Precision Medicine for Diffuse Large B-Cell Lymphoma Megan S

Published OnlineFirst March 17, 2016; DOI: 10.1158/1078-0432.CCR-16-0232

CCR Translations Clinical Cancer Research Precision Medicine for Diffuse Large B-cell Lymphoma Megan S. Lim1,2 and Kojo S.J. Elenitoba-Johnson1,3

This study demonstrates the clinical utility of a targeted pave the way to precision therapy era for patients with this gene sequencing panel "the Lymphopanel," which enables form of aggressive lymphoma. Clin Cancer Res; 22(12); 1–3. the detection of actionable mutations and subtype-enriched 2016 AACR. gene alterations in diffuse large B-cell lymphoma that will See related article by Dubois et al., p. 2919

In this issue of Clinical Cancer Research, Dubois and collea- detection of actionable mutations and subtype-enriched gene gues (1) demonstrate the clinical utility of a targeted gene alterations. sequencing panel for diffuse large B-cell lymphoma (DLBCL). Despite a significant genetic heterogeneity within subtypes of DLBCL is an aggressive cancer and represents the most common DLBCL, the premise of translating the genetic signatures by form of lymphoma in adults, accounting for 30% to 40% of leveraging next-generation sequencing technology for clinical newly diagnosed non-Hodgkin lymphoma (2). Importantly, application is a welcome development. Using a custom panel although immunochemotherapies have improved the outcome designed to identify mutations in 34 genes that have been pre- of many patients with DLBCL, a subset of patients with relapsed viously implicated in DLBCL, the authors evaluated the tumor or refractory disease suffer from poor outcomes. Extensive gene DNA of a large cohort of patients (n ¼ 215) enrolled in a expression profiling (GEP) studies over the last decade have led prospective, multicenter randomized clinical trial (LNH-03B to the recognition of three main molecular subtypes: germinal LYSA). The results thus allow the authors to gain unique infor- center B-cell like (GCB), activated B-cell like (ABC; ref. 3), and mation for assessing the prognostic value of the genetic altera- primary mediastinal B-cell lymphomas (PMBL; ref. 4). Subse- tions. Further adding to the power was the availability of GEP- quent studies revealed that ABC subtypes are characterized by based cell of origin molecular classification. This provided the aberrant activation of the NF-kB pathway, while PMBL dem- opportunity to correlate the prognostic impact on molecularly onstrate JAK–STAT activation. Indeed, current NCCN Clinical defined subtypes of DLBCL. Practice Guidelines in Oncology (5) advocate the evaluation of The 34 genes covered 8 pathways important in lymphomagen- DLBCL for subclassification into GCB type from non-GCB and esis including immunity (CIITA, B2M, TNFRSF14, and CD58), PMBL using either immunohistochemical methods or GEP. NOTCH (NOTCH1 and NOTCH2), apoptosis/cell cycle (MFHAS1, Despite these advances in our understanding of the pathobio- XPO1, MYC, CDKN2A/B, FOXO1, TP53, GNA13, and BCL2), logic basis of DLBCL, the immediate impact on clinical man- NF-kB(TNFAIP3, MYD88, PIM1, CARD11, IRF4, and PRDM1), agement and translation to the bedside has been lacking. epigenetic regulation (EZH2, KMT2D, EP300, MEF2B,and Recent advances in sequencing technology have provided novel CREBBP), MAPK (BRAF), JAK-STAT (SOCS1 and STAT6 ), and BCR insights into the genetic alterations that are present in these (CD79A/B, ITPKB, TCF3, and ID3). subtypes and the identification of recurrent somatic mutations Importantly, gene mutation frequencies were variable among that are enriched in particular subtypes (6, 7). Dubois and the patients, from 1 to 124. Furthermore, the results confirmed colleagues (1) demonstrate the clinical utility of a targeted the enrichment of certain mutations in the 3 subtypes. For gene sequencing panel "the Lymphopanel," which enables the example, mutations in genes of the NF-kB pathways (45% of total variants) and epigenetic regulation (20.2% of total variants) were dominant in ABC subtypes. In GCB subtypes, 1Department of Pathology and Laboratory Medicine, Hospital of the mutations in genes in the epigenetic pathway (32.3% of total University of Pennsylvania, University of Pennsylvania, Philadelphia, variants) and the apoptosis/cell cycle pathway (26.3% of total Pennsylvania. 2Department of Pathology and Laboratory Medicine, variants) were common. PMBLs were characterized by muta- The Children's Hospital of Philadelphia, Perelman School of Medicine, tions in the JAK/STAT pathway (29.1% of total variants), University of Pennsylvania, Philadelphia, Pennsylvania. 3Center for Personalized Diagnostics, Department of Pathology and Laboratory immunity (20.9% of total variants), and apoptosis/cell-cycle Medicine, Hospital of the University of Pennsylvania, University of pathways (20.9% of total variants). Of interest, PMBLs were Pennsylvania, Philadelphia, Pennsylvania. characterized by a higher number of variants per sample than Corresponding Author: Megan S. Lim, Department of Pathology and Laboratory the other subtypes. Despite the use of a limited number of Medicine, University of Pennsylvania School of Medicine, Room 609C, 422 Curie genes in the "Lymphopanel," gene alterations not previously Boulevard, Philadelphia, PA 19104. Phone: 215-614-0978; Fax: 215-662-7529; reported in PMBL, such as ITPKB, MFHAS1,andXPO1,were E-mail: [email protected] seen to be highly enriched in PMBL. doi: 10.1158/1078-0432.CCR-16-0232 Given the current and increasing interest in personalizing 2016 American Association for Cancer Research. selection of therapies to those that target cancer-specific

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Lim and Elenitoba-Johnson

Precision medicine for DLBCL

GCB type ABC type PMBL

Figure 1. Lymphopanel Identiﬁcation of genetic features next-generation highly enriched in the GCB, ABC sequencing subtypes of DLBCL and PMBL using targeted next-generation sequencing BCL2, CREBBP, CD79B, PIM1, panel will provide an opportunity EZH2, STAT6, GNA13, for precision therapy. PRDM1, IRF4, B2M, TNFRSF14, SOCS1, CIITA, CD58, KMT2D, EP300 MEF2B, KMT2D, MFHAS1, ITPKB MYD88 MYC

Prognosis Therapy JAK/ EZH2i HDACi BCL2i BTKi PIMi NF-κBi SINE STATi

aberrations, it is important that the "Lymphopanel" included of DLBCL subtypes. Rare cases with mutations that are highly genes for which disease-associated mutations could provide actionable were identified such as V600E BRAF and NOTCH1. information relevant to therapy. Examples of actionable muta- These studies demonstrate the feasibility of leveraging mutations include those impacting MYD88 and CD79B, which is tional signatures of subtypes of DLBCL to obtain information for associated with significant response to ibrutinib, a BTK inhibitor the selection of targeted therapies and correlation with prognosis (8). In contrast, CARD11 and TNFAIP3 mutations are associated and pave the way for precision medicine for patients with this with decreased response to both ibrutinib and sotrastaurin, a aggressive form of lymphoma. protein kinase C inhibitor (9). Although IRF4 lacks a recognized therapeutic inhibitor, ABC subtype DLBCLs have been shown to Disclosure of Potential Conflicts of Interest be addicted to IRF4 and confer response to the immunomodu- K.S.J. Elenitoba-Johnson is an uncompensated consultant/advisory board lator, lenalidomide (10). IRF4 mutations were observed in 7.9% member for Genomenon. No potential conflicts of interest were disclosed by of DLBCL representing 13.6% of ABC subtype, 11.1% of PMBL, the other author. and 4.8% of GCB subtype. In addition, high frequency mutations of PIM1 were present in 33.3% of ABC type DLBCL, suggesting the Authors' Contributions opportunity to evaluate PIM1 inhibitors (11) as a therapeutic Conception and design: M.S. Lim option. Writing, review, and/or revision of the manuscript: M.S. Lim, K.S.J. Elenitoba- Targetable gene mutations in the GCB type cohort included Johnson Administrative, technical, or material support (i.e., reporting or organizing BCL2, which was present in 24.1% of cases. Although BCL2 can be data, constructing databases): M.S. Lim targeted by BH3-mimetics, the mutations identified in this cohort did not impact the BH3 domain, suggesting that the BH3 mimetic Grant Support activity would not be hampered in these patients. Genes associ- M.S. Lim and K.S.J. Elenitoba-Johnson are supported by the Department of ated with epigenetic function (EZH2, CREBBP, KMT2D, and Pathology and Laboratory Medicine, University of Pennsylvania. EP300) were highly represented in GCB types. More than 18% harbored EZH2 mutations highlighting the potential relevance in utilizing EZH2 inhibitors (12) for a subset of GCB type of Received February 17, 2016; accepted February 29, 2016; published DLBCL. Figure 1 summarizes the genetic signatures characteristic OnlineFirst March 17, 2016.

OF2 Clin Cancer Res; 22(12) June 15, 2016 Clinical Cancer Research

Personalized Approach to Diffuse Large B-cell Lymphoma

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Precision Medicine for Diffuse Large B-cell Lymphoma

Megan S. Lim and Kojo S.J. Elenitoba-Johnson

Clin Cancer Res Published OnlineFirst March 17, 2016.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-16-0232

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