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Circulating Free Dna and Plasma Kras Mutations in Metastatic Colorectal Cancer Patients Treated with Bi-Weekly Cetuximab and Irinotecan
Annals of Oncology 25 (Supplement 4): iv58–iv84, 2014 doi:10.1093/annonc/mdu326.50
biomarkers 216P
CIRCULATING FREE DNA AND PLASMA KRAS MUTATIONS IN METASTATIC COLORECTAL CANCER PATIENTS TREATED WITH BI-WEEKLY CETUXIMAB AND IRINOTECAN
abstracts
Aim: Small fractions of cell-free DNA (cfDNA) can be quantified from blood samples, is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumor specific hotspot mutations such as KRAS. We investigated the total cfDNA and the tumor specific circulating DNA with KRAS mutations in plasma from patients with metastatic colorectal cancer (mCRC) treated with third line cetuximab and irinotecan. Methods: Patients with histopathologically verified mCRC and adequate PS and organ function were included. All patients were resistant to 5-FU, oxaliplatin and irinotecan and treated with 3rd line irinotecan (180 mg/m2) and cetuximab (500 mg/m2) every second week in a prospective phase II study until disease progression or unacceptable toxicity. Plasma was obtained from a pre-treatment EDTA blood-sample, and the total cfDNA and plasma mutations were quantified by an in-house qPCR method. Quantitative levels of cfDNA were analyzed in relation to clinical data, and to tumor volume as estimated from pretreatment PET-CT. Results: Ninety-five patients were included. There was a significantly higher PFS and OS in patients with low levels of cfDNA, and decreasing median survival with increasing number of alleles. The OS in patients with total cfDNA in the lowest quartile was 17,0 months (95% CI 12.7 -19,8 months ) and 12,1 months (9.6–13,4 ), 9,2 months (6,9 -14,0) and 6,9 months (4,3–8,6) in the higher, respectively ( p = 0.0001). The HR for patients with cfDNA levels above the 75% quartile indicated a strong detrimental effect on survival in this group of patients. The rate of tumor KRAS mutation (Exon 2) in this cohort was 34%, and a total of 30 patients had detectable plasma KRAS mutations. The levels of total cfDNA and tumor KRAS mutational alleles in the plasma were strongly correlated (spearman rank 0.88, p = 0.0001). Studies investigating the correlation of both total cfDNA and number of mutated alleles to tumor volume as estimated from PET-CT scans are on-going. Conclusions: The present study confirms a strong prognostic value of circulating DNA, and correlation between tumor and plasma KRAS. The results of relation to tumor volume will be presented at the meeting. Disclosure: All authors have declared no conflicts of interest.
© European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/iv73/2240955 by guest on 24 October 2019
K.G. Spindler1, N. Pallisgaard2, K. Skovgaard3, R. Andersen4, H. Hendel5, M. Yilmaz6, P. Pfeiffer7, D.L. Nielsen3, J. Johansen3, E. Hoegdall8, A. Jakobsen9, B. Vittrup3 1 Oncology, Aarhus University Hospital, Aarhus, DENMARK 2 Clinical Biochemistry, Vejle Hospital Sygehus Lillebaelt, Vejle Sygehus, Vejle, DENMARK 3 Oncology, Herlev Hospital, Herlev, DENMARK 4 Department of Clinical Biochemistry, Vejle Hospital Sygehus Lillebaelt, Vejle Sygehus, Vejle, DENMARK, Vejle, DENMARK 5 Radiology, Herlev Hospital, Herlev, DENMARK 6 Oncology, Aalborg Hospital, Aalborg, DENMARK 7 Oncology, Odense University Hospital, Odense, DENMARK 8 Pathology, Herlev Hospital, Herlev, DENMARK 9 Oncology, Vejle Hospital Sygehus Lillebaelt, Vejle Sygehus, Vejle, DENMARK
biomarkers 216P
CIRCULATING FREE DNA AND PLASMA KRAS MUTATIONS IN METASTATIC COLORECTAL CANCER PATIENTS TREATED WITH BI-WEEKLY CETUXIMAB AND IRINOTECAN
abstracts
Aim: Small fractions of cell-free DNA (cfDNA) can be quantified from blood samples, is a mixture of DNA from malignant and normal cells, and can be used as a liquid biopsy to detect and quantify tumor specific hotspot mutations such as KRAS. We investigated the total cfDNA and the tumor specific circulating DNA with KRAS mutations in plasma from patients with metastatic colorectal cancer (mCRC) treated with third line cetuximab and irinotecan. Methods: Patients with histopathologically verified mCRC and adequate PS and organ function were included. All patients were resistant to 5-FU, oxaliplatin and irinotecan and treated with 3rd line irinotecan (180 mg/m2) and cetuximab (500 mg/m2) every second week in a prospective phase II study until disease progression or unacceptable toxicity. Plasma was obtained from a pre-treatment EDTA blood-sample, and the total cfDNA and plasma mutations were quantified by an in-house qPCR method. Quantitative levels of cfDNA were analyzed in relation to clinical data, and to tumor volume as estimated from pretreatment PET-CT. Results: Ninety-five patients were included. There was a significantly higher PFS and OS in patients with low levels of cfDNA, and decreasing median survival with increasing number of alleles. The OS in patients with total cfDNA in the lowest quartile was 17,0 months (95% CI 12.7 -19,8 months ) and 12,1 months (9.6–13,4 ), 9,2 months (6,9 -14,0) and 6,9 months (4,3–8,6) in the higher, respectively ( p = 0.0001). The HR for patients with cfDNA levels above the 75% quartile indicated a strong detrimental effect on survival in this group of patients. The rate of tumor KRAS mutation (Exon 2) in this cohort was 34%, and a total of 30 patients had detectable plasma KRAS mutations. The levels of total cfDNA and tumor KRAS mutational alleles in the plasma were strongly correlated (spearman rank 0.88, p = 0.0001). Studies investigating the correlation of both total cfDNA and number of mutated alleles to tumor volume as estimated from PET-CT scans are on-going. Conclusions: The present study confirms a strong prognostic value of circulating DNA, and correlation between tumor and plasma KRAS. The results of relation to tumor volume will be presented at the meeting. Disclosure: All authors have declared no conflicts of interest.
© European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/iv73/2240955 by guest on 24 October 2019
K.G. Spindler1, N. Pallisgaard2, K. Skovgaard3, R. Andersen4, H. Hendel5, M. Yilmaz6, P. Pfeiffer7, D.L. Nielsen3, J. Johansen3, E. Hoegdall8, A. Jakobsen9, B. Vittrup3 1 Oncology, Aarhus University Hospital, Aarhus, DENMARK 2 Clinical Biochemistry, Vejle Hospital Sygehus Lillebaelt, Vejle Sygehus, Vejle, DENMARK 3 Oncology, Herlev Hospital, Herlev, DENMARK 4 Department of Clinical Biochemistry, Vejle Hospital Sygehus Lillebaelt, Vejle Sygehus, Vejle, DENMARK, Vejle, DENMARK 5 Radiology, Herlev Hospital, Herlev, DENMARK 6 Oncology, Aalborg Hospital, Aalborg, DENMARK 7 Oncology, Odense University Hospital, Odense, DENMARK 8 Pathology, Herlev Hospital, Herlev, DENMARK 9 Oncology, Vejle Hospital Sygehus Lillebaelt, Vejle Sygehus, Vejle, DENMARK