title: Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study.
abstract: BACKGROUND
  Diffuse large-B-cell lymphoma is curable, but when treatment fails, outcome is poor. Although imaging can help to identify patients at risk of treatment failure, they are often imprecise, and radiation exposure is a potential health risk. We aimed to assess whether circulating tumour DNA encoding the clonal immunoglobulin gene sequence could be detected in the serum of patients with diffuse large-B-cell lymphoma and used to predict clinical disease recurrence after frontline treatment.
  
  
  METHODS
  We used next-generation DNA sequencing to retrospectively analyse cell-free circulating tumour DNA in patients assigned to one of three treatment protocols between May 8, 1993, and June 6, 2013. Eligible patients had diffuse large-B-cell lymphoma, no evidence of indolent lymphoma, and were previously untreated. We obtained serial serum samples and concurrent CT scans at specified times during most treatment cycles and up to 5 years of follow-up. VDJ gene segments of the rearranged immunoglobulin receptor genes were amplified and sequenced from pretreatment specimens and serum circulating tumour DNA encoding the VDJ rearrangements was quantitated.
  
  
  RESULTS
  Tumour clonotypes were identified in pretreatment specimens from 126 patients who were followed up for a median of 11 years (IQR 6·8-14·2). Interim monitoring of circulating tumour DNA at the end of two treatment cycles in 108 patients showed a 5-year time to progression of 41·7% (95% CI 22·2-60·1) in patients with detectable circulating tumour DNA and 80·2% (69·6-87·3) in those without detectable circulating tumour DNA (p<0·0001). Detectable interim circulating tumour DNA had a positive predictive value of 62·5% (95% CI 40·6-81·2) and a negative predictive value of 79·8% (69·6-87·8). Surveillance monitoring of circulating tumour DNA was done in 107 patients who achieved complete remission. A Cox proportional hazards model showed that the hazard ratio for clinical disease progression was 228 (95% CI 51-1022) for patients who developed detectable circulating tumour DNA during surveillance compared with patients with undetectable circulating tumour DNA (p<0·0001). Surveillance circulating tumour DNA had a positive predictive value of 88·2% (95% CI 63·6-98·5) and a negative predictive value of 97·8% (92·2-99·7) and identified risk of recurrence at a median of 3·5 months (range 0-200) before evidence of clinical disease.
  
  
  CONCLUSIONS
  Surveillance circulating tumour DNA identifies patients at risk of recurrence before clinical evidence of disease in most patients and results in a reduced disease burden at relapse. Interim circulating tumour DNA is a promising biomarker to identify patients at high risk of treatment failure.
  
  
  BACKGROUND
  National Cancer Institute and Adaptive Biotechnologies.
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Roschewski
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Kieron
authors.initials: K
authors.lastname: Dunleavy
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Adaptive Biotechnologies, South San Francisco, CA, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Moorhead
authors.affiliation: Adaptive Biotechnologies, South San Francisco, CA, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Pepin
authors.affiliation: Adaptive Biotechnologies, South San Francisco, CA, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kong
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Shovlin
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lai
authors.affiliation: Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Nuclear Medicine Division, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Clara C
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Adaptive Biotechnologies, South San Francisco, CA, USA.
authors.forename: Jianbiao
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Adaptive Biotechnologies, South San Francisco, CA, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Willis
authors.affiliation: Adaptive Biotechnologies, South San Francisco, CA, USA.
authors.forename: Malek
authors.initials: M
authors.lastname: Faham
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Electronic address: wilsonw@mail.nih.gov.
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D002648:Child; D004273:DNA, Neoplasm / Q000235:genetics* / Q000302:isolation & purification; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D014057:Tomography, X-Ray Computed
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm
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