Abstract C123: Pharmacogenomic analysis of patients newly diagnosed with glioblastoma multiforme treated with capecitabine concurrent with radiation therapy: Gene expression profiles associated with clinical outcome
Authors: Grunda Jessica M. , Nabors L. Burt , Fiveash John B. , Fathallah-Shaykh Hassan M. , Cantor Alan B. , Palmer Cheryl A. , Johnson Martin R. 
Published: June 2012

Purpose: Previous pharmacogenomic studies of glioblastoma multiforme (GBM) tissues and xenograft models suggested that concurrent administration of capecitabine and radiation could be an effective new treatment modality for GBM. In the current study, toxicity and outcome to this treatment regimen was clinically investigated and the expression of genes previously associated with capecitabine and radiotherapy response were assessed with the ultimate goal of exploring gene expression-based predictor models of patient outcome.

Methods: Eighteen patients diagnosed with primary GBM received capecitabine at 625 mg/m2 BID (escalating by 25%) concurrently with irradiation (60 Gy in 30 fractions) for 6 weeks followed by 4 weeks of capecitabine only. Following a one-week hiatus, patients received maintenance capecitabine (1250 mg/m2 BID) for 14 days every 3 weeks until progression or unacceptable toxicity. Patient time-to-progression (TTP) and overall survival (OS) were assessed using the Kaplan and Meier method. Expression analysis of 94 genes involved in capecitabine metabolism and radiation response was performed on resected and biopsied GBM tissues obtained prior to therapy. The relationship between gene expression and outcome (TTP and OS) was investigated using a semi-supervised statistical approach incorporating univariate Cox proportional hazards regression, semi-supervised principle component analysis (SSPCA), and class prediction modeling.

Results: The maximum tolerated dose of capecitabine was identified as 625 mg/m2 BID, with no unexpected toxicities observed. Median patient TTP and OS were 247 and 367 days respectively. Cox regression analysis demonstrated a significant association between the expression of 24 genes and TTP and/or OS (p&lt;0.025). Subsequent SSPCA identified two GBM patient populations that were significantly different in both TTP (p = 0.005) and OS (p = 0.015), which were subsequently designated as poor and good outcome subgroups. Class prediction modeling of the patient subgroups identified an 8 gene expression-based predictor model (RAD54B, FRAP1, DCTD, APEX2, TK1, RRM2, SLC29A1, and ERCC6) that accurately classified all patients as either good or poor outcome.

Conclusions: Capecitabine and concurrent radiation for newly diagnosed GBM appears safe and well tolerated without unexpected toxicities. Assessment of patient TTP and OS suggests capecitabine radiotherapy is comparable to the currently accepted standard of care of concurrent temozolomide radiotherapy and warrants further clinical investigation. Importantly, these exploratory studies identified a gene expression profile predictive of patient outcome that may be useful in the future stratification of GBM patients for capecitabine therapy.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C123.