Reply to S.M. Ali et al
Authors: Siân Lennon, Claire Barton, Ludger Banken, Luca Gianni, Michel Marty, Jose Baselga, Brian Leyland-Jones
Journal: Journal of Clinical Oncology (2009)

We would like to respond to the observations made by Ali et al 1 on our study 2 and to propose that our findings are not so very different to their recently published work. 3 Ali et al 1 state that the number of patients who were human epidermal growth factor receptor 2 (HER2)/neu tissue positive and treated with first-line trastuzumab and had both baseline and follow-up serum HER2/neu was 105 in our study (v 235 in the Ali et al 3 study).However, our study actually included 268 patients with a baseline and at least one follow-up extracellular domain (ECD) sample.Of these, 212 were treated with trastuzumab (with or without concomitant chemotherapy) in the first-line setting (ie, they were enrolled in the WO16229 study, the M77004 study, or the trastuzumab-containing arm of the M77001 study).We believe that one of the strengths of our study is that it also included patients with HER2-positive disease treated with chemotherapy alone.This resulted in the observation of very similar ECD changes in patients treated with chemotherapy alone-an intriguing finding which raises questions about the specificity of ECD changes in relation to trastuzumab therapy.Ali et al 1 defined a significant decline in serum ECD as a 20% decrease from baseline at a median of 30 days after commencing trastuzumab.Because ECD was used as continuous covariable in the logistic regression analyses in our study, we did not need to define a significant decline in serum ECD to create a categoric variable.Overall response was defined as two categories: response (complete or partial) versus no response (stable disease or progressive disease).Best response was defined as complete response, partial response, stable disease, or progressive disease (four categories).The distinction between overall and best response is mentioned briefly in the Methods section of our article (where logistic regression analyses are described). 2Response was assessed according to WHO criteria in all four studies included.We acknowledge that further analyses including response duration, time to progression, and overall survival would be of some interest.However, these analyses were not planned at the time of our study and our relatively negative findings did not prompt further exploration.Importantly, the purpose of our study was to evaluate whether measurements of ECD might be clinically useful in guiding treatment of individual patients.We found some correlations between changes in ECD levels and clinical events but these were not sufficiently robust to enable individual patient decisions.We believe that our findings are consistent with those of Ali et al. 3 In particular, Ali et al found that a decrease in serum ECD of at least 20% was associated with a significantly higher response rate (57% compared with 28% for patients who did not achieve a decline in serum ECD of at least 20%), as well as longer time to disease progression, duration of response, and survival.However, although these correlations were undoubtedly of statistical significance, from a practical point of view, 28% of patients who did not achieve a 20% decline in ECD also responded to trastuzumab-based therapy.Thus,