As reported in The Lancet by Aron Goldhirsch, MD, of the European Institute of Oncology in Milan, Italy, and colleagues from the Breast International Group (BIG), the comparison of 1 vs 2 years of trastuzumab (Herceptin) in patients with HER2-positive early breast cancer in the phase III HERA trial has shown no advantage of 2 years over 1 year of treatment.¹ However, an update of the HERA trial comparison of 1 year of trastuzumab vs observation showed continued significant disease-free survival benefit and a significant overall survival benefit of trastuzumab after a median follow-up of 8 years, despite substantial crossover to trastuzumab.

Study Details

In this international open-label trial, 5,102 patients with HER2-positive early breast cancer were randomly assigned to 1 year (n = 1,703) or 2 years (n = 1,701) of trastuzumab or observation (n = 1,698) after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both. The comparison of 2 years vs 1 year of trastuzumab treatment involved a landmark analysis of 3,105 patients who were disease-free at 12 months after randomization and was planned to occur after observation of ≥ 725 disease-free survival events. The primary endpoint was disease-free survival.

The 1-year group (n = 1,552) and 2-year group (n = 1,553) were well balanced for age (< 35 years in 7% in both, 35–49 years in 45% in both, ­50–59 years in 32% and 33%, and ≥ 60 years in 16% in both), receipt of adjuvant chemotherapy (89% in both), receipt of neoadjuvant chemotherapy (11% in both), and previous neoadjuvant/adjuvant therapy (anthracycline but no taxane in 68.5% and 69%, anthracycline and taxane in 25.5% and 26%, no anthracycline in 6% in both).

The two groups were also well matched for menopause status (premenopausal in 15% and 13%, postmenopausal in 44.5% and 46%), pathologic tumor size (not assessed–neoadjuvant therapy in 11% in both, 0–2 cm in 40% and 39%, > 2–5 cm in 45% and 44%, > 5 in 4% and 6%), nodal status (negative in 33% in both, 1–3 positive nodes in 29% and 30%, ≥ 4 positive in 27% in both), hormone receptor status (estrogen and progesterone receptor–positive in 51% in both, estrogen and progesterone receptor–negative in 49% in both), and proportion of hormone receptor–positive patients receiving adjuvant endocrine therapy (92% and 93%).

2- vs 1-Year Outcomes

After a median follow-up of 8 years, there was no significant difference between the 2-year group and the 1-year group in disease-free survival (hazard ratio [HR] = 0.99, P = .86). At 8 years, disease-free survival rates were 75.8% in the 2-year group and 76.0% in the 1-year group.

Disease-free survival events consisted of local recurrence in 4.1% vs 3.7% of patients, regional recurrence in 0.9% vs 1.4%, distant recurrence in 14.4% vs 13.4%, contralateral breast cancer in 1.9% vs 2.0%, second primary malignancy in 2.1% vs 2.5%, and death with no evidence of disease in 0.3% vs 0.6%. There were no significant differences between groups in disease-free survival according to hormone receptor–positive status (HR = 1.05, P = .67) or hormone receptor–negative status (HR = 0.93, P = .51). Similarly, overall survival did not differ between the two groups (HR = 1.05, P = .63).

Separate assessment of the contributions of breast cancer–related events and competing risks to disease-free survival using standard cumulative incidence methods indicated that results were similar for the 2-year and 1-year groups, with the exception that breast cancer–related events seemed to be nonsignificantly more common in patients with hormone receptor–negative disease in the 1-year group. No difference was observed among patients with hormone receptor–positive disease, almost all of whom were receiving adjuvant endocrine therapy.

Updated 1-Year vs Observation Analysis

The updated intention-to-treat comparison of 1 year of trastuzumab (n = 1,702) vs observation (n = 1,697) included 3,399 patients at a median follow-up of 8 years (range, 0–10 years). After publication of the initial trial results, 52.1% of the observation group crossed over to receive trastuzumab before occurrence of a disease-free survival event.

Despite this crossover, the updated analysis showed persistence of benefits in the 1-year group. Disease-free survival was significantly prolonged in the 1-year group (HR = 0.76, P < .001), and overall survival, which was nonsignificantly prolonged in the 1-year group at median follow-up of 4 years (HR = 0.85, P = .1087), was significantly prolonged at 8-year follow-up (HR = 0.76, P = .0005).

Adverse Events

Grade 3 or 4 adverse events (20.4% vs 16.3%, and 8.2% in observation group) and decreases in left-ventricular ejection fraction during treatment (7.2% vs 4.1%, and 0.9% in observation group) were reported more frequently in the 2-year vs 1-year group. Fatal adverse events occurred in 1.2% of the 2-year group, 1.1% of the 1-year group, and 0.4% of the observation group. Primary cardiac endpoints occurred in 1.0%, 0.8%, and 0.1%, respectively.

The body systems with the highest frequency of grade 3 or 4 adverse events were neoplasms (4.6% of 2-year group, 3.6% of 1-year group, and 1.8% of observation group), infections and infestations (3.3%, 2.2%, and 0.7%), nervous system disorders (2.0%, 0.8%, and 0.7%), vascular disorders (2.0%, 1.8%, and 1.0%), and cardiac disorders (1.9%, 1.9%, and 0.5%).

The investigators concluded, “Two years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer. [One] year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care.” ■

Disclosure: The study was funded by F Hoffmann-La Roche (Roche). For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al: 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomised controlled trial. Lancet 382:1021-1028, 2013.