Gene expression profiling offers the promise to identify novel therapeutic targets, form the basis for new prognostic classification systems, assess mechanisms of action versus resistance to therapies, and ultimately identify those patients most likely to respond to a given therapy. In order to achieve these goals, correlative genomic studies need to be performed on samples obtained from uniformly treated patients with rigorous clinical annotation. Often this will require large multicenter randomized trials, which add complexity and obstacles ranging from adequate sample acquisition to appropriate bioinformatic analysis and interpretation for meaningful clinical application.
In this paper, Mulligan et al. correlated the baseline transcriptional profiles with clinical response to the novel proteasome inhibitor Bortezomib in two large phase II clinical trials of Bortezomib treatment for patients with relapsed and refractory disease, as well as a large multicenter phase III clinical trial comparing Bortezomib with Dexamethasone treatment for patients with relapsed myeloma. In this study, a pre-treatment gene expression profile associated with response to Bortezomib was identified. Most importantly, however, there are several lessons from this study regarding the challenges that implementation of similar research studies may face in the present and future.
In Brief
In these multicenter trials, uniform protocols were applied to obtain informed consent to acquire bone marrow samples for genomics analysis, separate myeloma cells from bone marrow samples, and prepare tumor cell RNA. However, isolated RNA samples were deemed of inadequate quantity or quality for analysis in nearly half of the patients enrolled in the trials. This is a major potential confounder of the correlation of transcriptional profiles with clinical outcome, highlighting the need for methodologies which assure adequate sample collection in the majority of patients enrolled to allow for meaningful analysis.
Secondly, this study analyzed genomics data from several clinical trials, including two phase II trials in which more heavily pretreated relapsed refractory patients were enrolled, and a phase III trial targeting patients earlier in the disease course with relapsed myeloma. Therefore, patients were not uniform in disease status, further confounding clinical interpretation and application.
Finally, despite the rapid translation of Bortezomib from the bench to the bedside, more than four years elapsed between collection of initial samples in the phase II trials and the analyses of updated survival data from the phase III trial. During this interval, changes in methodologies for collection and processing of samples (e.g., hybridization using different batches of arrays for analysis) may add further complexity to meaningful data interpretation.
Mulligan and colleagues have successfully identified a gene signature of response to the novel proteasome inhibitor Bortezomib to be validated in future studies. Importantly, they have identified several practical obstacles to be overcome if the promise of correlative genomic studies is to translate to improved clinical practice.
Competing Interests
Dr. Anderson indicated no relevant conflicts of interest.
