NO BENEFIT OF 2 YEAR ADJUVANT HERCEPTIN

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.” ■