Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib

Ann L A Wong, Jing S J Lim, Arvind Sinha, Anil Gopinathan, Robert Lim, Chee Seng Tan, Thomas Soh, Sudhakar K Venkatesh, Christina Titin, Sabrina S. Sapari, Soo Chin Lee, Wei Peng Yong, Ping S P Tan, Brendan Pang, Ting Ting Wang, Ying Kiat Zee, Richie Soong, Zuzana Trnkova, Chetan Lathia, Jean Paul Thiery & 3 others Scott Wilhelm, Michael Jeffers, Boon Cher Goh

Research output: Contribution to journalArticle

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Abstract

Background: Regorafenib, a multi-kinase inhibitor, is used in the treatment of patients with metastatic colorectal cancer refractory to standard therapy. However, this benefit was limited to 1.4 months improvement in overall survival, with more than half of patients experiencing grade 3 to 4 adverse events. We aim to elucidate the pharmacodynamic effects of regorafenib in metastatic colorectal cancer and discover potential biomarkers that may predict clinical benefit. Methods: Patients with metastatic colorectal adenocarcinoma refractory to standard therapy with tumours amenable to biopsy were eligible for the study. Regorafenib was administered orally at 160 mg daily for 3 out of 4 weeks with tumour assessment every 2 cycles. Metabolic response was assessed by FDG PET-CT scans (pre-treatment and day 15). paired tumour biopsies (pre-treatment and day 21 post-treatment) were sampled for immunohistochemistry and proteomic profiling analyses. Plasma circulating cell free DNA was quantified serially before and after treatment. Results: There were 2(6%) partial responses out of 35 patients, and 8(23%) patients had stable disease for more than 7 months. Adverse event profile was similar to reported data. Recurrent somatic mutations in K-RAS, PIK3CA and BRAF were detected in plasma circulating cell free DNA in 14 patients. some mutations were not found in archival tumour. Total plasma circulating cell free DNA inversely correlated with progression free survival (PFS), and presence of KRAS mutations associated with shorter PFS. Immunohistochemistry of pre- and post- treatment biopsies showed majority of patients had downregulation of phosphorylated-VEGFR2, podoplanin, phosphorylated-AKT, Ki-67 and upregulation of the MEK-ERK axis, phosphorylated-C-MET, phosphorylated-SRC, phosphorylated-STAT3 and phosphorylated-JUN. Proteomic analysis of fine needle tumour aspirates showed down-regulation of PI3K was associated with longer PFS. Conclusion: Plasma circulating cell free DNA may yield potential predictive biomarkers of regorafenib treatment. Downregulation of the PI3K-AKT axis may be an important predictor of clinical benefit.

Original languageEnglish (US)
Article number57
JournalJournal of Translational Medicine
Volume13
Issue number1
DOIs
StatePublished - Feb 12 2015
Externally publishedYes

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Pharmacodynamics
Circulating Neoplastic Cells
Refractory materials
Tumors
Colorectal Neoplasms
Biopsy
DNA
Plasmas
Plasma Cells
Biomarkers
Phosphatidylinositol 3-Kinases
Disease-Free Survival
Therapeutics
Down-Regulation
Computerized tomography
Neoplasms
Mitogen-Activated Protein Kinase Kinases
Proteomics
Mutation
Needles

Keywords

  • Colorectal carcinoma
  • Pharmacodynamics
  • Plasma cell-free DNA
  • Regorafenib

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib. / Wong, Ann L A; Lim, Jing S J; Sinha, Arvind; Gopinathan, Anil; Lim, Robert; Tan, Chee Seng; Soh, Thomas; Venkatesh, Sudhakar K; Titin, Christina; Sapari, Sabrina S.; Lee, Soo Chin; Yong, Wei Peng; Tan, Ping S P; Pang, Brendan; Wang, Ting Ting; Zee, Ying Kiat; Soong, Richie; Trnkova, Zuzana; Lathia, Chetan; Thiery, Jean Paul; Wilhelm, Scott; Jeffers, Michael; Goh, Boon Cher.

In: Journal of Translational Medicine, Vol. 13, No. 1, 57, 12.02.2015.

Research output: Contribution to journalArticle

Wong, ALA, Lim, JSJ, Sinha, A, Gopinathan, A, Lim, R, Tan, CS, Soh, T, Venkatesh, SK, Titin, C, Sapari, SS, Lee, SC, Yong, WP, Tan, PSP, Pang, B, Wang, TT, Zee, YK, Soong, R, Trnkova, Z, Lathia, C, Thiery, JP, Wilhelm, S, Jeffers, M & Goh, BC 2015, 'Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib', Journal of Translational Medicine, vol. 13, no. 1, 57. https://doi.org/10.1186/s12967-015-0405-4
Wong, Ann L A ; Lim, Jing S J ; Sinha, Arvind ; Gopinathan, Anil ; Lim, Robert ; Tan, Chee Seng ; Soh, Thomas ; Venkatesh, Sudhakar K ; Titin, Christina ; Sapari, Sabrina S. ; Lee, Soo Chin ; Yong, Wei Peng ; Tan, Ping S P ; Pang, Brendan ; Wang, Ting Ting ; Zee, Ying Kiat ; Soong, Richie ; Trnkova, Zuzana ; Lathia, Chetan ; Thiery, Jean Paul ; Wilhelm, Scott ; Jeffers, Michael ; Goh, Boon Cher. / Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib. In: Journal of Translational Medicine. 2015 ; Vol. 13, No. 1.
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abstract = "Background: Regorafenib, a multi-kinase inhibitor, is used in the treatment of patients with metastatic colorectal cancer refractory to standard therapy. However, this benefit was limited to 1.4 months improvement in overall survival, with more than half of patients experiencing grade 3 to 4 adverse events. We aim to elucidate the pharmacodynamic effects of regorafenib in metastatic colorectal cancer and discover potential biomarkers that may predict clinical benefit. Methods: Patients with metastatic colorectal adenocarcinoma refractory to standard therapy with tumours amenable to biopsy were eligible for the study. Regorafenib was administered orally at 160 mg daily for 3 out of 4 weeks with tumour assessment every 2 cycles. Metabolic response was assessed by FDG PET-CT scans (pre-treatment and day 15). paired tumour biopsies (pre-treatment and day 21 post-treatment) were sampled for immunohistochemistry and proteomic profiling analyses. Plasma circulating cell free DNA was quantified serially before and after treatment. Results: There were 2(6{\%}) partial responses out of 35 patients, and 8(23{\%}) patients had stable disease for more than 7 months. Adverse event profile was similar to reported data. Recurrent somatic mutations in K-RAS, PIK3CA and BRAF were detected in plasma circulating cell free DNA in 14 patients. some mutations were not found in archival tumour. Total plasma circulating cell free DNA inversely correlated with progression free survival (PFS), and presence of KRAS mutations associated with shorter PFS. Immunohistochemistry of pre- and post- treatment biopsies showed majority of patients had downregulation of phosphorylated-VEGFR2, podoplanin, phosphorylated-AKT, Ki-67 and upregulation of the MEK-ERK axis, phosphorylated-C-MET, phosphorylated-SRC, phosphorylated-STAT3 and phosphorylated-JUN. Proteomic analysis of fine needle tumour aspirates showed down-regulation of PI3K was associated with longer PFS. Conclusion: Plasma circulating cell free DNA may yield potential predictive biomarkers of regorafenib treatment. Downregulation of the PI3K-AKT axis may be an important predictor of clinical benefit.",
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T1 - Tumour pharmacodynamics and circulating cell free DNA in patients with refractory colorectal carcinoma treated with regorafenib

AU - Wong, Ann L A

AU - Lim, Jing S J

AU - Sinha, Arvind

AU - Gopinathan, Anil

AU - Lim, Robert

AU - Tan, Chee Seng

AU - Soh, Thomas

AU - Venkatesh, Sudhakar K

AU - Titin, Christina

AU - Sapari, Sabrina S.

AU - Lee, Soo Chin

AU - Yong, Wei Peng

AU - Tan, Ping S P

AU - Pang, Brendan

AU - Wang, Ting Ting

AU - Zee, Ying Kiat

AU - Soong, Richie

AU - Trnkova, Zuzana

AU - Lathia, Chetan

AU - Thiery, Jean Paul

AU - Wilhelm, Scott

AU - Jeffers, Michael

AU - Goh, Boon Cher

PY - 2015/2/12

Y1 - 2015/2/12

N2 - Background: Regorafenib, a multi-kinase inhibitor, is used in the treatment of patients with metastatic colorectal cancer refractory to standard therapy. However, this benefit was limited to 1.4 months improvement in overall survival, with more than half of patients experiencing grade 3 to 4 adverse events. We aim to elucidate the pharmacodynamic effects of regorafenib in metastatic colorectal cancer and discover potential biomarkers that may predict clinical benefit. Methods: Patients with metastatic colorectal adenocarcinoma refractory to standard therapy with tumours amenable to biopsy were eligible for the study. Regorafenib was administered orally at 160 mg daily for 3 out of 4 weeks with tumour assessment every 2 cycles. Metabolic response was assessed by FDG PET-CT scans (pre-treatment and day 15). paired tumour biopsies (pre-treatment and day 21 post-treatment) were sampled for immunohistochemistry and proteomic profiling analyses. Plasma circulating cell free DNA was quantified serially before and after treatment. Results: There were 2(6%) partial responses out of 35 patients, and 8(23%) patients had stable disease for more than 7 months. Adverse event profile was similar to reported data. Recurrent somatic mutations in K-RAS, PIK3CA and BRAF were detected in plasma circulating cell free DNA in 14 patients. some mutations were not found in archival tumour. Total plasma circulating cell free DNA inversely correlated with progression free survival (PFS), and presence of KRAS mutations associated with shorter PFS. Immunohistochemistry of pre- and post- treatment biopsies showed majority of patients had downregulation of phosphorylated-VEGFR2, podoplanin, phosphorylated-AKT, Ki-67 and upregulation of the MEK-ERK axis, phosphorylated-C-MET, phosphorylated-SRC, phosphorylated-STAT3 and phosphorylated-JUN. Proteomic analysis of fine needle tumour aspirates showed down-regulation of PI3K was associated with longer PFS. Conclusion: Plasma circulating cell free DNA may yield potential predictive biomarkers of regorafenib treatment. Downregulation of the PI3K-AKT axis may be an important predictor of clinical benefit.

AB - Background: Regorafenib, a multi-kinase inhibitor, is used in the treatment of patients with metastatic colorectal cancer refractory to standard therapy. However, this benefit was limited to 1.4 months improvement in overall survival, with more than half of patients experiencing grade 3 to 4 adverse events. We aim to elucidate the pharmacodynamic effects of regorafenib in metastatic colorectal cancer and discover potential biomarkers that may predict clinical benefit. Methods: Patients with metastatic colorectal adenocarcinoma refractory to standard therapy with tumours amenable to biopsy were eligible for the study. Regorafenib was administered orally at 160 mg daily for 3 out of 4 weeks with tumour assessment every 2 cycles. Metabolic response was assessed by FDG PET-CT scans (pre-treatment and day 15). paired tumour biopsies (pre-treatment and day 21 post-treatment) were sampled for immunohistochemistry and proteomic profiling analyses. Plasma circulating cell free DNA was quantified serially before and after treatment. Results: There were 2(6%) partial responses out of 35 patients, and 8(23%) patients had stable disease for more than 7 months. Adverse event profile was similar to reported data. Recurrent somatic mutations in K-RAS, PIK3CA and BRAF were detected in plasma circulating cell free DNA in 14 patients. some mutations were not found in archival tumour. Total plasma circulating cell free DNA inversely correlated with progression free survival (PFS), and presence of KRAS mutations associated with shorter PFS. Immunohistochemistry of pre- and post- treatment biopsies showed majority of patients had downregulation of phosphorylated-VEGFR2, podoplanin, phosphorylated-AKT, Ki-67 and upregulation of the MEK-ERK axis, phosphorylated-C-MET, phosphorylated-SRC, phosphorylated-STAT3 and phosphorylated-JUN. Proteomic analysis of fine needle tumour aspirates showed down-regulation of PI3K was associated with longer PFS. Conclusion: Plasma circulating cell free DNA may yield potential predictive biomarkers of regorafenib treatment. Downregulation of the PI3K-AKT axis may be an important predictor of clinical benefit.

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KW - Pharmacodynamics

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