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Soluble KIT correlates with clinical outcome in patients with metastatic breast cancer treated with sunitinib.

ABSTRACT: Sunitinib inhibits vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors, and stem cell factor receptor (KIT). The ability of soluble (s)KIT, VEGF-A, sVEGFR-2, and sVEGFR-3 to predict clinical outcome was analyzed in 61 patients with previously treated metastatic breast cancer (MBC) in a phase II study of sunitinib monotherapy (ClinicalTrials.gov NCT00078000).Plasma concentrations of soluble proteins were measured at baseline and during treatment with sunitinib 50 mg/day (4 weeks on treatment, 2 weeks off treatment). Baseline concentrations and maximal percent change during the first two treatment cycles were stratified by median values and evaluated for correlation with median time to tumor progression (TTP) and overall survival (OS). This latter fixed time period was chosen to avoid bias accruing from patients who were on study for longer periods of time.TTP was significantly longer in patients having median or higher maximal percent sKIT change compared with patients with less than the median change (21.7 vs. 7.9 weeks; p < 0.0001). Similarly, OS was significantly longer in patients having median or higher sKIT change versus less than the median change (53.7 vs. 25.7 weeks; p = 0.018). Significant prolongation of OS (62.6 vs. 32.3 weeks; p = 0.032), but not TTP, was observed in patients with a median or higher maximal percent VEGF-A change compared with less than the median change. Maximal percent change of sVEGFR-2 or sVEGFR-3 concentrations and baseline concentrations of all four proteins were not predictive of clinical outcome.This exploratory analysis suggests that changes in sKIT and possibly VEGF-A early during sunitinib treatment may be predictive of clinical outcome in MBC.

SUBMITTER: Keyvanjah K

PROVIDER: S-EPMC3499375 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Soluble KIT correlates with clinical outcome in patients with metastatic breast cancer treated with sunitinib.

Keyvanjah Kiana K DePrimo Samuel E SE Harmon Charles S CS Huang Xin X Kern Kenneth A KA Carley William W

Journal of translational medicine 20120816

<h4>Background</h4>Sunitinib inhibits vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors, and stem cell factor receptor (KIT). The ability of soluble (s)KIT, VEGF-A, sVEGFR-2, and sVEGFR-3 to predict clinical outcome was analyzed in 61 patients with previously treated metastatic breast cancer (MBC) in a phase II study of sunitinib monotherapy (ClinicalTrials.gov NCT00078000).<h4>Methods</h4>Plasma concentrations of soluble proteins were measured at ba ...[more]

PMID: 22897944

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Project description:PurposeWe identified sunitinib alternative schedules that maintained dose intensity while decreasing adverse events in patients with metastatic renal cell cancer. We also determined the impact of alternative schedules on clinical outcomes.Materials and methodsWe retrospectively reviewed the records of patients 18 years old or older with clear cell metastatic renal cell cancer who received first line sunitinib between January 26, 2006 and March 1, 2011 at our major comprehensive cancer center. A subset of patients was switched at the first intolerable adverse event from the traditional schedule of 28 days on and 14 days off to a schedule of 14 days on and 7 days off or other alternative schedules. A control group underwent standard dose reduction. We estimated progression-free and overall survival by the Kaplan-Meier method. Predictors of progression-free and overall survival were analyzed using Cox regression.ResultsA total of 187 patients were included in analysis, of whom 87% were on the traditional schedule at baseline. During treatment 53% of patients continued on the traditional schedule and 47% began or were transitioned to alternative schedules. Baseline characteristics were similar. Adverse events prompting schedule modification included fatigue in 64% of cases, hand-foot syndrome in 38% and diarrhea in 32%. Median time to alternative schedules was 5.6 months. Median overall survival was 17.7 months (95% CI 10.8-22.2) on the traditional schedule compared to 33.0 months (95% CI 29.3-not estimable) on alternative schedules (p <0.0001). On multivariable analysis poor Eastern Cooperative Oncology Group (ECOG) performance status, increased lactate dehydrogenase, decreased albumin, unfavorable Heng criteria and the traditional schedule were associated with decreased overall survival (p <0.05).ConclusionsSunitinib administered on alternative schedules may mitigate adverse events while achieving outcomes comparable to those of the traditional schedule in patients with metastatic renal cell cancer. Prospective investigations of alternate dosing schemas are warranted.

Project description:BACKGROUND:Nivolumab is an anti-PD1 checkpoint inhibitor active in patients with advanced melanoma and as adjuvant therapy in high-risk metastatic melanoma patients. METHODS:In this single-center retrospective analysis, we investigated the CD73 enzyme activity in patients with metastatic melanoma stage IV and its correlation with the response to nivolumab. The soluble CD73 (sCD73) enzyme activity was measured in the serum of 37 melanoma patients before receiving nivolumab and the Harrel's C index was used to find the best cut-off for this biomarker. The multivariate Cox proportional hazard model was used to evaluate the prognostic value of CD73 enzyme activity for survival and progression-free survival. RESULTS:Our results show that high levels of sCD73 enzyme activity were significantly associated with poor overall survival and progression-free survival in patients with metastatic melanoma. The median progression-free survival was 2.6 months [95% confidence interval (CI) 1.9-3.3] in patients with high sCD73 enzyme activity (> 27.8 pmol/min/mg protein), and 14.2 months (95% CI 4.6-23.8) in patients with lower CD73 enzyme activity, when patients were follow-up for a median of 24 months range. The median overall survival was not reached in patients with low sCD73 activity (< 27.8 pmol/min/mg protein) compared with 6.1 months (95% CI 0-14.8) in patients with higher sCD73 activity. In multivariate analyses, the sCD73 enzyme activity emerged as the strongest prognostic factor for overall survival and progression-free survival. Elevated basal levels of sCD73 enzyme activity, before starting nivolumab treatment, were associated with lower response rates to therapy. CONCLUSIONS:We observed a significant association between the activity of sCD73 in the blood and clinical outcomes in patients with metastatic melanoma stage IV, receiving nivolumab. Although our results need to be confirmed and validated, we suggest that sCD73 might be used as serologic prognostic biomarker. Potentially evaluating sCD73 enzyme activity in the peripheral blood before treatment could help to estimate the response to nivolumab.

Project description:Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-? (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population.This is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre-imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson ?(2) test) in the same molecular subgroups.Of the 1124 sunitinib-treated patients in the treatment-use study, 230 (20%) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39-0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy of sunitinib treatment.This large retrospective analysis confirms the prognostic significance of KIT mutation status in patients with GIST. This analysis also confirms the effectiveness of sunitinib as a post-imatinib therapy, regardless of mutational status.NCT01459757.

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Soluble KIT correlates with clinical outcome in patients with metastatic breast cancer treated with sunitinib.

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Soluble KIT correlates with clinical outcome in patients with metastatic breast cancer treated with sunitinib.

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