Evaluation of KRAS mutations, angiogenic biomarkers, and DCE-MRI in patients with advanced non-small-cell lung cancer receiving sorafenib

Ronan J. Kelly, Arun Rajan, Jeremy Force, Ariel Lopez-Chavez, Corrine Keen, Liang Cao, Yunkai Yu, Peter Choyke, Baris Turkbey, Mark Raffeld, Liqiang Xi, Seth M. Steinberg, John J. Wright, Shivaani Kummar, Martin Gutierrez, Giuseppe Giaccone

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Purpose: Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non-small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity. Experimental Design: Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters Ktrans, Kep, and Ve were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54. Results: Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%) showed no correlation with response, PFS, or OS. Kep, was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (<6 vs. >6 pg/mL; P=0.042), whereas a PFS benefit was seen with bFGF at day 28 (<6 vs. >6; P = 0.028). Conclusions: KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition.

Original languageEnglish (US)
Pages (from-to)1190-1199
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number5
DOIs
StatePublished - Mar 1 2011
Externally publishedYes

Fingerprint

Non-Small Cell Lung Carcinoma
Disease-Free Survival
Biomarkers
Mutation
Survival
Cytokines
Vascular Endothelial Growth Factor A
Blood Vessels
Research Design
sorafenib
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Evaluation of KRAS mutations, angiogenic biomarkers, and DCE-MRI in patients with advanced non-small-cell lung cancer receiving sorafenib. / Kelly, Ronan J.; Rajan, Arun; Force, Jeremy; Lopez-Chavez, Ariel; Keen, Corrine; Cao, Liang; Yu, Yunkai; Choyke, Peter; Turkbey, Baris; Raffeld, Mark; Xi, Liqiang; Steinberg, Seth M.; Wright, John J.; Kummar, Shivaani; Gutierrez, Martin; Giaccone, Giuseppe.

In: Clinical Cancer Research, Vol. 17, No. 5, 01.03.2011, p. 1190-1199.

Research output: Contribution to journalArticle

Kelly, RJ, Rajan, A, Force, J, Lopez-Chavez, A, Keen, C, Cao, L, Yu, Y, Choyke, P, Turkbey, B, Raffeld, M, Xi, L, Steinberg, SM, Wright, JJ, Kummar, S, Gutierrez, M & Giaccone, G 2011, 'Evaluation of KRAS mutations, angiogenic biomarkers, and DCE-MRI in patients with advanced non-small-cell lung cancer receiving sorafenib', Clinical Cancer Research, vol. 17, no. 5, pp. 1190-1199. https://doi.org/10.1158/1078-0432.CCR-10-2331
Kelly, Ronan J. ; Rajan, Arun ; Force, Jeremy ; Lopez-Chavez, Ariel ; Keen, Corrine ; Cao, Liang ; Yu, Yunkai ; Choyke, Peter ; Turkbey, Baris ; Raffeld, Mark ; Xi, Liqiang ; Steinberg, Seth M. ; Wright, John J. ; Kummar, Shivaani ; Gutierrez, Martin ; Giaccone, Giuseppe. / Evaluation of KRAS mutations, angiogenic biomarkers, and DCE-MRI in patients with advanced non-small-cell lung cancer receiving sorafenib. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 5. pp. 1190-1199.
@article{568a429ada934089872bd6b8d93176f3,
title = "Evaluation of KRAS mutations, angiogenic biomarkers, and DCE-MRI in patients with advanced non-small-cell lung cancer receiving sorafenib",
abstract = "Purpose: Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non-small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity. Experimental Design: Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters Ktrans, Kep, and Ve were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54. Results: Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65{\%}. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32{\%}) and EGFR mutations (22{\%}) showed no correlation with response, PFS, or OS. Kep, was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (<6 vs. >6 pg/mL; P=0.042), whereas a PFS benefit was seen with bFGF at day 28 (<6 vs. >6; P = 0.028). Conclusions: KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition.",
author = "Kelly, {Ronan J.} and Arun Rajan and Jeremy Force and Ariel Lopez-Chavez and Corrine Keen and Liang Cao and Yunkai Yu and Peter Choyke and Baris Turkbey and Mark Raffeld and Liqiang Xi and Steinberg, {Seth M.} and Wright, {John J.} and Shivaani Kummar and Martin Gutierrez and Giuseppe Giaccone",
year = "2011",
month = "3",
day = "1",
doi = "10.1158/1078-0432.CCR-10-2331",
language = "English (US)",
volume = "17",
pages = "1190--1199",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

TY - JOUR

T1 - Evaluation of KRAS mutations, angiogenic biomarkers, and DCE-MRI in patients with advanced non-small-cell lung cancer receiving sorafenib

AU - Kelly, Ronan J.

AU - Rajan, Arun

AU - Force, Jeremy

AU - Lopez-Chavez, Ariel

AU - Keen, Corrine

AU - Cao, Liang

AU - Yu, Yunkai

AU - Choyke, Peter

AU - Turkbey, Baris

AU - Raffeld, Mark

AU - Xi, Liqiang

AU - Steinberg, Seth M.

AU - Wright, John J.

AU - Kummar, Shivaani

AU - Gutierrez, Martin

AU - Giaccone, Giuseppe

PY - 2011/3/1

Y1 - 2011/3/1

N2 - Purpose: Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non-small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity. Experimental Design: Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters Ktrans, Kep, and Ve were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54. Results: Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%) showed no correlation with response, PFS, or OS. Kep, was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (<6 vs. >6 pg/mL; P=0.042), whereas a PFS benefit was seen with bFGF at day 28 (<6 vs. >6; P = 0.028). Conclusions: KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition.

AB - Purpose: Sorafenib, a multikinase inhibitor targeting Raf and VEGFR, has shown activity in unselected patients with non-small-cell lung cancer (NSCLC). At present there are no validated biomarkers indicative of sorafenib activity. Experimental Design: Patients received sorafenib 400 mg BID daily to determine activity and tolerability and to measure its biological effects. KRAS mutation status (N = 34), angiogenesis markers (VEGF, bFGF, FLT-1, PLGF-1) and imaging with DCE-MRI (dynamic contrast enhanced MRI) to determine early changes in tumor vascular characteristics were evaluated. Three parameters Ktrans, Kep, and Ve were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54. Results: Thirty-seven patients with previously treated stage IV NSCLC were enrolled in this single-center phase II trial. In 34 evaluable patients, 2 had partial responses and 20 had stable disease for 3 to 17 months, a disease control rate of 65%. The median progression-free survival (PFS) was 3.4 months, and median overall survival (OS) was 11.6 months. Toxicity was consistent with the known side effects of sorafenib. KRAS (32%) and EGFR mutations (22%) showed no correlation with response, PFS, or OS. Kep, was significant in predicting an improvement in OS (P = 0.035) and PFS (P = 0.029). Cytokine analysis demonstrated an improved OS for bFGF day 0 (<6 vs. >6 pg/mL; P=0.042), whereas a PFS benefit was seen with bFGF at day 28 (<6 vs. >6; P = 0.028). Conclusions: KRAS and EGFR mutational status showed no correlation with response, PFS, or OS. Radiologic and cytokine changes may act as biomarkers indicative of early angiogenesis inhibition.

UR - http://www.scopus.com/inward/record.url?scp=79952269551&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952269551&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-10-2331

DO - 10.1158/1078-0432.CCR-10-2331

M3 - Article

C2 - 21224376

AN - SCOPUS:79952269551

VL - 17

SP - 1190

EP - 1199

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 5

ER -