Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy

TY - JOUR

T1 - Clinical utility of KRAS status in circulating plasma DNA compared to archival tumour tissue from patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy

AU - Spindler, Karen-Lise Garm

AU - Pallisgaard, Niels

AU - Appelt, Ane Lindegaard

AU - Andersen, Rikke Fredslund

AU - Schou, Jakob V

AU - Nielsen, Dorte

AU - Pfeiffer, Per

AU - Yilmaz, Mette

AU - Johansen, Julia S

AU - Hoegdall, Estrid V

AU - Jakobsen, Anders

AU - Jensen, Benny V

N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/11

Y1 - 2015/11

N2 - BACKGROUND: Circulating cell-free DNA (cfDNA) in plasma is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumour specific mutations e.g. KRAS. We investigated the clinical value of KRAS mutations when detected in plasma compared to tumour in patients from metastatic colorectal cancer (mCRC) prior to anti-epidermal growth factor receptor (anti-EGFR) therapy. Secondly, we investigated the concentration of total cfDNA in relation to clinical outcome.PATIENTS AND METHODS: Patients were resistant to 5-FU, oxaliplatin and irinotecan and treated with 3rd line irinotecan (180 mg/m(2)) and cetuximab (500 mg/m(2)) q2w in a prospective phase II trial. The study was conducted prior to implementation of KRAS as selection criteria. Plasma was obtained from a pre-treatment EDTA blood-sample, and the total cfDNA, and KRAS mutations were quantified by an in-house qPCR method. Results are presented according to REMARK.RESULTS: One-hundred-and-forty patients were included. Thirty-four percent had detectable KRAS mutations in the tumour, compared to 23% in plasma. KRAS detection in archival tumour tissue showed no correlation to survival, whereas plasma KRAS status remained a strong predictive and prognostic factor in multivariate analysis (Hazard Ratio (HR)=2.98 (95% CI 1.53-5.80, p=0.001) and 2.84 (1.46-5.53, p=0.002), for OS and PFS, respectively). Combining the information of total cell free DNA levels and plasma KRAS mutation status, produced an additional prognostic effect.CONCLUSION: The value of clinically relevant mutations could be improved by performing the analysis on circulation plasma DNA rather than archival tumour tissue.

AB - BACKGROUND: Circulating cell-free DNA (cfDNA) in plasma is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumour specific mutations e.g. KRAS. We investigated the clinical value of KRAS mutations when detected in plasma compared to tumour in patients from metastatic colorectal cancer (mCRC) prior to anti-epidermal growth factor receptor (anti-EGFR) therapy. Secondly, we investigated the concentration of total cfDNA in relation to clinical outcome.PATIENTS AND METHODS: Patients were resistant to 5-FU, oxaliplatin and irinotecan and treated with 3rd line irinotecan (180 mg/m(2)) and cetuximab (500 mg/m(2)) q2w in a prospective phase II trial. The study was conducted prior to implementation of KRAS as selection criteria. Plasma was obtained from a pre-treatment EDTA blood-sample, and the total cfDNA, and KRAS mutations were quantified by an in-house qPCR method. Results are presented according to REMARK.RESULTS: One-hundred-and-forty patients were included. Thirty-four percent had detectable KRAS mutations in the tumour, compared to 23% in plasma. KRAS detection in archival tumour tissue showed no correlation to survival, whereas plasma KRAS status remained a strong predictive and prognostic factor in multivariate analysis (Hazard Ratio (HR)=2.98 (95% CI 1.53-5.80, p=0.001) and 2.84 (1.46-5.53, p=0.002), for OS and PFS, respectively). Combining the information of total cell free DNA levels and plasma KRAS mutation status, produced an additional prognostic effect.CONCLUSION: The value of clinically relevant mutations could be improved by performing the analysis on circulation plasma DNA rather than archival tumour tissue.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Camptothecin

KW - Cetuximab

KW - Colorectal Neoplasms

KW - DNA, Neoplasm

KW - Female

KW - Humans

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Multivariate Analysis

KW - Mutation

KW - Neoplasm Metastasis

KW - Outcome Assessment (Health Care)

KW - Paraffin Embedding

KW - Prognosis

KW - Proportional Hazards Models

KW - Prospective Studies

KW - Proto-Oncogene Proteins p21(ras)

KW - Receptor, Epidermal Growth Factor

KW - Tissue Fixation

U2 - 10.1016/j.ejca.2015.06.118

DO - 10.1016/j.ejca.2015.06.118

M3 - Journal article

C2 - 26508156

SN - 0959-8049

VL - 51

SP - 2678

EP - 2685

JO - European journal of cancer (Oxford, England : 1990)

JF - European journal of cancer (Oxford, England : 1990)

IS - 17

ER -