Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies

To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers). Reproducibility of COO assignment using th...

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Veröffentlicht in:	Journal of clinical oncology Jg. 33; H. 26; S. 2848
Hauptverfasser:	Scott, David W, Mottok, Anja, Ennishi, Daisuke, Wright, George W, Farinha, Pedro, Ben-Neriah, Susana, Kridel, Robert, Barry, Garrett S, Hother, Christoffer, Abrisqueta, Pau, Boyle, Merrill, Meissner, Barbara, Telenius, Adele, Savage, Kerry J, Sehn, Laurie H, Slack, Graham W, Steidl, Christian, Staudt, Louis M, Connors, Joseph M, Rimsza, Lisa M, Gascoyne, Randy D
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 10.09.2015
Schlagworte:	Adolescent Adult Aged Aged, 80 and over Antibodies, Monoclonal, Murine-Derived - therapeutic use Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biopsy Cyclophosphamide - therapeutic use Doxorubicin - therapeutic use Female Gene Expression Humans Lymphoma, Large B-Cell, Diffuse - chemistry Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - mortality Lymphoma, Large B-Cell, Diffuse - pathology Male Middle Aged Paraffin Embedding Prednisone - therapeutic use Prognosis Proto-Oncogene Proteins c-bcl-2 - analysis Proto-Oncogene Proteins c-myc - analysis Tissue Array Analysis Vincristine - therapeutic use
ISSN:	1527-7755, 1527-7755
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Abstract	To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers). Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays. The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression). Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.
AbstractList	To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers).PURPOSETo evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers).Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays.PATIENTS AND METHODSReproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays.The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression).RESULTSThe Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression).Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.CONCLUSIONAssignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression. To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison with International Prognostic Index (IPI) score and MYC/BCL2 coexpression status (dual expressers). Reproducibility of COO assignment using the Lymph2Cx assay was tested employing repeated sampling within tumor biopsies and changes in reagent lots. The assay was then applied to pretreatment formalin-fixed paraffin-embedded tissue (FFPET) biopsies from 344 patients with de novo diffuse large B-cell lymphoma (DLBCL) uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the British Columbia Cancer Agency. MYC and BCL2 protein expression was assessed using immunohistochemistry on tissue microarrays. The Lymph2Cx assay provided concordant COO calls in 96% of 49 repeatedly sampled tumor biopsies and in 100% of 83 FFPET biopsies tested across reagent lots. Critically, no frank misclassification (activated B-cell-like DLBCL to germinal center B-cell-like DLBCL or vice versa) was observed. Patients with activated B-cell-like DLBCL had significantly inferior outcomes compared with patients with germinal center B-cell-like DLBCL (log-rank P < .001 for time to progression, progression-free survival, disease-specific survival, and overall survival). In pairwise multivariable analyses, COO was associated with outcomes independent of IPI score and MYC/BCL2 immunohistochemistry. The prognostic significance of COO was particularly evident in patients with intermediate IPI scores and the non-MYC-positive/BCL2-positive subgroup (log-rank P < .001 for time to progression). Assignment of DLBCL COO by the Lymph2Cx assay using FFPET biopsies identifies patient groups with significantly different outcomes after R-CHOP, independent of IPI score and MYC/BCL2 dual expression.
Author	Mottok, Anja Barry, Garrett S Meissner, Barbara Slack, Graham W Hother, Christoffer Farinha, Pedro Ennishi, Daisuke Sehn, Laurie H Steidl, Christian Savage, Kerry J Rimsza, Lisa M Kridel, Robert Scott, David W Abrisqueta, Pau Staudt, Louis M Wright, George W Telenius, Adele Ben-Neriah, Susana Connors, Joseph M Gascoyne, Randy D Boyle, Merrill
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Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 3 givenname: Daisuke surname: Ennishi fullname: Ennishi, Daisuke organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 4 givenname: George W surname: Wright fullname: Wright, George W organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 5 givenname: Pedro surname: Farinha fullname: Farinha, Pedro organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. 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Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 11 givenname: Merrill surname: Boyle fullname: Boyle, Merrill organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 12 givenname: Barbara surname: Meissner fullname: Meissner, Barbara organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 13 givenname: Adele surname: Telenius fullname: Telenius, Adele organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 14 givenname: Kerry J surname: Savage fullname: Savage, Kerry J organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 15 givenname: Laurie H surname: Sehn fullname: Sehn, Laurie H organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 16 givenname: Graham W surname: Slack fullname: Slack, Graham W organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 17 givenname: Christian surname: Steidl fullname: Steidl, Christian organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 18 givenname: Louis M surname: Staudt fullname: Staudt, Louis M organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 19 givenname: Joseph M surname: Connors fullname: Connors, Joseph M organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 20 givenname: Lisa M surname: Rimsza fullname: Rimsza, Lisa M organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ – sequence: 21 givenname: Randy D surname: Gascoyne fullname: Gascoyne, Randy D organization: David W. Scott, Anja Mottok, Daisuke Ennishi, Pedro Farinha, Susana Ben-Neriah, Robert Kridel, Garrett S. Barry, Christoffer Hother, Pau Abrisqueta, Merrill Boyle, Barbara Meissner, Adele Telenius, Kerry J. Savage, Laurie H. Sehn, Graham W. Slack, Christian Steidl, Joseph M. Connors, and Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; George W. Wright and Louis M. Staudt, National Cancer Institute, Bethesda, MD; and Lisa M. Rimsza, University of Arizona, Tucson, AZ
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Snippet	To evaluate the prognostic impact of cell-of-origin (COO) subgroups, assigned using the recently described gene expression-based Lymph2Cx assay in comparison...
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SubjectTerms	Adolescent Adult Aged Aged, 80 and over Antibodies, Monoclonal, Murine-Derived - therapeutic use Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biopsy Cyclophosphamide - therapeutic use Doxorubicin - therapeutic use Female Gene Expression Humans Lymphoma, Large B-Cell, Diffuse - chemistry Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - mortality Lymphoma, Large B-Cell, Diffuse - pathology Male Middle Aged Paraffin Embedding Prednisone - therapeutic use Prognosis Proto-Oncogene Proteins c-bcl-2 - analysis Proto-Oncogene Proteins c-myc - analysis Tissue Array Analysis Vincristine - therapeutic use
Title	Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin Determined by Digital Gene Expression in Formalin-Fixed Paraffin-Embedded Tissue Biopsies
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