Simon RM, Paik S, Hayes DFUse of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 101: 1446-1452

Biometric Research Branch, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892-7434, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 10/2009; 101(21):1446-52. DOI: 10.1093/jnci/djp335
Source: PubMed


The development of tumor biomarkers ready for clinical use is complex. We propose a refined system for biomarker study design,
conduct, analysis, and evaluation that incorporates a hierarchal level of evidence scale for tumor marker studies, including
those using archived specimens. Although fully prospective randomized clinical trials to evaluate the medical utility of a
prognostic or predictive biomarker are the gold standard, such trials are costly, so we discuss more efficient indirect “prospective–retrospective”
designs using archived specimens. In particular, we propose new guidelines that stipulate that 1) adequate amounts of archived
tissue must be available from enough patients from a prospective trial (which for predictive factors should generally be a
randomized design) for analyses to have adequate statistical power and for the patients included in the evaluation to be clearly
representative of the patients in the trial; 2) the test should be analytically and preanalytically validated for use with
archived tissue; 3) the plan for biomarker evaluation should be completely specified in writing before the performance of
biomarker assays on archived tissue and should be focused on evaluation of a single completely defined classifier; and 4)
the results from archived specimens should be validated using specimens from one or more similar, but separate, studies.

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Available from: Richard Simon, Sep 17, 2014
    • "Assessment of study risk of bias. An assessment of the methodological quality of the studies included in meta-analyses was based on guidance for the evaluation of the conduct of biomarker studies that use archived tumour specimens (Simon et al, 2009; Patterson et al, 2011). For each included pharmacogenomic substudy of a RCT, four domains were used to assess the risk of bias (high, moderate, or low): (1) biomarker sample ascertainment, (2) assay analytical performance, (3) prespecified analysis plan, and (4) parent RCT. "
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    ABSTRACT: Metastatic colorectal cancer (mCRC) that harbours a BRAF V600E mutation (BRAF MT) is associated with poorer outcomes. However, whether this mutation is predictive of treatment benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) is uncertain. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) published up to July 2014 that evaluated the effect of BRAF MT on the treatment benefit from anti-EGFR mAbs for mCRC. Seven RCTs met the inclusion criteria for assessment of overall survival (OS), whereas eight RCTs met the inclusion criteria for assessment of progression-free survival (PFS). For RAS WT/BRAF MT tumours, the hazard ratio for OS benefit with anti-EGFR mAbs was 0.97 (95% CI; 0.67-1.41), whereas the hazard ratio was 0.81 (95% CI; 0.70-0.95) for RAS WT/BRAF WT tumours. However, the test of interaction (P=0.43) was not statistically significant, highlighting that the observed differences in the effect of anti-EGFR mAbs on OS according to the BRAF mutation status may be due to chance alone. Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 0.86 (95% CI; 0.61-1.21) for RAS WT/BRAF MT tumours as compared with 0.62 (95% CI; 0.50-0.77) for RAS WT/BRAF WT tumours (test of interaction, P=0.07). This meta-analysis demonstrates that there is insufficient evidence to definitively state that RAS WT/BRAF MT individuals attain a different treatment benefit from anti-EGFR mAbs for mCRC compared with RAS WT/BRAF WT individuals. As such, there are insufficient data to justify the exclusion of anti-EGFR mAb therapy for patients with RAS WT/BRAF MT mCRC.British Journal of Cancer advance online publication, 19 May 2015; doi:10.1038/bjc.2015.173
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    • "Validated molecular biomarkers that provide objective measures of tumor biology and improve risk stratification are needed [4] [5]. Clinical adoption of biomarkers requires that they (1) be analytically validated to provide robust, reproducible results; (2) be validated to predict clinically relevant end points; and (3) offer equivalent performance across a spectrum of disease including race and age [6] [7] [8]. "

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    • "Clinical data for biomarker development can come from retrospective or prospective clinical trials.23 Retrospective trial analysis requires that adequate biomarker specimens were collected in most of the study patients and analyzed according to a prespecified plan.24 The advantages of retrospective analysis include availability of adequate follow-up, the inclusion of patients with biomarker-positive and biomarker-negative cancers in the data set, and a cost savings over conducting an additional prospective trial. "
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    ABSTRACT: On February 2, 2012, the National Cancer Institute (NCI) sponsored a 2-day workshop with the NCI Thoracic Malignancies Steering Committee and the Food and Drug Administration to bring together leading academicians, clinicians, industry and government representatives to identify challenges and potential solutions in the clinical development of novel targeted therapies for lung cancer. Measures of success are rapidly evolving from a scientific and regulatory perspective and the objectives of this workshop were to achieve initial consensus on a high priority biomarker-driven clinical trial designed to rapidly assess the activity of targeted agents in molecularly defined lung cancer subsets and to facilitate generation of data leading to approval of these new therapies. Additionally, the meeting focused on identification of the barriers to conduct such a trial and the development of strategies to overcome those barriers. The "Lung Master Protocols" recently launched by NCI were the direct outcome of this workshop.
    Full-text · Article · Oct 2014 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer
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