Dataset Information

Clinical and kinomic analysis identifies peripheral blood mononuclear cells as a potential pharmacodynamic biomarker in metastatic renal cell carcinoma patients treated with sunitinib.

ABSTRACT:

Background

Sunitinib is a protein tyrosine kinase (PTK) inhibitor that has immune-modulating properties. In this context, peripheral blood mononuclear cells (PBMC), mainly constituted by lymphocytes, could be a perfect surrogate tissue for identifying and assaying pharmacodynamic biomarkers of sunitinib. In this study, we investigated the changes in lymphocytes count as pharmacodynamic biomarker in metastatic renal cell carcinoma (mRCC) patients under sunitinib therapy. Thereafter, we studied the ex vivo effect of sunitinib and SU12262 (active metabolite) on PBMC from naïve mRCC patients using a high throughput kinomic profiling method.

Methods

The prognostic value of total lymphocytes count between Day 0 and Day 21 (expressed as a ratio D21/D0) was retrospectively investigated in 88 mRCC patients under sunitinib therapy. PTK PamChip® microarrays were used to explore prospectivelythe ex vivo effect of sunitinib and SU12662 on PTK activity in PBMC from 21 naïve mRCC patients.

Results

In this retrospective study, D21/D0 lymphocytes ratio (Hazard Ratio, 1.83; CI95%, 1.24-2.71; p=0.0023) was independently associated with PFS. Interestingly, kinomic analysis showed that D21/D0 lymphocytes ratio and Heng prognostic model was statistically associated with the ex vivo sunitinib and SU12662 effect in PBMC.

Conclusion

The present study highlights that D21/D0 total lymphocytes ratio could be a promising pharmacodynamic biomarker in mRCC patients treated with sunitinib. Additionally, it paves the way to investigate the kinomic profile in PBMC as a prognostic factor in a larger cohort of mRCC patients under sunitinib therapy.

SUBMITTER: Noe G

PROVIDER: S-EPMC5341893 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

Clinical and kinomic analysis identifies peripheral blood mononuclear cells as a potential pharmacodynamic biomarker in metastatic renal cell carcinoma patients treated with sunitinib.

Noé Gaёlle G Bellesoeur Audrey A Thomas-Schoemann Audrey A Rangarajan Savithri S Naji Faris F Puszkiel Alicja A Huillard Olivier O Saidu Nathaniel N Golmard Lisa L Alexandre Jerome J Goldwasser Francois F Blanchet Benoit B Vidal Michel M

Oncotarget 20161001 41

<h4>Background</h4>Sunitinib is a protein tyrosine kinase (PTK) inhibitor that has immune-modulating properties. In this context, peripheral blood mononuclear cells (PBMC), mainly constituted by lymphocytes, could be a perfect surrogate tissue for identifying and assaying pharmacodynamic biomarkers of sunitinib. In this study, we investigated the changes in lymphocytes count as pharmacodynamic biomarker in metastatic renal cell carcinoma (mRCC) patients under sunitinib therapy. Thereafter, we st ...[more]

PMID: 27589830

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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.

Dataset Information

Clinical and kinomic analysis identifies peripheral blood mononuclear cells as a potential pharmacodynamic biomarker in metastatic renal cell carcinoma patients treated with sunitinib.

Background

Methods

Results

Conclusion

Publications

Clinical and kinomic analysis identifies peripheral blood mononuclear cells as a potential pharmacodynamic biomarker in metastatic renal cell carcinoma patients treated with sunitinib.

Similar Datasets

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