New molecular assay for the proliferation signature in mantle cell lymphoma applicable to formalin-fixed paraffin-embedded biopsies

David W. Scott, Pau Abrisqueta, George W. Wright, Graham W. Slack, Anja Mottok, Diego Villa, Pedro Jares, Hilka Rauert-Wunderlich, Cristina Royo, Guillem Clot, Magda Pinyol, Merrill Boyle, Fong Chun Chan, Rita Braziel, Wing C. Chan, Dennis D. Weisenburger, James R. Cook, Timothy C. Greiner, Kai Fu, German OttJan Delabie, Erlend B. Smeland, Harald Holte, Elaine S. Jaffe, Christian Steidl, Joseph M. Connors, Randy D. Gascoyne, Andreas Rosenwald, Louis M. Staudt, Elias Campo, Lisa M. Rimsza

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30 Scopus citations

Abstract

Purpose Mantle cell lymphoma is an aggressive B-cell neoplasm that displays heterogeneous outcomes after treatment. In 2003, the Lymphoma/Leukemia Molecular Profiling Project described a powerful biomarker—the proliferation signature—using gene expression in fresh frozen material. Herein, we describe the training and validation of a new assay that measures the proliferation signature in RNA derived from routinely available formalin-fixed paraffin-embedded (FFPE) biopsies. Methods Forty-seven FFPE biopsies were used to train an assay on the NanoString platform, using microarray gene expression data of matched fresh frozen biopsies as a gold standard. The locked assay was applied to pretreatment FFPE lymph node biopsies from an independent cohort of 110 patients uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Seventeen biopsies were tested across three laboratories to assess assay reproducibility. Results The MCL35 assay, which contained a 17-gene proliferation signature, yielded gene expression of sufficient quality to assign an assay score and risk group in 108 (98%) of 110 archival FFPE biopsies. The MCL35 assay assigned patients to high-risk (26%), standard-risk (29%), and low-risk (45%) groups, with different lengths of overall survival (OS): a median of 1.1, 2.6, and 8.6 years, respectively (log-rank for trend, P, .001). In multivariable analysis, these risk groups and the Mantle Cell Lymphoma International Prognostic Index were independently associated with OS (P, .001 for both variables). Concordance of risk assignment across the three independent laboratories was 100%. Conclusion The newly developed and validated MCL35 assay for FFPE biopsies uses the proliferation signature to define groups of patients with significantly different OS independent of the Mantle Cell Lymphoma International Prognostic Index. Importantly, the analytic and clinical validity of this assay defines it as a reliable biomarker to support risk-adapted clinical trials.

Original languageEnglish (US)
Pages (from-to)1668-1677
Number of pages10
JournalJournal of Clinical Oncology
Volume35
Issue number15
DOIs
Publication statusPublished - May 20 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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