Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade

Evan Lipson, Victor E Velculescu, Theresa S. Pritchard, Mark Sausen, Andrew Mark Pardoll, Suzanne Topalian, Luis A. Diaz

Research output: Contribution to journalArticle

Abstract

Background: Assessment of therapeutic activity of drugs blocking immune checkpoints such as CTLA-4 and PD-1/PD-L1 can be challenging, as tumors may seem to enlarge or appear anew before regressing, due to intratumoral inflammation. We assessed whether circulating tumor DNA (ctDNA) levels could serve as an early indicator of true changes in tumor burden in patients undergoing treatment with these agents.Findings: Tumors from 12 patients with metastatic melanoma undergoing treatment with checkpoint blocking drugs were analyzed for the presence of hotspot somatic mutations in BRAF, cKIT, NRAS, and TERT. Plasma was collected serially from each patient and levels of ctDNA were compared with radiologic and clinical outcomes.In 5 of 10 patients studied, mutations were detected in BRAF(1), NRAS(2), TERT(1) and ALK(1). Analysis of plasma from 4 of 5 patients identified mutations identical to those found in tumor specimens. Plasma ctDNA levels ranged from undetectable (

Original languageEnglish (US)
Article number42
JournalJournal for ImmunoTherapy of Cancer
Volume2
Issue number1
DOIs
StatePublished - Dec 16 2014

Fingerprint

Tumor Burden
Melanoma
DNA
Neoplasms
Mutation
Therapeutics
Pharmaceutical Preparations
Inflammation

Keywords

  • Anti-PD-1
  • Biomarker
  • Checkpoint blockade
  • Circulating tumor DNA
  • Immunotherapy
  • Ipilimumab

ASJC Scopus subject areas

  • Oncology
  • Immunology and Allergy
  • Cancer Research
  • Molecular Medicine
  • Pharmacology
  • Immunology

Cite this

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abstract = "Background: Assessment of therapeutic activity of drugs blocking immune checkpoints such as CTLA-4 and PD-1/PD-L1 can be challenging, as tumors may seem to enlarge or appear anew before regressing, due to intratumoral inflammation. We assessed whether circulating tumor DNA (ctDNA) levels could serve as an early indicator of true changes in tumor burden in patients undergoing treatment with these agents.Findings: Tumors from 12 patients with metastatic melanoma undergoing treatment with checkpoint blocking drugs were analyzed for the presence of hotspot somatic mutations in BRAF, cKIT, NRAS, and TERT. Plasma was collected serially from each patient and levels of ctDNA were compared with radiologic and clinical outcomes.In 5 of 10 patients studied, mutations were detected in BRAF(1), NRAS(2), TERT(1) and ALK(1). Analysis of plasma from 4 of 5 patients identified mutations identical to those found in tumor specimens. Plasma ctDNA levels ranged from undetectable (",
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AU - Lipson, Evan

AU - Velculescu, Victor E

AU - Pritchard, Theresa S.

AU - Sausen, Mark

AU - Pardoll, Andrew Mark

AU - Topalian, Suzanne

AU - Diaz, Luis A.

PY - 2014/12/16

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N2 - Background: Assessment of therapeutic activity of drugs blocking immune checkpoints such as CTLA-4 and PD-1/PD-L1 can be challenging, as tumors may seem to enlarge or appear anew before regressing, due to intratumoral inflammation. We assessed whether circulating tumor DNA (ctDNA) levels could serve as an early indicator of true changes in tumor burden in patients undergoing treatment with these agents.Findings: Tumors from 12 patients with metastatic melanoma undergoing treatment with checkpoint blocking drugs were analyzed for the presence of hotspot somatic mutations in BRAF, cKIT, NRAS, and TERT. Plasma was collected serially from each patient and levels of ctDNA were compared with radiologic and clinical outcomes.In 5 of 10 patients studied, mutations were detected in BRAF(1), NRAS(2), TERT(1) and ALK(1). Analysis of plasma from 4 of 5 patients identified mutations identical to those found in tumor specimens. Plasma ctDNA levels ranged from undetectable (

AB - Background: Assessment of therapeutic activity of drugs blocking immune checkpoints such as CTLA-4 and PD-1/PD-L1 can be challenging, as tumors may seem to enlarge or appear anew before regressing, due to intratumoral inflammation. We assessed whether circulating tumor DNA (ctDNA) levels could serve as an early indicator of true changes in tumor burden in patients undergoing treatment with these agents.Findings: Tumors from 12 patients with metastatic melanoma undergoing treatment with checkpoint blocking drugs were analyzed for the presence of hotspot somatic mutations in BRAF, cKIT, NRAS, and TERT. Plasma was collected serially from each patient and levels of ctDNA were compared with radiologic and clinical outcomes.In 5 of 10 patients studied, mutations were detected in BRAF(1), NRAS(2), TERT(1) and ALK(1). Analysis of plasma from 4 of 5 patients identified mutations identical to those found in tumor specimens. Plasma ctDNA levels ranged from undetectable (

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