Abstract 5448: In vitro drug response (IVDR), biomarkers (BM) and clinical outcome (CO) in malignant glioma (GM) patients

Abstract

Abstract Assessment of the tumor-associated (TA) response factors may serve to guide targeted salvage therapy. This is a retrospective correlative analysis of in vitro test results with clinical outcome of anonymized patients with MG. In a centralized testing facility, IVDR to at least ten chemotherapeutic drugs (Chemo) and immunohistochemistry (IHC)-derived TA BMs (including Ki67, p53, EGFR, MGMT, GSTpi, and MDR-1) were assessed in viable tumor resections from 65 previously treated (PT) and untreated (UT) patients with progressive and recurrent MGs (10 astrocytomas [A], 36 glioblastoma multiforme [GBM], and 19 gliomas of various histology), and correlated results with CO (response [RES] and time to progression [TTP]). IVDR results were generated by exposing aliquots of tumor cell suspensions to single agent Chemo at physiologic doses for 5-days, and determining the percentage of cell growth inhibition (PCI) via tritium uptake. Chemo included Camptothecin (SN-38 is active species), Carmustine (BCNU), platinum analogs Carboplatin (CARBO) and cisplatin (CP), Temozolomide (TEMO) and Dacarbazine (DTIC). For each drug tested, tumor responses were categorized into either extreme drug resistance (EDR) or Intermediate plus Low Drug Resistance [IDR/LDR]. Standard IHC tests on paraffin-embedded tumor tissue sections yielded BM expression from which frequency rates were determined. Patients’ resections and treatments were performed at a single medical center between 1994 and 1998; and included surgery alone or combined with irradiation (XRT) and single-agent or combination Chemo. Biopsies were obtained from recurrent patients prior to second-line therapy. The median time between treatment and TTP or recurrence was 10 months. For each drug, IVDR profiles were comparatively similar, with the exception of tumors from PT patients which were significantly more resistant to CARBO (N = 20; 2-tailed t test, p = 0.0433) and CPLAT (N = 22; p = 0.0076). Frequencies of BM expression between PT (N = 29) and UT patients (N = 54) were similar among tumor types, except for GBMs from patients who progressed following treatment. Their tumors generally overexpressed EGFR (1.8-fold) and MGMT (2.4-fold). Patients’ overall RES rate was 24%, while rates for A (33%), GBMs (6%) and other gliomas (58%) differed significantly (Fisher exact test, p = 0.0104). Most patients (81%) exhibited PD following therapy, and had relatively similar EDR vs. IDR/LDR response profiles for median TTP (10 months vs. 10 months), and median survival. For TEMO, CPT-11, and BCNU - common drugs used against MGs, there were no significant differences in median TTP, median survival, or overall survival (Log-rank, p<0.05, p = 0.1301 and p = 0.6123, respectively). Results suggest that a detailed assessment of molecular mechanisms related to IVDR and TA BMs may be required to identify (non)response factors that facilitate stratifying patient treatment leading to improved CO. Citation Format: Ricardo J. Parker, Michael Myers, Patric Schiltz. In vitro drug response (IVDR), biomarkers (BM) and clinical outcome (CO) in malignant glioma (GM) patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5448. doi:10.1158/1538-7445.AM2015-5448