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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.

A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer. The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1:1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m2) followed by four cycles of fluorouracil (500 mg/m2), epirubicin (75 mg/m2), and cyclophosphamide (500 mg/m2), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (Ctrough) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0·80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of −12·5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300. 299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery Ctrough was 51·8 μg/mL (coefficient of variation 52·5%) in the intravenous group and 69·0 μg/mL (55·8%) in the subcutaneous group. The geometric mean ratio of Ctrough subcutaneous to Ctrough intravenous was 1·33 (90% CI 1·24–1·44). 107 (40·7%) of 263 patients in the intravenous group and 118 (45·4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4·7% (95% CI −4·0 to 13·4). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3–5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33·2%] of 298 patients in the intravenous group vs 86 [29·0%] of 297 in the subcutaneous group), leucopenia (17 [5·7%] vs 12 [4·0%]), and febrile neutropenia (10 [3·4%] vs 17 [5·7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8·1%] in the subcutaneous group vs 13 [4·4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two—both in the subcutaneous group—were deemed to be treatment related. Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative. F Hoffmann-La Roche.

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. 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. 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. 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. F Hoffmann-La Roche.

Several randomised trials have confirmed the benefit of adjuvant trastuzumab for patients with HER2-positive early breast cancer. However, concern has been expressed that adjuvant trastuzumab might be associated with an increased frequency of CNS relapses. We assessed the frequency and course of CNS relapses, either as first event or at any time, using data from the HERA trial. We estimated the cumulative incidence of first disease-free survival (DFS) events in the CNS versus other sites by competing risks analysis in patients with HER2-positive early breast cancer who had been randomly assigned to receive 1 year of trastuzumab or to observation in the HERA trial after a median follow-up of 4 years (IQR 3·5–4·8). To obtain further information about CNS relapse at any time before death, we circulated a data collection form to investigators to obtain standardised information about CNS events that occurred in all patients who had died before July, 2009. We estimated the cumulative incidence of CNS relapse at any time with a competing risks analysis. Of 3401 patients who had been assigned to receive 1 year of trastuzumab or to observation, 69 (2%) had a CNS relapse as first DFS event and 747 (22%) had a first DFS event not in the CNS. The frequency of CNS relapses as first DFS event did not differ between the group given 1 year of trastuzumab (37 [2%] of 1703 patients) and the observation group (32 [2%] of 1698; p=0·55 [Gray's test]). 481 data collection forms were distributed, of which 413 (86%) were returned. The proportion of patients who had died and experienced a CNS relapse was numerically higher in the observation group (129 [57%] of 227) than in the group given trastuzumab for 1 year (88 [47%] of 186; p=0·06 [Gray's test]). Most CNS relapses were symptomatic (189 [87%] of 217). Adjuvant trastuzumab does not increase the risk of CNS relapse in patients with HER2-positive early breast cancer. None.

Comparisons of duration of response (DoR) and duration of clinical benefit (DoCB) within clinical trials are prone to biases. To address these biases, we used new methodology to prospectively analyze expected DoR and expected DoCB. Objective response rate and clinical benefit rate were calculated for fulvestrant 500 and 250 mg, and used to calculate expected DoR and expected DoCB for each dose group. The ratios for expected DoR and expected DoCB (expected DoR 500 /expected DoR 250 and expected DoCB 500 /expected DoCB 250 ) were then calculated, thereby allowing statistical comparisons of these endpoints between each arm of the COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) trial. Expected DoRs for fulvestrant 500 and 250 mg were 3.2 and 3.6 months, respectively. The expected DoR ratio between fulvestrant 500 and 250 mg was not statistically significant (0.89; 95 % CI, 0.48–1.67, P  = 0.724). The expected DoCBs for fulvestrant 500 and 250 mg were 9.8 and 7.2 months, respectively. The expected DoCB ratio showed that the expected DoCB for fulvestrant 500 mg was significantly improved compared with the expected DoCB for fulvestrant 250 mg (1.36; 95 % CI, 1.07–1.73, P  = 0.013). Analysis of the expected DoR and expected DoCB showed fulvestrant 500 mg significantly increased expected DoCB compared with fulvestrant 250 mg in the CONFIRM trial.