RESUMEN
PURPOSE: The anticancer activity of valproic acid (VPA) is attributed to the inhibition of histone deacetylase. We previously published the genomically derived sensitivity signature for VPA (GDSS-VPA), a gene expression biomarker that predicts breast cancer sensitivity to VPA in vitro and in vivo. We conducted a window-of-opportunity study that examined the tolerability of VPA and the ability of the GDSS-VPA to predict biologic changes in breast tumors after treatment with VPA. PATIENTS AND METHODS: Eligible women had untreated breast cancer with breast tumors larger than 1.5 cm. After a biopsy, women were given VPA for 7 to 12 days, increasing from 30 mg/kg/d orally divided into two doses per day to a maximum of 50 mg/kg/d. After VPA treatment, serum VPA level was measured and then breast surgery or biopsy was performed. Tumor proliferation was assessed by using Ki-67 immunohistochemistry. Histone acetylation of peripheral blood mononuclear cells was assessed by Western blot. Dynamic contrast-enhanced magnetic resonance imaging scans were performed before and after VPA treatment. RESULTS: Thirty women were evaluable. The median age was 54 years (range, 31-73 years). Fifty-two percent of women tolerated VPA at 50 mg/kg/d, but 10% missed more than two doses as a result of adverse events. Grade 3 adverse events included vomiting and diarrhea (one patient) and fatigue (one patient). The end serum VPA level correlated with a change in histone acetylation of peripheral blood mononuclear cells (ρ = 0.451; P = .024). Fifty percent of women (three of six) with triple-negative breast cancer had a Ki-67 reduction of at least 10% compared with 17% of other women. Women whose tumors had higher GDSS-VPA were more likely to have a Ki-67 decrease of at least 10% (area under the curve, 0.66). CONCLUSION: VPA was well tolerated and there was a significant correlation between serum VPA levels and histone acetylation. VPA treatment caused a decrease in proliferation of breast tumors. The genomic biomarker correlated with decreased proliferation. Inhibition of histone deacetylase is a valid strategy for drug development in triple-negative breast cancer using gene expression biomarkers.
RESUMEN
INTRODUCTION: Erlotinib improves survival in patients with advanced non-small cell lung cancer who have been previously treated with systemic chemotherapy. The current trial was designed to evaluate erlotinib as a primary therapy before chemotherapy in patients with minimally restricted eligibility criteria. METHODS: Eligibility criteria included stage IIIB/IV or recurrent non-small cell lung cancer, no prior chemotherapy for systemic disease, performance status = 0 to 1, no history of brain metastases, and weight loss less than 10%. Patients received erlotinib 150 mg/d until objective or symptomatic progression when they were offered conventional chemotherapy. The primary end point was progression-free survival. RESULTS: Forty patients were accrued. The median age was 65 years, 35 had performance status = 1, 8 were never-smoker, and 23 were former smokers. Histologies were adenocarcinoma in 22 and squamous cell in six. The major toxicity was rash (grade 1, 12; grade 2, 16; grade 3, 3). Partial responses were observed in six (15%), stable in 11 (28%), and progressive disease in 23 (58%). The median time on erlotinib was 8 weeks. The median survival was 50 weeks with 1, 2, and 3 years survivals of 44%, 18%, and 16%. Retrospective epidermal growth factor receptor mutational analysis was performed in 18 subjects and four mutations (22%) were identified. Only 25 patients have received subsequent chemotherapy (too early, 4; refused, 9; and unable because of performance status, 2), and, of these, 9 (36%) achieved unconfirmed responses. CONCLUSIONS: Despite a modest response rate, lack of enrichment for never-smokers and absence of conventional chemotherapy in many patients, the median and long-term survivals were comparable with those expected after conventional sequencing of chemotherapy. Erlotinib as initial therapy was well tolerated and warrants randomized evaluation as first-line treatment for advanced lung cancer.
