Authors’ reply

Autor: Squillace, Rachel M, Frampton, Garrett M, Stephens, Phil J, Ross, Jeffrey S, Miller, Vincent A, Weiss, Glen J, Penny, Robert J, Mallery, David W, Morris, Scott M, Thompson, Eric J, Loesch, David M, Khemka, Vivek
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: OncoTargets and therapy
ISSN: 1178-6930
Popis: Dear editor We read with concern the paper “Evaluation and comparison of two commercially available targeted next-generation sequencing platforms to assist oncology decision-making”.1 The study directly compared results for the Paradigm Cancer Diagnostic test to the FoundationOne test for formalin-fixed, paraffin-embedded specimen pairs from 21 advanced cancer cases. We believe this study is fundamentally flawed, misleading, and potentially dangerous for patient care, for the reasons outlined herein. The paper neglected to address innumerable discordances between a rigorously analytically validated test (FoundationOne) and the experimental assay. It erroneously ascribes categorization of many genomic alterations detected on FoundationOne as “none”, when in fact available drugs have demonstrated activity or mechanism-based clinical trials exist, and it claims high levels of actionability based on the results of RNA-expression profiling of a single gene – TOPO2A. This study is notable for a remarkable lack of concordance between the genomic alterations detected on each platform, even in genes common to both assays. For the majority of specimens, there were no genomic alterations in common, and only six of 21 samples shared a single alteration, matching at the gene level. Paradigm DNA-based testing found only two cases wherein a result was labeled by them as “commercially available” or “clinical trial”, an EGFR mutation in a lung adenocarcinoma, and a KIT mutation in a colon adenocarcinoma. This KIT mutation was not detected by FoundationOne. Similarly, lack of concordance is noted for mutations in ARID1A (case 1), PDGFRA and PI3K (case 2), KRAS, PI3K and PTEN (case 5), PTEN and ARID1A (case 6), EGFR amplification (case 9), ERBB2 (cases 12, 14), and PI3K (case 19). Given the significant discordance in the genomic alterations detected and reported, it must reasonably be concluded that at least one assay has extremely poor mutation-detection performance. FoundationOne underwent an extensive 2-year analytic validation study. This study rigorously demonstrated the test’s high-performance characteristics.2 The Paradigm assay has no published analytic validation studies. The lack of concordance between the two platforms calls into serious question the performance of the Paradigm assay and the validity of the data. Clinical activity and/or mechanism-directed trials exist for genomic (DNA-based) alterations in PTEN,3 RICTOR,4 CDK6 (NCT02187783), FGFR4 (NCT02325739), ERRFI1,5 FBXW7,6 and PI3KR1 (NCT01971515). The “actionable target” determination, as displayed in Table 2, also reveals a failure to acknowledge KRAS as a gene for which therapeutic approaches exist in clinical trials, and for which prior genomically driven trials have shown selected activity.7 Although an acknowledged therapeutic challenge, KRAS-mutated tumors have been the object of no fewer than 26 clinical trials with targeted agents requiring a KRAS mutation as molecular eligibility entry criteria (www.ClinicalTrials.gov). Despite this, all of these genes are scored as “none” as shown in Table 2, column two.1 The authors report RNA alterations linked to potential therapeutic intervention in 16 of 21 cases: eleven with TOPO2A overexpression alone, four with ERBB2 over-expression alone, and one case with both; however, in only two of five cases was ERBB2 amplification detected by FoundationOne, an assay that has undergone rigorous concordance testing with the gold-standard assays of fluorescence in situ hybridization and immunohistochemistry. TOPO2A overexpression was present in six of six lung adenocarcinomas. Unfortunately, this result is not surprising or helpful, as anthracyclines have no reproducible activity in NSCLC, ie, the results provide no useful clinical information. Furthermore, it is well known that TOPO2A expression is regulated by the cell cycle8 and is independent of TOPO2A gene amplification.9 It is TOPO2A gene amplification, not TOPO2A expression, that has been linked in some but not all studies as a biomarker of anthracycline efficacy in breast cancer.10 In order to permit a fully informed comparison between commercial cancer genome-profiling assays, we believe it necessary for all parties to make public most aspects of their test methodology and data. In this case, we believe the authors need to publish all aspects of the testing methodology for the Paradigm Cancer Diagnostic test. For example, which exons of which genes are targeted in this test? Is the test achieving high, even coverage of target regions? Are reported sequence coverage metrics from unique input DNA molecules and not PCR duplicates? Are appropriate computational methods employed? None of these critical questions can be evaluated with the information provided. Oncologists increasingly rely upon results of comprehensive genomic profiling in making important treatment decisions. For this reason, rigorous peer-reviewed validation of genomic tests offered for use in clinical applications is essential. We believe the Paradigm study does not meet this standard and is sufficiently flawed such that we encourage the authors to consider retracting the paper.
Databáze: OpenAIRE
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