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New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies. 2017
David W Scott, and
Pau Abrisqueta, and
George W Wright, and
Graham W Slack, and
Anja Mottok, and
Diego Villa, and
Pedro Jares, and
Hilka Rauert-Wunderlich, and
Cristina Royo, and
Guillem Clot, and
Magda Pinyol, and
Merrill Boyle, and
Fong Chun Chan, and
Rita M Braziel, and
Wing C Chan, and
Dennis D Weisenburger, and
James R Cook, and
Timothy C Greiner, and
Kai Fu, and
German Ott, and
Jan Delabie, and
Erlend B Smeland, and
Harald Holte, and
Elaine S Jaffe, and
Christian Steidl, and
Joseph M Connors, and
Randy D Gascoyne, and
Andreas Rosenwald, and
Louis M Staudt, and
Elias Campo, and
Lisa M Rimsza, and
David W. Scott, Pau Abrisqueta, Graham W. Slack, Anja Mottok, Diego Villa, Merrill Boyle, Fong Chun Chan, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, BC Cancer Agency; Anja Mottok, Christian Steidl, and Randy D. Gascoyne, University of British Columbia, Vancouver, British Columbia; Jan Delabie, University of Toronto, Toronto, Ontario, Canada; Pau Abrisqueta, Vall d'Hebron University Hospital; Pedro Jares, Cristina Royo, Guillem Clot, Magda Pinyol, and Elias Campo, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; George W. Wright, Elaine S. Jaffe, and Louis M. Staudt, National Institutes of Health, Bethesda, MD; Hilka Rauert-Wunderlich and Andreas Rosenwald, University of Würzburg, Würzburg; German Ott, Robert Bosch Hospital and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; Rita M. Braziel, Oregon Health & Sciences University, Portland, OR; Wing C. Chan and Dennis D. Weisenburger, City of Hope, Duarte, CA; James R. Cook, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH; Timothy C. Greiner and Kai Fu, University of Nebraska Medical Center, Omaha, NE; Erlend B. Smeland and Harald Holte, Oslo University Hospital, Oslo, Norway; and Lisa M. Rimsza, Mayo Clinic, Phoenix, AZ.
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.
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