Neoadjuvant and adjuvant trastuzumab in patients with HER2–positive locally advanced breast cancer (NOAH): follow–up of a randomised controlled superiority trial with a parallel HER2–negative cohort
In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2–positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event–free survival. We report updated results from our primary analysis to establish the long–term benefit of trastuzumab–containing neoadjuvant therapy.
We did this multicentre, open–label, randomised trial in women with HER2–positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2–negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event–free survival. Analysis was by intention to treat. This study is registered at www.controlled–trials.com, ISRCTN86043495.
Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2–positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2–negative disease were included in the parallel cohort. After a median follow–up of 5.4 years (IQR 3.1–6.8) the event–free–survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2–positive disease. 5 year event–free survival was 58% (95% CI 48–66) in patients in the trastuzumab group and 43% (34–52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event–free survival between the two randomised HER2–positive treatment groups was 0.64 (95% CI 0.44–0.93; two–sided log–rank p=0.016). Event–free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event–free survival between those with and without trastuzumab was 0.29 (95% CI 0.11–0.78). During follow–up only four cardiovascular adverse events were regarded by the investigator to be drug–related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy–alone group).
These results show a sustained benefit in event–free survival from trastuzumab–containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long–term outcomes in HER2–positive disease.
F Hoffmann–La Roche.