Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study.

BACKGROUND: Neoadjuvant trials conducted using a double HER2 blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab. PATIENTS AND METHODS: Patients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1 : 1 : 1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab + lapatinib at the same dose. The primary end point was pCR rate defined as ypT0/is. Secondary end points included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies. RESULTS: From October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 assessable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib + trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%). Frequency (%) of the most common grade 3-4 toxicities in the lapatinib /trastuzumab/lapatinib + trastuzumab arms were: febrile neutropenia 23/15/10, diarrhoea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8. CONCLUSIONS: This study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity. CLINICALTRIALSGOV: NCT00450892.

Correlation between gliotoxin production and virulence of Aspergillus fumigatus in Galleria mellonella.

Aspergillus fumigatus is a pathogenic fungus capable of causing both allergic lung disease and invasive aspergillosis, a serious, life-threatening condition in neutropenic patients. Aspergilli express an array of mycotoxins and enzymes which may facilitate fungal colonisation of host tissue. In this study we investigated the possibility of using the insect, Galleria mellonella, for in vivo pathogenicity testing of Aspergillus species. Four clinical isolates of Aspergillus fumigatus and a single strain of Aspergillus niger were characterised for catalase and elastase activity and for the production of gliotoxin. Gliotoxin is an immunosuppressive agent previously implicated in assisting tissue penetration. Results illustrated a strain dependent difference in elastase activity but no significant difference in catalase activity. Gliotoxin production was detected in vitro and in vivo by Reversed Phase-High Performance Liquid Chromatography, with highest amounts being produced by A. fumigatus ATCC 26933 (350 ng/mg hyphae). Survival probability plots (Kaplan-Meier) of experimental groups infected with Aspergillus conidia indicate that G. mellonella is more susceptible to fungal infection by A. fumigatus ATCC 26933, implicating a critical role for gliotoxin production rather than growth rate or enzymatic activity in the virulence of A. fumigatus in this model.