Abstract 4667: Circulating microRNA profile predicts disease progression in patients receiving second-line treatment of lapatinib and capecitabine for metastatic pancreatic cancer. (2013)

Abstract Background: Serum microRNAs (miRNAs) have been reported as potential prognostic and/or predictive markers. We described an association between circulating miRNAs targeting the EGFR pathway and clinical outcomes in a phase II open-label, single arm study to evaluate the combination of lapatinib, a dual tyrosine kinase inhibitor of EGFR1 and HER-2, and capecitabine in treatment of metastatic pancreatic cancer. Methods: Seventeen patients with metastatic, gemcitabine-refractory pancreatic cancer received treatment of lapatinib 1,250 mg PO daily, and capecitabine 1,000 mg/m2 PO twice daily on days 1-14 of each 21-day cycle. The primary endpoint was median overall survival (OS). Serum samples were collected at baseline (before treatment) and every 3 weeks while on study. The expression profile of a panel of miRNAs that are focused on EGFR1 and HER-2 pathways (miR-16, miR-21, miR-210, miR-221, and miR-7) was analyzed for fold change in expression (compared to baseline). Results: Six of the 17 patients had disease progression after 2 cycles (nonresponders), 6 of 17 patients had stable disease and received more than 4 cycles (responders, range 4-22 cycles). The median PFS was 9 weeks (95% CI 7.1-18.9), median OS was 25 weeks (95% CI 11-34). 6-17% patients developed grade 3 adverse events including nausea, vomiting, diarrhea, limb edema and fatigue. Serum samples were collected serially from 8 patients (3 nonresponders and 5 responders). The mean survival from the time of enrollment was 6.5 months (median 6.5) in nonresponders v.s. 10.4 months (median 8.3) in responders. The miRNA analysis showed significant up-regulation of circulating miRNAs (target panel) at earlier time point (3-6 weeks) only in the nonresponders but not in the responders (fold change: 5.47 ± 1.47 v.s. 0.66 ± 0.08, p&amp;lt; 0.05). Moreover, in responders, no change (0.5-2 fold) or down-regulation (&amp;lt;0.5 fold) in the circulating miRNAs were observed at earlier time point (3-6 weeks), and the expression of miRNAs tend to increase with progression of the disease. Conclusions: The combination of lapatinib and capecitabine is a tolerated regimen for patients with gemcitabine-refractory pancreatic cancer. The increase in circulating miRNAs from a targeted panel (focused on EGFR1 and HER-2 pathway) as an early response is associated with poor prognosis and lack of response to lapatanib and capecitabine treatment. Our results offer justification to further evaluate the utility of the miRNA panel described here as a predictive non-invasive biomarker for routine use in the anti EGFR1/HER-2 treatment regimen. Citation Format: Zheng Wu, Narayan Shivapurkar, John L. Marshall, Jimmy Hwang, Michael J. Pishvaian, Tingting Zhuang, Anton Wellstein, Louis M. Weiner, Lisa Ley, Aiwu R. He. Circulating microRNA profile predicts disease progression in patients receiving second-line treatment of lapatinib and capecitabine for metastatic pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4667. doi:10.1158/1538-7445.AM2013-4667