Elsevier

The Lancet

Volume 375, Issue 9712, 30 January–5 February 2010, Pages 377-384
The Lancet

Articles
Neoadjuvant 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

https://doi.org/10.1016/S0140-6736(09)61964-4Get rights and content

Summary

Background

The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients with early, operable, and metastatic breast cancer that has HER2 (also known as ERBB2) overexpression or amplification. We aimed to assess event-free survival in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab.

Methods

We compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no trastuzumab (118), in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Randomisation was done with a computer program and minimisation technique, taking account of geographical area, disease stage, and hormone receptor status. Investigators were informed of treatment allocation. A parallel cohort of 99 patients with HER2-negative disease was included and treated with the same chemotherapy regimen. Primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered, number ISRCTN86043495.

Findings

Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer (3-year event-free survival, 71% [95% CI 61–78; n=36 events] with trastuzumab, vs 56% [46–65; n=51 events] without; hazard ratio 0·59 [95% CI 0·38–0·90]; p=0·013). Trastuzumab was well tolerated and, despite concurrent administration with doxorubicin, only two patients (2%) developed symptomatic cardiac failure. Both responded to cardiac drugs.

Interpretation

The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival, survival, and clinical and pathological tumour responses.

Funding

F Hoffmann-La Roche.

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)

  • J Baselga et al.

    Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule

    J Clin Oncol

    (2005)
  • DJ Slamon et al.

    Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2

    N Engl J Med

    (2001)
  • M Marty et al.

    Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group

    J Clin Oncol

    (2005)
  • EH Romond et al.

    Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer

    N Engl J Med

    (2005)
  • D Slamon et al.

    Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study

    Breast Cancer Res Treat

    (2005)
  • G Bianchi et al.

    Pilot trial of trastuzumab starting with or after the doxorubicin component of a doxorubicin plus paclitaxel regimen for women with HER2-positive advanced breast cancer

    Clin Cancer Res

    (2003)
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