ArticlesNeoadjuvant chemotherapy 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 HER2-negative cohort
Introduction
Locally advanced breast cancer accounts for 6–10% of new cases of breast cancer and has a worse prognosis than does early operable disease, although patients with locally advanced disease have a better outlook than do those with distant metastases.1, 2 Inflammatory breast cancer is a rare clinical and pathological subtype that follows an aggressive course and needs systemic therapy even when apparently localised. Preoperative systemic (neoadjuvant) therapy has an important role in patients with locally advanced and inflammatory cancers, treating distant micrometastases, downstaging tumours, improving operability, and sometimes allowing breast-conserving surgery to take place.3 Anthracycline-based and taxane-based therapies are frequently used as preoperative treatments. In patients with operable disease, a non-cross-resistant regimen containing both agents was well tolerated and produced high response rates (78%) and rates of breast-conserving surgery (63%), with a low frequency of symptomatic cardiac dysfunction (≤0·5%).4
Amplification or overexpression, or both, of human epidermal growth factor receptor-2 (HER2, also known as ERBB2), a transmembrane receptor tyrosine kinase, is present in around 22% of early breast cancers, 35% of locally advanced and metastatic tumours, and 40% of inflammatory breast cancers, and is associated with aggressive disease and poor prognosis.5, 6 Patients with HER2-positive locally advanced or inflammatory breast cancer are therefore in particular need of effective treatment. Trastuzumab (Herceptin, Roche, Basel, Switzerland), a recombinant humanised monoclonal antibody that targets HER2, has efficacy as monotherapy7, 8 and improves results of chemotherapy in patients with HER2-positive metastatic9, 10 and early operable breast cancer.11, 12, 13 It is widely approved for use as monotherapy and in combination with chemotherapy or hormone therapy in these patients, but not specifically in those with locally advanced or inflammatory breast cancer. In a pilot study,14 anthracycline and paclitaxel were successfully combined with trastuzumab in patients with metastastic disease. To reduce risk of cardiac toxic effects, only three cycles of doxorubicin were given in the pilot study, which corresponds to a cumulative dose of 180 mg per m2 of body surface area.15 No patient developed symptomatic cardiac dysfunction, although four patients (of 16) had reversible asymptomatic decreases in left ventricular ejection fraction to 50% or lower.
The neoadjuvant Herceptin (NOAH) study was designed to assess efficacy of neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone in patients with HER2-positive locally advanced or inflammatory breast cancer.
Section snippets
Study design
NOAH was an international, open-label, phase 3 trial in women with newly diagnosed locally advanced or inflammatory breast cancer. We randomly allocated patients with HER2-positive disease to receive neoadjuvant trastuzumab plus chemotherapy followed by adjuvant trastuzumab, or neoadjuvant chemotherapy alone. However, after positive results of adjuvant trastuzumab trials became available, HER2-positive patients allocated to chemotherapy alone were offered 1 year of adjuvant trastuzumab
Results
Between June 20, 2002, and Dec 12, 2005, 334 patients entered the study. Figure 1 shows the trial profile. One patient with HER-positive disease who was allocated to receive trastuzumab was not included in event-free and overall survival analyses because of delayed approval of a protocol amendment by the ethics committee at that site. Table 1 summarises baseline characteristics. As expected, women in the HER2-negative group were less likely to have inflammatory or hormone receptor-negative
Discussion
The results of the NOAH study have shown that in patients with HER2-positive locally advanced or inflammatory breast cancer, addition of 1 year of trastuzumab (starting as neoadjuvant and continuing as adjuvant therapy) to neoadjuvant chemotherapy improved overall response rates, almost doubled rates of pathological complete response, and reduced risk of relapse, progression, or death compared with patients who did not receive trastuzumab. We recorded a benefit of trastuzumab in all subgroups
References (32)
- et al.
2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial
Lancet
(2007) - et al.
Efficacy of neoadjuvant trastuzumab in patients with inflammatory breast cancer: data from the NOAH (NeOAdjuvant Herceptin) phase III trial
Eur J Cancer
(2007) - et al.
Hormone-receptor status and likelihood of predicting pathological complete response (pCR) in the NOAH trial of neoadjuvant trastuzumab in patients (pts) with HER2-positive locally advanced breast cancer (LABC)
Eur J Cancer
(2008) - et al.
Trends in inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program at the National Cancer Institute
J Natl Cancer Inst
(2005) - et al.
Breast carcinoma survival in Europe and the United States
Cancer
(2004) - et al.
Locally advanced and inflammatory breast cancer
J Clin Oncol
(2008) - et al.
Addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate and fluorouracil, as adjuvant or primary systemic therapy: results of a randomized phase III European Cooperative Trial in Operable Breast Cancer (ECTO)
J Clin Oncol
(2009) - et al.
Prognostic impact of human epidermal growth factor-like receptor 2 and hormone receptor status in inflammatory breast cancer (IBC): analysis of 2,014 IBC patient cases from the California Cancer Registry
Breast Cancer Res
(2009) - et al.
The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine
Oncologist
(2009) - et al.
Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease
J Clin Oncol
(1999)