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The Lancet Oncology

Tuesday, January 13, 2009

Trastuzumab Given Prior to Surgery Improves the Chance of Survival in HER2-positive Breast Cancer

Primary efficacy analysis of the NeOAdjuvant Herceptin trial (NOAH) presented at the 31st Annual CRTC-AACR San Antonio Breast Cancer Symposium (SABCS, December 10 - 14, 2008) by Professor Luca Gianni, MD, from the Istituto Nazionale Tumori in Milan, a leading investigator of the NOAH trial, demonstrated that standard one year treatment with trastuzumab (Herceptin®, Genentech, 1 DNA Way South San Francisco, CA 94080-4990/F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland) provides long-term benefit to patients with high risk of recurrence of their breast cancer.

Incidence, Mortality and Prevalence
Breast cancer is, according to the World Health Organization (WHO), the most common cancer among women. Based one the GLOBOCAN 2002 data, each year more than one million new cases of breast cancer are diagnosed worldwide, and nearly 400,000 people will die of the disease annually.

Poor response
In HER2-positive breast cancer, increased quantities of the HER2 protein are present on the surface of the tumour cells. This is known as ‘HER2-positivity’ breast cancer. High levels of HER2 are present in a particularly aggressive form of the disease which responds poorly to chemotherapy. Research shows that HER2-positivity affects approximately 20 percent of women with breast cancer.

Mode of Action
Trastuzumab is a humanised antibody, designed to target and block the function of HER2, a protein produced by a specific gene with cancer-causing potential. The mode of action of trastuzumab is unique in that it activates the body’s immune system and suppresses HER2 to target and destroy the tumour. Trastuzumab has demonstrated unprecedented efficacy in treating both early and advanced (metastatic) HER2-positive breast cancer. Given on its own as monotherapy as well as in combination with or following standard chemotherapy, trastuzumab has been shown to improve response rates, disease-free survival and overall survival while maintaining quality of life in women with HER2-positive breast cancer.

Locally advanced breast cancer or LABC, including inflammatory breast cancer, is more common in Europe than in the US and accounting for about 10% of all new cases. The median survival time remains low, ranging from 3 years (for inflammatory breast cancer) to 6 years. Thus, new treatment approaches are critically important.

The largest neoadjuvant trial
The NeOAdjuvant Herceptin trial (NOAH) is the largest multicentre, randomised, open-label, Phase III trial, evaluating the benefits of giving neoadjuvant trastuzumab in combination with anthracycline- and taxane-based chemotherapy versus chemotherapy alone to women with locally advanced HER2-positive breast cancer.

A total of 228 patients with centrally confirmed locally advanced HER2-positive breast cancer, a particularly aggressive form of the disease, participated in this neoadjuvant study. 115 patients received standard chemotherapy plus trastuzumab (for one year) and 113 patients received chemotherapy alone before surgery. The primary end point was event-free survival (EFS), defined as the time between randomisation and disease recurrence or progression, or death from any cause. Secondary end points were pathological complete response (pCR), overall response rate (ORR), overall survival (OS) and safety.

Improving event free survival
The results of this study show that trastuzumab plus chemotherapy improved event free survival at 3 years to 70% vs 53% with chemotherapy alone - the addition of trastuzumab to chemotherapy reduced the relative risk of recurrence by about half (HR 0.56, p=0.006). In addition, trastuzumab plus chemotherapy was shown to completely eradicate the tumor (a pathological complete response to treatment) in nearly twice as many patients, 39%, compared with only 20% of patients treated with chemotherapy alone (p=0.002). The overall response rate was also significantly increased (89% vs 77%, p=0.02).

Treatment options
Standard treatment for locally advanced breast cancer currently includes neoadjuvant chemotherapy. In this study, outcomes were assessed in HER2-positive patients with locally advanced breast cancer treated with chemotherapy (3 cycles of doxorubicin and paclitaxel, 4 cycles of paclitaxel, 3 cycles of CMF; n=113) or with chemotherapy + trastuzumab (n=115). A control group of HER2-negative patients with LABC received chemotherapy only (n=99). The primary endpoint was event-free survival (EFS), with a median follow-up time of 3 years. For HER2-positive patients who received chemotherapy and trastuzumab, EFS was significantly improved compared with HER2-positive patients who only received chemotherapy (70.1% vs 53.3%, respectively; HR=0.56, P=.006). Overall survival, a secondary endpoint, was also improved in patients receiving trastuzumab, but the difference was not significant (85.3% vs 80.4%, respectively; HR=0.65, P=.18). EFS was similar in the HER2-positive arm treated with chemotherapy alone and the HER2-negative control arm over the first 18 months, but showed a divergence in favor of HER2-negative patients over a longer period of time. Adverse events from the 2 therapy regimens were within acceptable limits. Cardiac toxicity, as reflected by changes in left ventricular ejection fraction (LVEF), was minimal in the majority of patients (>95% of patients with CTC grade 0 or 1), with 2 cardiac events reported in the group receiving trastuzumab.

About 70% of women with locally advanced HER2-positive breast cancer were free of their disease three years after initiation of therapy when treated with trastuzumab plus chemotherapy before surgery, compared to only around 50% of patients receiving pre-operative chemotherapy alone.

The results from the final analysis of the NOAH (NeOAdjuvant Herceptin) phase III study offer welcome news as patients with this early, but locally advanced breast cancer whose disease has spread to tissues around the breast such as the skin, muscle or lymph nodes generally face a high chance of recurrence and short life-expectancy.

‘The positive results of the NOAH study show that starting trastuzumab treatment prior to surgery offers long-term benefits to women with HER2-positive breast cancer,’ said William M. Burns, CEO Division Roche Pharmaceuticals. ‘Herceptin continues to provide women with early breast cancer a much improved prognosis, even if their cancer has advanced locally.’

Commenting on the results, Professor Gianni explained: ‘Women with locally advanced HER2-positive breast cancer are difficult to treat,’ ‘The results of the NOAH study imply that starting chemotherapy with one year of Herceptin should become the standard of care for women with locally advanced HER2-positive breast cancer’.

The aim of pre-surgery (neoadjuvant) therapy given to women with breast cancer is to improve the local control of the tumour to facilitate surgery. At the same time, the objective is to determine the sensitivity of the tumour towards a specific treatment. The results of this study demonstrate that starting trastuzumab treatment prior to surgery helps shrink locally advanced breast cancer and improve long term outcomes.

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