[Show abstract][Hide abstract] ABSTRACT: The developmental pathway from discovery to clinical practice for biomarkers and biomarker-directed therapies is complex. While several issues need careful consideration, two critical issues that surround the validation of biomarkers are the choice of clinical trial design (which is based on the strength of the preliminary evidence and marker prevalence) and the biomarker assay related issues surrounding the marker assessment methods such as the reliability and reproducibility of the assay. This review focuses on trial designs for marker validation, both in the setting of early phase trials for initial validation, as well as in the context of larger definitive trials. Designs for biomarker validation are broadly classified as retrospective (i.e., using data from previously well-conducted, randomized, controlled trials) or prospective (enrichment, allcomers or adaptive). We believe that the systematic evaluation and implementation of these design strategies are essential to accelerate the clinical validation of biomarker-guided therapy, thereby taking us a step closer to the goal of personalized medicine.
[Show abstract][Hide abstract] ABSTRACT: Anthracyclines are among the most effective chemotherapy treatments available for various types of cancer. The anthracyclines commonly used in treatment of breast cancer are either epirubicin or doxorubicin. Epirubicin is an epimer of doxorubicin with important role in the chemotherapy treatment of both early and metastatic breast cancer. The efficacy of epirubicin is similar to doxorubicin while epirubicin has a different toxicity profile particularly in regard to cardiotoxicity. Epirubicin has been incorporated into most of the anthracycline containing chemotherapy combinations in well-conducted clinical trials involving large numbers of patients. It has also been investigated in studies involving the administration of epirubicin in dose-dense chemotherapy schedules. Short term follow up of dose-dense clinical trials demonstrated safety comparable to that of doxorubicin. This review summarizes published clinical trials investigating epirubicin in the treatment of early and advanced breast cancer.
Breast (Edinburgh, Scotland) 01/2012; 21(2):142-9. DOI:10.1016/j.breast.2011.12.012 · 2.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Biomarkers have many distinct purposes, and depending on their intended use, the validation process varies substantially.
The goal of this article is to provide an introduction to the topic of biomarkers, and then to discuss three specific types of biomarkers, namely, prognostic, predictive, and surrogate.
A principle challenge for biomarker validation from a statistical perspective is the issue of multiplicity. In general, the solution to this multiplicity challenge is well known to statisticians: pre-specification and replication. Critical requirements for prognostic marker validation include uniform treatment, complete follow-up, unbiased case selection, and complete ascertainment of the many possible confounders that exist in the context of an observational sample. In the case of predictive biomarker validation, observational data are clearly inadequate and randomized controlled trials are mandatory. Within the context of randomization, strategies for predictive marker validation can be grouped into two categories: retrospective versus prospective validation. The critical validation criteria for a surrogate endpoint is to ensure that if a trial uses a surrogate endpoint, the trial will result in the same inferences as if the trial had observed the true endpoint. The field of surrogate endpoint validation has now moved to the multi-trial or meta-analytic setting as the preferred method.
Biomarkers are a highly active research area. For all biomarker developmental and validation studies, the importance of fundamental statistical concepts remains the following: pre-specification of hypotheses, randomization, and replication. Further statistical methodology research in this area is clearly needed as we move forward.
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