Changes in mutational status during third-line treatment for metastatic colorectal cancer: results of consecutive measurement of cell free DNA, KRAS and BRAF in the plasma

Karen-Lise Garm Spindler, Niels Pallisgaard, Rikke Fredslund Andersen, Anders Jakobsen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

KRAS and BRAF mutations are responsible for primary resistance to epidermal growth factor receptor (EGFR) MoAbs in metastatic colorectal cancer (mCRC), but it is unknown what causes wildtype (wt) patients to develop resistance during treatment. We measured circulating free DNA (cfDNA), KRAS and BRAF in plasma and report the changes during third line treatment with cetuximab and irinotecan. One-hundred-and-eight patients received irinotecan 350 mg/m2 q3w and weekly cetuximab (250 mg/m2) until progression (RECIST) or unacceptable toxicity. cfDNA and number of mutated KRAS/BRAF alleles in plasma at baseline and before each cycle was analyzed by an in-house qPCR. cfDNA and pKRAS levels decreased from baseline to cycle three and increased at time of progression (p = 0.008). The decrease was larger in responding patients than in non-responding (p < 0.05). Two patients with primary mutant disease had different types of mutations detected in the plasma, including synchronous KRAS and BRAF. Twelve patients had a primary KRAS mutant tumor, but wild-type disease according to baseline plasma analysis, eight of these obtained stabilization of disease. In five patients with primary wt disease a mutation appeared in plasma before radiological evidence of progression. Loss of mutations may explain observed benefit of treatment in primary mutant disease, whereas appearance of mutations during therapy may be responsible for acquired resistance in primary wt disease. Benefit from EGFR MoAbs may be influenced by the quantitative level of mutational alleles rather than by mutational status alone, and plasma levels of cfDNA, KRAS and BRAF could be used to monitor patients during treatment.

OriginalsprogEngelsk
TidsskriftInternational Journal of Cancer
Vol/bind135
Udgave nummer9
Sider (fra-til)2215-22
ISSN0020-7136
DOI
StatusUdgivet - 1. nov. 2014

Fingeraftryk

Colorectal Neoplasms
irinotecan
DNA
Mutation
Epidermal Growth Factor Receptor
Alleles
Neoplasms

Emneord

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols
  • Colorectal Neoplasms
  • DNA, Neoplasm
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Polymerase Chain Reaction
  • Prognosis
  • Prospective Studies
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins B-raf
  • Tumor Markers, Biological
  • ras Proteins

Citer dette

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title = "Changes in mutational status during third-line treatment for metastatic colorectal cancer: results of consecutive measurement of cell free DNA, KRAS and BRAF in the plasma",
abstract = "KRAS and BRAF mutations are responsible for primary resistance to epidermal growth factor receptor (EGFR) MoAbs in metastatic colorectal cancer (mCRC), but it is unknown what causes wildtype (wt) patients to develop resistance during treatment. We measured circulating free DNA (cfDNA), KRAS and BRAF in plasma and report the changes during third line treatment with cetuximab and irinotecan. One-hundred-and-eight patients received irinotecan 350 mg/m2 q3w and weekly cetuximab (250 mg/m2) until progression (RECIST) or unacceptable toxicity. cfDNA and number of mutated KRAS/BRAF alleles in plasma at baseline and before each cycle was analyzed by an in-house qPCR. cfDNA and pKRAS levels decreased from baseline to cycle three and increased at time of progression (p = 0.008). The decrease was larger in responding patients than in non-responding (p < 0.05). Two patients with primary mutant disease had different types of mutations detected in the plasma, including synchronous KRAS and BRAF. Twelve patients had a primary KRAS mutant tumor, but wild-type disease according to baseline plasma analysis, eight of these obtained stabilization of disease. In five patients with primary wt disease a mutation appeared in plasma before radiological evidence of progression. Loss of mutations may explain observed benefit of treatment in primary mutant disease, whereas appearance of mutations during therapy may be responsible for acquired resistance in primary wt disease. Benefit from EGFR MoAbs may be influenced by the quantitative level of mutational alleles rather than by mutational status alone, and plasma levels of cfDNA, KRAS and BRAF could be used to monitor patients during treatment.",
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author = "Spindler, {Karen-Lise Garm} and Niels Pallisgaard and Andersen, {Rikke Fredslund} and Anders Jakobsen",
note = "{\circledC} 2014 UICC.",
year = "2014",
month = "11",
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Changes in mutational status during third-line treatment for metastatic colorectal cancer : results of consecutive measurement of cell free DNA, KRAS and BRAF in the plasma. / Spindler, Karen-Lise Garm; Pallisgaard, Niels; Andersen, Rikke Fredslund; Jakobsen, Anders.

I: International Journal of Cancer, Bind 135, Nr. 9, 01.11.2014, s. 2215-22.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Changes in mutational status during third-line treatment for metastatic colorectal cancer

T2 - results of consecutive measurement of cell free DNA, KRAS and BRAF in the plasma

AU - Spindler, Karen-Lise Garm

AU - Pallisgaard, Niels

AU - Andersen, Rikke Fredslund

AU - Jakobsen, Anders

N1 - © 2014 UICC.

PY - 2014/11/1

Y1 - 2014/11/1

N2 - KRAS and BRAF mutations are responsible for primary resistance to epidermal growth factor receptor (EGFR) MoAbs in metastatic colorectal cancer (mCRC), but it is unknown what causes wildtype (wt) patients to develop resistance during treatment. We measured circulating free DNA (cfDNA), KRAS and BRAF in plasma and report the changes during third line treatment with cetuximab and irinotecan. One-hundred-and-eight patients received irinotecan 350 mg/m2 q3w and weekly cetuximab (250 mg/m2) until progression (RECIST) or unacceptable toxicity. cfDNA and number of mutated KRAS/BRAF alleles in plasma at baseline and before each cycle was analyzed by an in-house qPCR. cfDNA and pKRAS levels decreased from baseline to cycle three and increased at time of progression (p = 0.008). The decrease was larger in responding patients than in non-responding (p < 0.05). Two patients with primary mutant disease had different types of mutations detected in the plasma, including synchronous KRAS and BRAF. Twelve patients had a primary KRAS mutant tumor, but wild-type disease according to baseline plasma analysis, eight of these obtained stabilization of disease. In five patients with primary wt disease a mutation appeared in plasma before radiological evidence of progression. Loss of mutations may explain observed benefit of treatment in primary mutant disease, whereas appearance of mutations during therapy may be responsible for acquired resistance in primary wt disease. Benefit from EGFR MoAbs may be influenced by the quantitative level of mutational alleles rather than by mutational status alone, and plasma levels of cfDNA, KRAS and BRAF could be used to monitor patients during treatment.

AB - KRAS and BRAF mutations are responsible for primary resistance to epidermal growth factor receptor (EGFR) MoAbs in metastatic colorectal cancer (mCRC), but it is unknown what causes wildtype (wt) patients to develop resistance during treatment. We measured circulating free DNA (cfDNA), KRAS and BRAF in plasma and report the changes during third line treatment with cetuximab and irinotecan. One-hundred-and-eight patients received irinotecan 350 mg/m2 q3w and weekly cetuximab (250 mg/m2) until progression (RECIST) or unacceptable toxicity. cfDNA and number of mutated KRAS/BRAF alleles in plasma at baseline and before each cycle was analyzed by an in-house qPCR. cfDNA and pKRAS levels decreased from baseline to cycle three and increased at time of progression (p = 0.008). The decrease was larger in responding patients than in non-responding (p < 0.05). Two patients with primary mutant disease had different types of mutations detected in the plasma, including synchronous KRAS and BRAF. Twelve patients had a primary KRAS mutant tumor, but wild-type disease according to baseline plasma analysis, eight of these obtained stabilization of disease. In five patients with primary wt disease a mutation appeared in plasma before radiological evidence of progression. Loss of mutations may explain observed benefit of treatment in primary mutant disease, whereas appearance of mutations during therapy may be responsible for acquired resistance in primary wt disease. Benefit from EGFR MoAbs may be influenced by the quantitative level of mutational alleles rather than by mutational status alone, and plasma levels of cfDNA, KRAS and BRAF could be used to monitor patients during treatment.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Colorectal Neoplasms

KW - DNA, Neoplasm

KW - Disease Progression

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Neoplasm Metastasis

KW - Neoplasm Staging

KW - Polymerase Chain Reaction

KW - Prognosis

KW - Prospective Studies

KW - Proto-Oncogene Proteins

KW - Proto-Oncogene Proteins B-raf

KW - Tumor Markers, Biological

KW - ras Proteins

U2 - 10.1002/ijc.28863

DO - 10.1002/ijc.28863

M3 - Journal article

C2 - 24659028

VL - 135

SP - 2215

EP - 2222

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 9

ER -