Abstract P4-01-03: HDACi (vorinostat) in metastatic breast cancer to restore sensitivity to ER-directed (AI) therapy: A phase II clinical trial with FES imaging correlates

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 24_Supplement; pp. P4 - P4-01-03
• Main Authors: Linden, HM, Kurland, BF, Link, JM, Novakova, A, Chai, X, Specht, JM, Gadi, VK, Gralow, JR, Schubert, EK, Peterson, LM, Eary, J, Shields, A, Mankoff, DA, Krohn, KA
• Format: Journal Article
• Language: English
• Published: 15.12.2013
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS13-P4-01-03

Abstract Background: Histone deacetylase inhibitors (HDACi) have shown pre-clinical promise in estrogen receptor(ER)-modulation and restoring sensitivity to endocrine manipulation, suggesting potential clinical benefit (Sabnis 2011) (Huang 2000) in ER+ breast cancer. Vorinostat is an FDA-approved HDACi for CTCL, and could have a beneficial role in restoring ER-signaling in endocrine-resistant tumors (Munster 2011) (Yardley 2011). [F-18]fluoroestradiol (FES) PET imaging may be used to monitor regional tumor ER expression in patients with breast cancer (Linden 2011). Methods: Patients with metastatic breast cancer with prior clinical benefit from endocrine manipulation who progressed on an AI therapy are eligible for this ongoing trial. In part A, patients were given vorinostat for 2 weeks, then resumed AI for 6 W. In part B (reflecting results of prior HDACi trials) patients are given vorinostat 400mg po daily 5/7 days 3/4 weeks while AI is given continuously. Paired FES and FDG PET are performed at baseline, week 2 and 8; clinical/radiologic assessment of disease is also performed at week 8. Patients with clinical benefit (response or stable disease) may continue on treatment until progressive disease or study withdrawal. Lesion-level analysis of the association between baseline FES uptake (logged) and FES/FDG ratio used generalized estimating equations (GEE) with small-sample adjustments to standard errors. Results: 12/ 20 planned patients have accrued, and the treatment is well tolerated. Enrolled women were postmenopausal, the majority with primary infiltrating ductal tumors, bone/soft tissue dominant with longstanding metastatic disease, exposed to multiple endocrine and chemotherapy regimens. Five patients have had clinical benefit (2/4 on part B with greater HDACi exposure). One patient withdrew from the study due to toxicity. FES and FDG uptake was analyzed in 42 lesions in 11 patients. Average FES uptake was 2.0 (SULmean) for patients with clinical benefit, and 1.2 in patients with progressive disease by 8 weeks (p = 0.09). FES/FDG ratio at baseline was also associated with response (p = 0.04). Conclusions: HDACi therapy is promising in relapsed ER+ breast cancer. Imaging of metabolic pathways in parallel with clinical trials may accelerate understanding of the underlying tumor biology and refine treatment selection. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-03.