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    edi tor ial s

    n engl j med 366;12 nejm.org march 22, 20121152

    T h e n e w e n g l a n d j o u r n a l o f me dicine

    Profiles in LeukemiaLucy A. Godley, M.D., Ph.D.

    For years, scientists have postulated the evolu-

    tion of a cancer as a series of acquired mutations

    and epigenetic alterations that accumulate in a

    progressive way, beginning with a single trans-

    formed cell. Within this process, subclones of

    cells develop that acquire new properties, giving

    cells advantages, such as the ability to resist che-

    motherapy or to metastasize. With the publica-

    tion of two articles in this issue of the Journal,1,2

    we have experimental evidence for this model of

    cancer and a glimpse of how we may evaluate

    patients with cancer in the near future.

    In one article, Walter et al.1 used high-through-put sequencing, DNA copy-number analysis, andmicroarray-based gene-expression studies to de-fine the acquisition of gene mutations that ac-companied tumor progression from a precursormyelodysplastic syndrome to acute myeloid leu-kemia (AML) in seven patients. They found thatthe myelodysplastic-syndrome clones containedhundreds of acquired mutations and that theleukemias that arose subsequently were derivedfrom at least one subclone that had gained newmutations or genomic rearrangements, providingexperimental proof for the model of the sequen-tial development of cancer. From this large groupof mutated genes, Walter et al. were able toidentify 11 genes that mutated recurrently, 4 ofwhich had not been implicated previously in mye-loid diseases: UMODL1, CDH23, SMC3, andZSWIM4.

    This work suggests that the genetic definitionof tumor cells will provide new insights into thebiologic characteristics of cancer. In addition, itwill help to guide diagnostic, prognostic, andtherapeutic decisions, as shown by Patel et al.2

    Patel and colleagues have moved to this nextphase of molecular medicine by defining the mu-tational profiles of 18 genes in the stored sam-ples obtained from 502 patients with AML whohad participated in the Eastern Cooperative Oncol-ogy Group E1900 clinical trial (ClinicalTrials.gov

    number, NCT00049517), in which two doses ofinduction chemotherapy were tested. With veryeconomical use of patient material, the investi-gators were able to ask a new question usingdata already collected. What is the complementof mutations present in primary AML, and do theyhave prognostic value? They found that 97% of

    the patients with AML had mutations in the genesselected for analysis, a finding consistent withthe results of a study involving patients with mye-lodysplastic syndrome that showed that a major-ity of patients had detectable point mutations.3Poor survival was seen in patients with tandemduplication mutations of FLT3 or MLL and inthose with point mutations ofASXL1 or PHF6.Favorable outcomes were seen for patients withCEBPA or IDH2 mutations and for those withNPM1 mutations with concurrentIDH1 or IDH2mutations. Importantly, the group was able toshow that patients with mutations ofDNMT3A orNPM1 and those with MLL rearrangements hadimproved survival if they had been in the trialgroup that received high-dose daunorubicin.

    If we think about extending the findings ofPatel and colleagues to clinical practice, we wouldneed to know the genetic profile of patientswith AML within the first few days of presenta-tion, in order to tailor an induction regimen tothe patient. In at least one published case, thegenetic profiling of AML has provided critical

    diagnostic categorization, which was unachiev-able with standard approaches,4 arguing for in-creased reliance on these techniques. Rapid clini-cal assessment is under way within the Cancerand Leukemia Group B, which is identifying pa-tients with core-binding-factor leukemias bymeans of molecular testing within 48 hours afterpresentation, allowing those patients to partici-pate in a clinical trial (NCT01238211) testingthe effectiveness of adding dasatinib to induc-tion and consolidation therapy.

    The New England Journal of Medicine

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    editorials

    n engl j med 366;12 nejm.org march 22, 2012 1153

    So, how does the field of leukemia diagnos-tics and therapeutics, and oncology more gener-ally, move forward from here? Figure 1 showsthe current clinical evaluation of a patient withAML, as well as the challenges to implementingmolecular profiling routinely. Whether clinicalgenomic testing will be performed with the useof panels of genes with important diagnostic,prognostic, or therapeutic significance or wheth-er an unbiased sequencing approach will be usedremains to be seen. Given the results of thestudy by Walter et al.,1 it may be overwhelmingfor clinicians to receive a report with hundreds

    of gene mutations and expect them to make ra-tional clinical decisions. An approach in which afixed panel of genes was examined for mutationsof particular clinical signif icance might be moreaffordable and the results easier to understand.A critical question is whether the data presentedby Patel and colleagues2 are sufficient to justifythe expansion of the number of genetic muta-tions being examined in patients with AML atpresentation, beyond the current analysis ofFLT3,NPM1, and CEBPA. The findings of Patel and col-

    leagues challenge the field to address at whatpoint data are compelling enough to change rou-tine practice. It is exciting to think that the goalof personalized medicine is quickly approaching,but it will require careful thought to implementgenomic-based clinical evaluation in a way that ismeaningful for patients.5

    Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

    From the Section of HematologyOncology, Department ofMedicine, University of Chicago, Chicago.

    This article (10.1056/NEJMe1200409) was published on March14, 2012, at NEJM.org.

    1. Walter MJ, Shen D, Ding L, et al. Clonal architecture of sec-ondary acute myeloid leukemia. N Engl J Med 2012;366:1090-8.2. Patel JP, Gnen M, Figueroa ME, et al. Prognostic relevanceof integrated genetic profiling in acute myeloid leukemia. N EnglJ Med 2012;366:1079-89.3. Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical ef fect ofpoint mutations in myelodysplastic syndromes. N Engl J Med2011;364:2496-506.4. Welch JS, Westervelt P, Ding L, et al. Use of whole-genomesequencing to diagnose a cryptic fusion oncogene. JAMA 2011;305:1577-84.5. Sledge GW Jr. The challenge and promise of the genomicera. J Clin Oncol 2012;30:203-9.Copyright 2012 Massachusetts Medical Societ y.

    CurrentEvaluation

    Morphologic features

    Flow cytometric analysis

    CytogeneticFISH analysis

    Molecular studies

    FLT3

    NPM1

    CEBPA

    FLT3

    NPM1

    CEBPA

    ASXL1

    DNMT3A

    IDH1

    IDH2

    KIT

    MLL

    PHF6

    TET2

    WT1

    ANKRD26

    GATA2

    RUNX1

    TP53

    andothers

    FutureEvaluation Challenges

    Testing will need to be rapid ifresults will affect choice ofinduction regimen

    Clinicians will need to decide

    whether to do panel testing orwhole genome or exomesequencing

    The role of standard morphologic,flow cytometric, and cytogenetic-FISH testing will need to beevaluated

    Cost will need to be assessed

    Molecular profiling

    Real-time PCR

    Microarray analysis

    Next-generation sequencing

    Figure 1. Current Clinical Evaluation of Acute Myeloid Leukemia and Potential Future Testing.

    The current standard evaluation of acute myeloid leukemia samples includes morphologic evaluation, flow cytometric determination ofcell lineage, cytogenetic and fluorescence in situ hybridization (FISH) studies to delineate recurrent chromosomal rearrangements, andmolecular testing for expression of chromosomal fusion transcripts and the presence of mutations in FLT3, NPM1, and CEBPA (shown

    at the left of the figure). Testing in the future may be dominated by genomics-based molecular profiling, which may include real-timepolymerase-chain-reaction (PCR) assays, microarray analysis, and next-generation sequencing; together, these tests have the capacity to

    define the gene-expression signature of the leukemia and thereby determine the cell lineage of the disease, as well as to identify com-

    mon chromosomal rearrangements and gene mutations (shown to the right of the figure). In the future, prognostication in myeloid can-cers may rely on the analysis of many genes with clinical relevance. We may also have the capacity to study a patients germline simulta-

    neously with the disease, enabling an assessment of inherited predispositions. Several challenges exist to widespread implementation ofmolecular profiling to generate diagnostic and prognostic information, but these challenges may be overcome soon, and molecular pro-

    filing may herald a new approach to testing in leukemia and, by extension, other cancers.

    The New England Journal of Medicine

    Downloaded from nejm.org on May 9, 2012. For personal use only. No other uses without permission.

    Copyright 2012 Massachusetts Medical Society. All rights reserved.