Safety and efficacy in locally advanced breast cancer. Results of the NOAH study

Locally advanced breast cancer represents 6-10% of new cases in developed countries. It has a worse prognosis than early breast cancer. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 35% of these cases and in 40% of inflammatory tumors.

Trastuzumab, an anti-HER2 monoclonal antibody, improves chemotherapy results in both metastatic breast cancer and early breast cancer treatments. In a pilot study carried out in patients with metastatic disease, anthracyclines, paclitaxel and trastuzumab were safely and effectively combined. In order to decrease the heart-toxicity risk, an anthracycline cumulative dose of 180 mg/m2 (3 therapeutic courses) was used.

The NOAH study was designed to evaluate the efficacy of neoadjuvant chemotherapy with trastuzumab followed by trastuzumab versus chemotherapy alone in patients with HER-2 positive locally advanced or inflammatory breast cancer.

A phase III open study assigned 334 patients to receive 60 mg/m2 of adriamycin plus 80 mg/m2 of paclitaxel during three courses of treatment every 21 days, followed by 175 mg/m2 of paclitaxel every 21 days and then three courses of cytoxan, methotrexate and fluorouracil (CMF). Afterwards, surgery and radiotherapy. HER2 positive patients were randomly assigned to receive trastuzumab every 21 days during chemotherapy and one more year of the antibody after surgery, or to the control group. Parallely, there was a HER2 negative cohort with the aim of analyzing its progression.

Disease-free survival was considered the primary endpoint and complete pathologic response, overall response, cardiovascular toxicity and overall survival were secondary endpoints. Twenty seven percent of patients had inflammatory tumors and 42%, non-inflammatory T4 tumors.In 64%, both were HR-negative. Ninety one percent of the HER2-positive patients completed chemotherapy; 7% discontinued the administration of trastuzumab before the first year.

After a follow-up of 3.2 years, disease-free survival was higher in the trastuzumab group (hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.38-0.90; p = 0.013), which means a 41% reduction in the risk of recurrence, progression or death with the use of trastuzumab. The benefits were maintained in all analyzed sub-groups. A higher percentage of complete pathologic response was also observed (43% versus 22%).
Adverse events were similar in the three groups; there was no greater grade 3-4 heart toxicity in the trastuzumab group. Even though there were decreases in the ventricular ejection fraction, these were mainly grade 1.

The results of this trial show an improvement in disease-free survival and in the percentage of complete pathologic response in HER2-positive patients with the use of trastuzumab plus chemotherapy.

Despite the concurrent use of doxorubicin and trastuzumab, the incidence of symptomatic heart failure was lower than 2%.

Gianni L, Eiermann V, Semiglazov V. Neoadjuvant chemoterapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2 positive locally advanced breast cancer (the NOAH trial): A randomised controlled superiority trial with a parallel HER 2 negative cohort. Lancet 2010;375:377.