Inflammatory Myofibroblastic Tumors Harbor Multiple Potentially Actionable Kinase Fusions

Published OnlineFirst May 29, 2014; DOI: 10.1158/2159-8290.CD-14-0377

Research Brief

Christine M. Lovly1, Abha Gupta2, Doron Lipson3, Geoff Otto3, Tina Brennan3, Catherine T. Chung4, Scott C. Borinstein5, Jeffrey S. Ross3,6, Philip J. Stephens3, Vincent A. Miller3, and Cheryl M. Coffin7

Abt s ract Inflammatory myofibroblastic tumor (IMT) is a neoplasm that typically occurs in children. The genetic landscape of this tumor is incompletely understood and therapeutic options are limited. Although 50% of IMTs harbor anaplastic lymphoma kinase (ALK) rearrangements, no therapeutic targets have been identified in ALK-negative tumors. We report for the first time that IMTs harbor other actionable targets, including ROS1 and PDGFRβ fusions. We detail the case of an 8-year-old boy with treatment-refractory ALK-negative IMT. Molecular tumor profiling revealed a ROS1 fusion, and he had a dramatic response to the ROS1 inhibitor crizotinib. This case prompted assessment of a larger series of IMTs. Next-generation sequencing revealed that 85% of cases evalu- ated harbored kinase fusions involving ALK, ROS1, or PDGFRβ. Our study represents the most comprehensive genetic analysis of IMTs to date and also provides a rationale for routine molecular profiling of these tumors to detect therapeutically actionable kinase fusions.

SIGNIFICANCE: Our study describes the most comprehensive genomics-based evaluation of IMT to date. Because there is no “standard-of-care” therapy for IMT, the identification of actionable genomic alterations, in addition to ALK, is expected to redefine management strategies for patients with this disease. Cancer Discov; 4(8); 1–7. ©2014 AACR.

See related commentary by Le and Doebele, p. 870.

INTRODUCTION estimated 150 to 200 new cases are diagnosed annually in the United States (2). These soft-tissue tumors can occur Inflammatory myofibroblastic tumor (IMT) is a rare mes- at multiple anatomic sites, but most commonly involve the enchymal tumor that can occur at any age, but has a predi- lung, abdomen/pelvis, and retroperitoneum. The mainstay lection for children, adolescents, and young adults (1). An of treatment for IMT is surgical resection; however, treat-

1Department of Medicine, Vanderbilt University, Nashville, Tennessee. Corresponding Author: Christine M. Lovly, Vanderbilt University School 2Division of Hematology/Oncology, The Hospital for Sick Children, Uni- of Medicine, 2220 Pierce Avenue South, 777 Preston Research Building, versity of Toronto, Toronto, Canada. 3Foundation Medicine, Cambridge, Nashville, TN 37232-6307. Phone: 615-936-3457; Fax: 615-343-2973; Massachusetts. 4Division of Pathology, The Hospital for Sick Children, Uni- E-mail: [email protected] 5 versity of Toronto, Toronto, Canada. Department of Pediatrics, Vanderbilt doi: 10.1158/2159-8290.CD-14-0377 University, Nashville, Tennessee. 6Albany Medical College, Albany, New York. 7Department of Pathology, Microbiology, and Immunology, Vanderbilt ©2014 American Association for Cancer Research. University, Nashville, Tennessee. Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

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RESEARCH BRIEF Lovly et al. ment options are limited for patients with unresectable nosis, his laboratory parameters were indicative of a micro- and/or advanced disease. cytic anemia and an inflammatory state. Several treatment IMTs are diagnosed pathologically using criteria estab- regimens were administered, including anti-inflammatory lished by the World Health Organization (WHO; ref. 3). agents (naproxen, corticosteroids, and indomethacin) as well These tumors are characterized histologically by a spindle as cytotoxic chemotherapy (methotrexate–vinorelbine), over myofibroblastic cell proliferation with a lymphoplasmacytic the course of 24 months (Supplementary Fig. S1), with inflammatory infiltrate (4). Approximately 50% of IMTs are no antitumor response and minimal improvement of his positive for anaplastic lymphoma kinase (ALK) expression anemia. While he was receiving methotrexate–vinorelbine, by IHC. The most common mechanism of ALK expression we performed targeted NGS-based genomic profiling of his and activation involves structural rearrangements in the ALK tumor using formalin-fixed and paraffin-embedded (FFPE) gene, leading to the formation of a chimeric fusion protein. tissue and surprisingly detected a TFG–ROS1 fusion (Fig. 1A). Several ALK fusion partners have been identified retrospec- ROS1 TKIs, such as crizotinib, have proven to be an effec- tively (5), as tumor sequencing is not yet the standard of care tive therapeutic strategy in lung cancers harboring ROS1 for IMTs. ALK fusions have been validated as a therapeutic kinase fusions (8, 9). Therefore, he was treated with crizotinib target. A patient with a RANBP2–ALK-positive IMT had a (250 mg), obtained through a compassionate access program, partial response to the ALK tyrosine kinase inhibitor (TKI) twice daily orally. He experienced grade 1 diarrhea and visual crizotinib, whereas a patient whose IMT lacked an ALK fusion disturbance, both of which resolved with no dose reduction. did not respond to this agent (6). Within 3 cycles of crizotinib therapy, he symptomatically In contrast, actionable genomic alterations have not yet felt better, with decreased cough and significantly increased been described in the 50% of IMT samples that are negative energy. Imaging studies revealed, for the first time since diag- for ALK by IHC. ALK-negative IMTs may be more aggres- nosis, a decrease in the size of his tumor mass (Fig. 1B). Nota- sive with a higher frequency of metastasis compared with bly, his hemoglobin (Hgb) and mean corpuscular volume ALK-positive IMT (7). Little is known on the genomic level (MCV) rapidly increased and his erythrocyte sedimentation about potential oncogenic drivers in this subset of IMTs and, rate (ESR) decreased (Fig. 1C and Supplementary Table S1). as such, there are no targeted therapies available for these He has now been on crizotinib for 4 months with excellent patients. tolerance, improved quality of life, and continued decrease in Here, we describe the case of an 8-year-old boy with his tumor burden. treatment-refractory ALK-negative IMT. Targeted next-generation sequencing (NGS)–based genomic profiling identified Patient and Tumor Characteristics the presence of a ROS1 kinase fusion within his tumor. On In an effort to further characterize cases of both ALK- the basis of this finding, he was treated with the ROS1/ALK/ positive and ALK-negative IMT, we obtained 37 samples from MET TKI, crizotinib, and experienced rapid symptomatic 33 patients with this rare disease (Table 1). Patients ranged improvement and significant decrease in his tumor burden. in age from infancy (less than 1 year old) to age 41. As is This case prompted us to perform genomic analysis on a typical for IMT, the tumors arose at multiple anatomic loca- larger series of this rare tumor. Our data show for the first tions, including thorax, mesentery, peritoneum, and bladder. time that kinase fusions are found in the majority of IMTs. The pathologic diagnosis was established based on criteria These data not only offer insight into this disease but also according to the WHO classification (3). ALK IHC was com- provide a rationale for routine molecular profiling to detect pleted on each sample as part of the standard pathologic therapeutically actionable kinase fusions and thereby offer evaluation (Supplementary Methods). Eleven of 37 (30%) of patients rational therapeutic strategies with existing TKIs the cases were ALK IHC negative and 26 of 37 (70%) of the based on the genomic profile of the tumor. cases were ALK IHC positive.

Targeted NGS Identified ALK, ROS1, and RESULTS PDGFRb Tyrosine Kinase Fusions in a Case Report Collection of IMT Samples A 6-year-old boy presented with a 1-year history of cough We hypothesized that further insight into the biology of and fatigue. Imaging demonstrated the presence of a large known fusions as well as discovery of novel kinase fusions left-sided chest mass. Biopsy of the mass revealed IMT, nega- would provide new therapeutic targets to treat patients with tive for ALK expression by standard clinical IHC and for IMT. To address this hypothesis, we analyzed genomic DNA ALK rearrangement by break-apart FISH. The tumor was from all 37 IMT samples using a targeted NGS-based assay deemed unresectable due to its intimate association with the (FoundationOne), which assesses 3,769 exons of 287 cancer pulmonary vein, aorta, and esophagus. At the time of diag- genes and 47 introns of 19 commonly rearranged genes,

Figure 1. Response to crizotinib in an 8-year-old boy with refractory IMT harboring a TFG–ROS1 fusion. A, schematic representation of the TFG–ROS1 fusion. ROS1 is located on chromosome 6q22 and TFG is located on 3q12. The breakpoint occurs in-frame between exon 4 of TFG and exon 36 of ROS1. B, CT scans before the initiation of crizotinib (left) and after 3 cycles of crizotinib (right) showing dramatic reduction in the tumor mass within the left lung. C, changes in Hgb, MCV, and ESR over the course of the patient’s treatments. Arrows below the graphs, initiation of the indicated therapies. The high (H) and low (L) limits of normal for each measured parameter are indicated on the blue graphs.

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Multiple Actionable Kinase Fusions in IMT RESEARCH BRIEF

TFG (chr3) ATG A 5

chr4: 1,808,677

TFG exons 1-4 ROS1 exons 35-43 ATG

TFG–ROS1 fusion

ROS1 (chr6) ATG 35

chr6: 117,643,755 B Pre-crizotinib After 3 cycles of crizotinib

C Hemoglobin (g/L)

162.5 150.0 137.5 125.0

g/L 112.5 100.0 87.5 75.0 MCV (fL) 100 95 90 85 80 fL 75 70 65 60 55 ESR (mm/hr) 125 100 75

mm/h 50 25 0 Jul Oct Jan 12 Apr Jul Oct Jan 13 Apr Jul Oct Jan 14

Steroid Methotrexate Crizotinib pulse + vinorelbine (11/20/2013)

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RESEARCH BRIEF Lovly et al.

T able 1. Summary of clinical characteristics and targeted NGS results for the study cohort

Sample ID Age (years) Gender Tumor site Tumor size (cm) ALK IHC Kinase fusion detected Coverage L1 14 F Mesentery 7 Neg No fusion detected 252 L2 16 F Mesentery 3 Neg No fusion detected 102 L3 22 F Buttock 10 Neg YWHAE–ROS1a 497 L4 22 F Pelvis Unknown Neg YWHAE–ROS1a 676 L5 38 F Lung 3 Neg EML4–ALK 607 L6 8 M Mesentery 6 Neg TFG–ROS1 179 L7 12 F Peritoneum >10 Neg NAB2–PDGFRβ 424 L8 5 M Lung 5 Neg No fusion detected 383 L9 41 M Nasopharynx 5 Neg TPM3–ALK 460 L10 12 F Peritoneum Unknown Neg NAB2–PDGFRβa 147 L11 6 M Omentum 14 Pos RANBP2–ALK 475 L12 7 F Mesentery 11 Pos LMNA–ALK 461 L13 2 F Mesentery 10 Pos TPM3–ALK 121 L14 3 F Mesentery 8 Pos TPM4–ALK 211 L15 29 M Mesentery 18 Pos TPM4–ALK 602 L16 36 F Lung 7 Pos No fusion detected 598 L17 13 M Lung 3 Pos Fail L18 2 M Bladder 5 Pos No fusion detected 341 L19 11 F Lung 2 Pos EML4–ALK 485 L20 7 M Mesentery 14 Pos TPM3–ALK 569 L21 20 F Mesentery 8 Pos TPM3–ALK 491 L22 1 M Mesentery 2 Pos Fail L23 6 F Lung 2 Pos SEC31A–ALKa 1,008 L24 4 M Mesentery 10 Pos Fail L25 14 M Pelvis 8 Pos TFG–ALKa 844 L26 26 F Bladder 3 Pos FN1–ALKa,b 511 L27 26 F Bladder 7 Pos CLTC–ALK 459 L28 14 M Mesentery 41 Pos CLTC–ALK 326 L29 8 F Bladder 3 Pos FN1–ALKa,b 1,235 L30 10 M Mesentery 8 Pos Fail L31 9 F Lung Unknown Pos CLTC–ALK 822 L32 4 F Lung Unknown Pos CLTC–ALK 781 L33 4 F Lung Unknown Pos CLTC–ALK 721 L34 4 F Lung Unknown Pos CLTC–ALK 915 L35 <1 F Shoulder Unknown Pos PRKAR1A–ALK 813 L36 9 F Lung Unknown Pos CLTC–ALK 849 L37 6 M Lung 10.1 Neg TFG–ROS1 660

NOTE: A total of 37 FFPE tumor samples from 33 different patients with IMT were included in the analysis. The following samples were obtained from the same patient at different times in his/her disease course: L3/L4, L7/L10, L31/L36, L32/L33/L34. There was 100% concordance in the kinase fusions detected across multiple samples from the same patient. aSufficient material was available to verify these kinase fusions with RNA sequencing. bInitial results from the FoundationOne genomic DNA analysis were negative. The FN1–ALK fusion, which harbors an atypical breakpoint within intron 18 of ALK, was detected by RNA sequencing.

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Multiple Actionable Kinase Fusions in IMT RESEARCH BRIEF

A ALK Figure 2. Kinase fusions identified in IMT by targeted sequencing. Starting with PDGFRβ 37 FFPE IMT samples (26 ALK IHC positive ROS1 and 11 ALK IHC negative), 33 tumors were

1 2 3 4 5 6 7 8 9 evaluable with targeted NGS. A, genomic 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 alterations identified in the 37 IMT tumor samples. Columns, samples; rows, genes. B Red bars, ALK fusions; green bars, PDGFRβ Targeted therapy fusions; blue bars, ROS1 fusions. The identified gene fusions were mutually exclusive. ex1 TFG ex4 ex36 ROS1 ex43 Crizotinib No other recurrent genomic alterations were ex1 YWHAE ex4 ex36 ROS1 ex43 identified by targeted NGS in these samples. B, schematic representation of the distinct Sorafenib ALK, PDGFRβ, and ROS1 fusions identified. Sunitinib ex1 NAB2 ex7 ex12 PDGFRβ ex23 In each case, the exons encompassed within Regorafenib each gene fusion partner are indicated. Axitinib

ex1 EML4 ex2 ex20 ALK ex29

ex1 TPM4 ex7 ex20 ALK ex29

ex1 PRKAR1A ex5 ex20 ALK ex29

ex1 LMNA ex2 ex20 ALK ex29

ex1 TPM3 ex7 ex20 ALK ex29 Crizotinib ex1 TFG ex6 ex20 ALK ex29

ex1 RANBP2 ex18 ex20 ALK ex29

ex1 SEC31A ex22 ex20 ALK ex29

ex1 FN1 ex23 ex19 ALK ex29

ex1 CLTC ex31 ex20 ALK ex29

including 8 tyrosine kinases (Supplementary Table S2). This RANBP2, CLTC, and FN1 (Table 1; Fig. 2A and B). Of note, platform has been previously described and successfully used the FN1–ALK fusion detected in samples L26 and L29 har- in several large genomic studies of various tumor types bors an atypical breakpoint within intron 18 of ALK. This (10–12). In each case, tumor DNA was isolated from FFPE fusion was initially missed by genomic DNA analysis (which tissue. Average coverage was 543×. Targeted NGS was success- targeted only intron 19 of ALK), but later identified with fully performed in 22 of 26 ALK-positive and 11 of 11 ALK- RNA sequencing. Novel ALK gene fusions were also detected, negative specimens (Table 1 and Supplementary Fig. S2). In including LMNA–ALK (sample L12) and PRKAR1A–ALK cases in which there was sufficient tumor material available, (sample L35). The remaining 2 ALK IHC–positive cases were the kinase fusions were verified with RNA sequencing. also negative for ALK kinase domain mutations and ALK Among the 11 ALK IHC–negative cases, kinase fusions amplification, suggesting a different mechanism of ALK were identified in 8 of 11 (73%) of the cases (Table 1, Fig. 2A expression in these tumor samples. and B). Two cases harbored ALK fusions (sample L5, EML4– ALK; sample L9, TPM3–ALK), which were missed by ALK IHC testing alone. Among the other 9 ALK-negative samples, 4 DISCUSSION contained distinct ROS1 fusions (sample L3/L4, YWHAE– IMT is a rare tumor that can arise at multiple anatomic loca- ROS1; sample L6, TFG–ROS1), including the index patient tions. There are limited systemic therapeutic options available (sample L37), and 2 contained a PDGFRβ fusion (samples for patients with surgically unresectable and/or metastatic L7/L10, NAB2–PDGFRβ). Notably, neither ROS1 nor PDGFRβ disease. Previous data have demonstrated that approximately fusions have been described in IMT to date. The genomic 50% of IMTs are positive for ALK expression based on results coordinates for each fusion identified are summarized in from IHC. Responses to the TKI crizotinib have been docu- Supplementary Table S3. Importantly, all kinase fusions mented in patients with ALK-positive IMT, demonstrating the identified in this study (ALK, ROS1, PDGFRβ) are therapeu- importance of identifying this target (6, 14). tically targetable with existing FDA-approved TKIs (8, 13–15). In our study, we successfully performed targeted NGS No other recurrent alterations were identified (Supplemen- in 20 of 22 ALK IHC–positive IMT samples and identified tary Table S3). Further analysis of the 3 of 11 samples for several different ALK gene fusions, with various 5′ gene which a kinase fusion was not detected in this targeted NGS fusion partners. Several of these fusion partners have been assay is ongoing. previously described, including TPM-3/4, ATIC, CLTC, CARS, Among the 22 ALK-positive cases analyzed, 20 harbored and RANBP2 (5). However, we also identified novel ALK gene ALK gene fusions with various previously described 5′ gene fusions, such as LMNA–ALK and PRKAR1A–ALK, the lat- fusion partners, including TPM3, TPM4, SEC31A, TFG, ter of which was detected in a congenital IMT. In addition,

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RESEARCH BRIEF Lovly et al. we identified ALK fusions with noncanonical fusion break- Genomic DNA Sequencing and Analysis points. FN1–ALK, which has previously been described in DNA was extracted from FFPE samples. Sequencing was performed ovarian cancer, has a breakpoint in intron 18 of the ALK gene, for 3,769 exons of 287 cancer genes and 47 introns of 19 commonly whereas most fusions have a breakpoint in ALK intron 19 rearranged genes, including 8 tyrosine kinases (FoundationOne Panel; (16). Because patients with tumors harboring intron 1 (exon Supplementary Table S2) as previously described (10). Tumor con- 19) ALK fusions can derive clinical benefit from ALK inhibi- tent was assessed by hematoxylin and eosin staining before analy- tor therapy (17), there is a need to incorporate these atypical sis; no micro/macro dissection tissue enrichment was performed. but recurrent fusions into NGS-based diagnostic platforms. Sequencing was performed on the HiSeq2000 instrument (Illumina) with 40-bp paired reads to an average depth of 543X. Resultant Notably, we also detected ALK fusions in 2 of 11 IMT samples sequences were analyzed for base substitutions, insertions, deletions, that tested negative for ALK expression by IHC. Therefore, copy-number alterations, and select gene fusions (10). Additional the possibility of targeted therapy with an ALK inhibitor information about the analytic validation of this assay as well as the would have been missed for these patients with ALK testing sequencing of RNA is provided in the Supplementary Methods. by IHC alone. In contrast, there are currently no data about potential Disclosure of Potential Conflicts of Interest oncogenic “drivers” in the ALK-negative subset of IMTs. We C.M. Lovly reports receiving a commercial research grant from identified actionable kinase fusions in 8 of 11 ALK-negative AstraZeneca, has received speakers’ bureau honoraria from Qiagen IMT tumors analyzed by targeted NGS, including ROS1 and and Abbott Molecular, and is a consultant/advisory board mem- PDGFRβ kinase fusions, which have not yet been described in ber for Pfizer. D. Lipson is director of and has ownership interest this disease. PDGFRβ kinase fusions have been described in (including patents) in Foundation Medicine. J.S. Ross is medical myeloproliferative disorders (18). ROS1 kinase fusions have director of, reports receiving a commercial research grant from, and been detected in a variety of malignancies, including lung has ownership interest (including patents) in Foundation Medicine. P.J. Stephens has ownership interest (including patents) in Founda- cancer, glioblastoma, cholangiocarcinoma, and Spitz tumors tion Medicine, Inc. V.A. Miller is CMO of and has ownership interest (reviewed in ref. 19). Crizotinib, which is FDA approved for (including patents) in Foundation Medicine. No potential conflicts the treatment of ALK fusion–positive lung cancer, is also a of interest were disclosed by the other authors. potent ROS1 inhibitor. Preliminary results from the phase I clinical trial of crizotinib in ROS1 fusion–positive lung cancer Authors’ Contributions demonstrated an objective response rate of 56% (9). However, Conception and design: C.M. Lovly, D. Lipson, J.S. Ross, C.M. Coffin responses in other ROS1 fusion–positive cancers have not Development of methodology: C.M. Lovly, D. Lipson, G. Otto, yet been documented. Here, we report that a young boy with T. Brennan, J.S. Ross, V.A. Miller, C.M. Coffin ROS1 fusion–positive IMT responded to crizotinib. This was Acquisition of data (provided animals, acquired and managed the first antitumor response this patient has experienced patients, provided facilities, etc.): C.M. Lovly, A. Gupta, C.T. Chung, since his initial diagnosis more than 2 years before starting S.C. Borinstein, J.S. Ross, C.M. Coffin crizotinib; his tumor previously did not respond to four dif- Analysis and interpretation of data (e.g., statistical analysis, ferent lines of therapy, including cytotoxic chemotherapy or biostatistics, computational analysis): C.M. Lovly, D. Lipson, anti-inflammatory agents. His tumor mass decreased in size, J.S. Ross, P.J. Stephens, V.A. Miller, C.M. Coffin Writing, review, and/or revision of the manuscript: C.M. Lovly, his paraneoplastic anemia improved, and he felt better symp- D. Lipson, C.T. Chung, S.C. Borinstein, J.S. Ross, P.J. Stephens, tomatically. This case clearly illustrates the need for improved V.A. Miller, C.M. Coffin diagnostic and therapeutic paradigms in this disease. Administrative, technical, or material support (i.e., reporting or Overall, our data show for the first time that kinase fusions organizing data, constructing databases): C.M. Lovly, T. Brennan, are found in the majority of IMTs (85% in our series). To our J.S. Ross, C.M. Coffin knowledge, this study represents the largest genomic analy- Study supervision: C.M. Lovly, C.M. Coffin sis of this tumor type to date, and our results redefine this heterogeneous disease as being largely a kinase fusion–driven Acknowledgments neoplasm. These data not only provide insight into this rare The authors thank Drs. Mace Rothenberg and Keith Wilner for disease but also offer rational targeted therapeutic strate- their assistance in obtaining crizotinib for the patient, Drs. William gies with existing FDA-approved TKIs based on the genomic Pao and Jeff Sosman for their critical review of this article, and Abudi profile of the tumor. Critical to successful deployment of Nashabi for administrative assistance. this evolving therapeutic paradigm is incorporation of testing with highly sensitive NGS platforms capable of detecting Grant Support both known and novel fusions in multiple oncogenes from a This work was supported by the Richard and Valerie Aronsohn single tumor specimen. Memorial Research Award from the Sarcoma Foundation of America and by the Joyce Family Foundation. C.M. Lovly was additionally supported by an NIH K12 training grant (K12 CA9060625) and a METHODS Damon Runyon Clinical Investigator Award. The costs of publication of this article were defrayed in part by Patients and Tumor Samples the payment of page charges. This article must therefore be hereby IMT samples and associated patient characteristics were analyzed marked advertisement in accordance with 18 U.S.C. Section 1734 with an Institutional Review Board–approved protocol (#090572). solely to indicate this fact. All clinical data were obtained and maintained according to Health Insurance Portability and Accountability Act (HIPAA) standards. All Received April 9, 2014; revised May 21, 2014; accepted May 21, unique identifiers have been removed before publication. 2014; published OnlineFirst May 29, 2014.

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Inflammatory Myofibroblastic Tumors Harbor Multiple Potentially Actionable Kinase Fusions

Christine M. Lovly, Abha Gupta, Doron Lipson, et al.

Cancer Discovery Published OnlineFirst May 29, 2014.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-14-0377

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