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

ABSTRACT: 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.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 K(trans), K(ep), and V(e) were measured by DCE-MRI at baseline and day 14 of cycle 1. Cytokine analysis was done on days 0, 14, 28, and 54.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. K(ep), 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).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.

SUBMITTER: Kelly RJ

PROVIDER: S-EPMC3048919 | biostudies-other | 2011 Mar

REPOSITORIES: biostudies-other

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

Kelly Ronan J RJ Rajan Arun A Force Jeremy J Lopez-Chavez Ariel A Keen Corrine C Cao Liang L Yu Yunkai Y Choyke Peter P Turkbey Baris B Raffeld Mark M Xi Liqiang L Steinberg Seth M SM Wright John J JJ Kummar Shivaani S Gutierrez Martin M Giaccone Giuseppe G

Clinical cancer research : an official journal of the American Association for Cancer Research 20110111 5

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 (dynami ...[more]

PMID: 21224376

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Project description:In this paper, our main objective was to predict survival outcomes using DCE-MRI biomarkers in patients with advanced hepatocellular carcinoma (HCC) after progression from 1st-line sorafenib treatment in two prospective phase II trials. This study included 74 participants (men/women = 64/10, mean age 60 ± 11.8 years) with advanced HCC who received 2nd-line targeted therapy (n = 41 with lenalidomide in one clinical trial; n = 33 with axitinib in another clinical trial) after sorafenib failure from two prospective phase II studies. Among them, all patients underwent DCE-MRI at baseline, and on days 3 and 14 of treatment. The relative changes (Δ) in the DCE-MRI parameters, including ΔPeak, ΔAUC, and ΔKtrans, were derived from the largest hepatic tumor. The treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The Cox model was used to investigate the associations of the clinical variables and DCE-MRI biomarkers with progression-free survival (PFS) and overall survival (OS). The objective response rate (ORR) was 10.8% (8/74) and the disease control rate (DCR) was 58.1% (43/74). The median PFS and OS values were 1.9 and 7.8 months, respectively. On day 3 (D3), participants with high reductions in ΔPeak_D3 (hazard ratio (HR) 0.4, 95% confidence interval (CI) 0.17-0.93, p = 0.017) or ΔAUC_D3 (HR 0.51, 95% CI 0.25-1.04, p = 0.043) were associated with better PFS. On day 14, participants with high reductions in ΔPeak_D14 (HR 0.51, 95% CI 0.26-1.01, p = 0.032), ΔAUC_D14 (HR 0.54, 95% CI 0.33-0.9, p = 0.009), or ΔKtrans_D14 (HR 0.26, 95% CI 0.12-0.56, p < 0.001) had a higher PFS than those with lower reduction values. In addition, high reductions in ΔAUC_D14 (HR 0.53, 95% CI 0.32-0.9, p = 0.016) or ΔKtrans_D14 (HR 0.47, 95% CI 0.23-0.98, p = 0.038) were associated with a better OS. Among the clinical variables, ORR was associated with both PFS (p = 0.001) and OS (p = 0.005). DCR was associated with PFS (p = 0.002), but not OS (p = 0.089). Cox multivariable analysis revealed that ΔKtrans_D14 (p = 0.002) remained an independent predictor of PFS after controlling for ORR and DCR. An early reduction in tumor perfusion detected by DCE-MRI biomarkers, especially on day 14, may predict favorable survival outcomes in participants with HCC receiving 2nd-line targeted therapy after sorafenib failure.

Project description:BACKGROUND:KRAS gene mutations are well known as a key driver of advanced non-small cell lung cancer (NSCLC). The impact of KRAS-mutant subtypes on the survival benefit from salvage chemotherapy is controversial. Here, we present a real-world study in patients across China with advanced NSCLC with KRAS mutations using a website-based patient self-report system. METHODS:We identified a total of 75 patients diagnosed with KRAS-mutant (determined by molecular sequencing) advanced NSCLC between 2014/5/9 and 2019/5/30. KRAS mutation subtypes were divided into G12C and non-G12C groups for statistical analysis. The clinicopathological characteristics and treatment survival benefit in all patients with a KRAS mutation were evaluated. Programmed death-ligand 1 (PD-L1) expression data were collected from 30 patients in the same cohort. RESULTS:In this study, 23 patients with stage IIIB NSCLC and 52 patients with stage IV NSCLC were enrolled with 58 men and 17 women; the median age was 60 years (39-84). All patients received regular chemotherapy/radiotherapy/targeted therapy/immune therapy as per the disease condition. Four main KRAS mutation subtypes were detected: G12C (33%), G12V (19%), G12A (12%), and G12D (12%). Three predominant KRAS comutations were detected: TP53-KRAS (31%), EGFR-KRAS (11%), and STK11-KRAS (8%). Compared with the KRAS non-G12C mutation subtype, patients with the KRAS G12C mutation had potentially longer progression-free survival (PFS) after first-line chemotherapy (4.7 vs. 2.5 months, p < 0.05). Pemetrexed-based chemotherapy appeared to be superior to taxanes- and gemcitabine-based chemotherapies in all patients (PFS: 5.0 vs. 1.5 and 2.3 months, respectively, p > 0.05). Cox regression analysis showed that the KRAS G12C mutation and pemetrexed-based first-line chemotherapy were positive influencers for PFS after first-line (hazard ratios = 0.31 and 0.55, respectively, P < 0.05), but not second-line chemotherapies. CONCLUSION:The KRAS G12C mutation could be a predictive biomarker for better survival benefit from first-line chemotherapy in patients with advanced NSCLC and KRAS mutations. The first-line chemotherapy regimen could possibly influence the outcome in patients with KRAS mutations. Larger and prospective clinical trials are warranted to confirm our conclusions.

Project description:Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.

Project description:BackgroundDiffusion weighted imaging (DWI) with intravoxel incoherent motion (IVIM) modelling can inform on tissue perfusion without exogenous contrast administration. Dynamic-contrast-enhanced (DCE) MRI can also characterise tissue perfusion, but requires a bolus injection of a Gadolinium-based contrast agent. This study compares the use of DCE-MRI and IVIM-DWI methods in assessing response to anti-angiogenic treatment in patients with colorectal liver metastases in a cohort with confirmed treatment response.MethodsThis prospective imaging study enrolled 25 participants with colorectal liver metastases to receive Regorafenib treatment. A target metastasis > 2 cm in each patient was imaged before and at 15 days after treatment on a 1.5T MR scanner using slice-matched IVIM-DWI and DCE-MRI protocols. MRI data were motion-corrected and tumour volumes of interest drawn on b=900 s/mm2 diffusion-weighted images were transferred to DCE-MRI data for further analysis. The median value of four IVIM-DWI parameters [diffusion coefficient D (10-3 mm2/s), perfusion fraction f (ml/ml), pseudodiffusion coefficient D* (10-3 mm2/s), and their product fD* (mm2/s)] and three DCE-MRI parameters [volume transfer constant Ktrans (min-1), enhancement fraction EF (%), and their product KEF (min-1)] were recorded at each visit, before and after treatment. Changes in pre- and post-treatment measurements of all MR parameters were assessed using Wilcoxon signed-rank tests (P<0.05 was considered significant). DCE-MRI and IVIM-DWI parameter correlations were evaluated with Spearman rank tests. Functional MR parameters were also compared against Response Evaluation Criteria In Solid Tumours v.1.1 (RECIST) evaluations.ResultsSignificant treatment-induced reductions of DCE-MRI parameters across the cohort were observed for EF (91.2 to 50.8%, P<0.001), KEF (0.095 to 0.045 min-1, P<0.001) and Ktrans (0.109 to 0.078 min-1, P=0.002). For IVIM-DWI, only D (a non-perfusion parameter) increased significantly post treatment (0.83 to 0.97 × 10-3 mm2/s, P<0.001), while perfusion-related parameters showed no change. No strong correlations were found between DCE-MRI and IVIM-DWI parameters. A moderate correlation was found, after treatment, between Ktrans and D* (r=0.60; P=0.002) and fD* (r=0.67; P<0.001). When compared to RECIST v.1.1 evaluations, KEF and D correctly identified most clinical responders, whilst non-responders were incorrectly identified.ConclusionIVIM-DWI perfusion-related parameters showed limited sensitivity to the anti-angiogenic effects of Regorafenib treatment in colorectal liver metastases and showed low correlation with DCE-MRI parameters, despite profound and significant post-treatment reductions in DCE-MRI measurements.Trial registrationNCT03010722 clinicaltrials.gov; registration date 6th January 2015.

Dataset Information

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

Publications

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

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