1251 randomised to 12 months and 1249 to 6 months of trastuzumab treatment. A total of 93% (2335/2500) received anthracyclines, 49% of these (1136/2335) with taxanes. Cardiotoxicity delayed treatment in 6% of 12-month and 4% of 6-month patients ( P =0.01), and stopped treatment early in 8% (96/1214) of 12-month and 4% (45/1216) of 6-month patients ( P <0.0001). Between 7 and 12 months, more 12-month than 6-month patients had LVEFs<50% (8% vs 5%; P =0.004). LVEFs showed quadratic change over time, and 6-month patients had a more rapid recovery ( P =0.02). In a landmark analysis twice as many 12-month patients, free of cardiac events at 6 months, had cardiac problems in months 7–12 (6% (66/1046) vs 3% (29/1035) of 6-month patients ( P =0.0002)). Lower baseline LVEF predicted more cardiac dysfunction in both arms (reference ⩾65%: 55 to <65% OR 1.61 (95% CI 1.26–2.04); <55% OR 5.22 (3.42–7.95)) as did increasing age (reference <50: 50–59 OR 1.58 (1.17–2.12), 60–69 OR 1.91 (1.42–2.57)) 70+ OR 2.72 (1.82–4.08)) and prior use of cardiac medication (OR 8.46 (4.69–15.25)). >3 cycles of anthracycline was associated with higher risk of cardiac events only for 12-month patients (OR 1.41 (1.04–1.90)), and not for 6-month patients (OR 1.28 (0.91–1.79)). Conclusions: We demonstrate significantly fewer cardiac events from 6 months of adjuvant trastuzumab compared with that from 12 months. This cardiac signal adds importance to the question of the optimum duration of adjuvant trastuzumab treatment. If 6 months is proven to have non-inferior outcomes to 12 months treatment, these data would support 6 months as the standard of care.