Results of Utility of Long-term Herceptin Use After Adjuvant Chemotherapy

Results of a 4-year follow-up of patients on the Herceptin Adjuvant (HERA) trial have been published in March edition of Lancet Oncology (DOI:10.1016/S1470-2045(11)70033-X). The HERA trial is an international, randomized Phase 3 trial that aimed to show whether treatment with Herceptin for 1 and 2 years after standard neoadjuvant or adjuvant chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive is beneficial for disease-free survival in early breast cancer.

Herceptin Fab (antibody): light and heavy chains, courtesy of Wikimedia Commons user RedAndr.

The one-year follow up demonstrated a significant benefit in disease-free survival in women given Herceptin for 1 year following chemotherapy, and the subsequent 2-year follow-up showed the same benefit as well as a significant difference in overall survival in patients taking Herceptin as adjuvant treatment for 1 year.

The current 4-year follow-up analysis has demonstrated that patients who received Herceptin treatment for 1 year after chemotherapy had a clinical benefit over those who did not receive the treatment. Additionally, patients in the observation group that did not receive the treatment who subsequently crossed over to the Herceptin cohort had improved outcomes.
 
Trial Design
The trial enrolled 5102 women between 2001 and 2005 who had HER2-positive early stage invasive breast cancer. All patients previously had surgery with or without radiation treatment and received neoadjuvant, adjuvant, or both types of chemotherapy. The study consisted of an observation, Herceptin for 1 year, and Herceptin for 2 years cohorts. Because a significant benefit of 1 year of Herceptin treatment was observed, 52% of patients in the observation group who were disease free crossed over into the treatment group.
 
4 year Follow-Up Results
The HERA study 4 -year follow up confirm the original observation that adjuvant Herceptin taken for 1 year is associated with a disease-free survival benefit among HER2-positive early breast cancer patients.

The caveat of having non-randomized patient cross over into the Herceptin cohort prevented the statistical analysis of overall survival benefit between the Herceptin-treated versus non-treated groups. However, the researchers note that their analysis suggest that patients who received delayed treatment with Herceptin at a median of 2 years following chemotherapy had lower risk of relapse compared with patients who remained in the observational, non-treated group.

Adverse events were more frequent in the 1-year Herceptin cohort and included symptomatic congestive heart failure. The frequency was 2% for 1-year Herceptin patients and 3% for patients who crossed over into the Herceptin treatment arm. 5% of patients in each of these groups discontinued treatment due to cardiac problems. The authors note, however, that the incidence of cardiac adverse events remains low with the long-term 4-year follow-up. 

Overall, the study shows that Herceptin is efficacious as an adjuvant treatment. Nevertheless, the result that extending the period between chemotherapy and the start of Herceptin to 1 to 3 years has a benefit for early breast cancer patients will need to be followed up with a controlled, randomized clinical trial. The optimal Herceptin duration of treatment is still not known and is the subject of ongoing clinical trials. Furthermore, as the author of the accompanying editorial mention, a 4-year follow up is still quite short for an adjuvant trial and it may still play out that concurrent chemotherapy and Herceptin treatment is a more effective strategy that chemotherapy followed by Herceptin in an adjuvant setting.