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Prospective Feasibility Trial for Genomics-Informed Treatment in Recurrent and Progressive Glioblastoma.

ABSTRACT: Purpose: Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma.Experimental Design: We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome-wide tumor/normal exome sequencing and tumor RNA sequencing were performed to identify molecular targets for potential matched therapy. A multidisciplinary molecular tumor board issued treatment recommendations based on the genomic results, blood-brain barrier penetration of the indicated therapies, drug-drug interactions, and drug safety profiles. Feasibility of generating genomics-informed treatment recommendations within 35 days of surgery was assessed.Results: Of the 20 patients enrolled in the study, 16 patients had sufficient tumor tissue for analysis. Exome sequencing was completed for all patients, and RNA sequencing was completed for 14 patients. Treatment recommendations were provided within the study's feasibility time frame for 15 of 16 (94%) patients. Seven patients received treatment based on the tumor board recommendations. Two patients reached 12-month progression-free survival, both adhering to treatments based on the molecular profiling results. One patient remained on treatment and progression free 21 months after surgery, 3 times longer than the patient's previous time to progression. Analysis of matched nonenhancing tissue from 12 patients revealed overlapping as well as novel putatively actionable genomic alterations.Conclusions: Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system-penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma. Clin Cancer Res; 24(2); 295-305. ©2017 AACRSee related commentary by Wick and Kessler, p. 256.

SUBMITTER: Byron SA

PROVIDER: S-EPMC7516926 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Prospective Feasibility Trial for Genomics-Informed Treatment in Recurrent and Progressive Glioblastoma.

Byron Sara A SA Tran Nhan L NL Halperin Rebecca F RF Phillips Joanna J JJ Kuhn John G JG de Groot John F JF Colman Howard H Ligon Keith L KL Wen Patrick Y PY Cloughesy Timothy F TF Mellinghoff Ingo K IK Butowski Nicholas A NA Taylor Jennie W JW Clarke Jennifer L JL Chang Susan M SM Berger Mitchel S MS Molinaro Annette M AM Maggiora Gerald M GM Peng Sen S Nasser Sara S Liang Winnie S WS Trent Jeffrey M JM Berens Michael E ME Carpten John D JD Craig David W DW Prados Michael D MD

Clinical cancer research : an official journal of the American Association for Cancer Research 20171026 2

<b>Purpose:</b> Glioblastoma is an aggressive and molecularly heterogeneous cancer with few effective treatment options. We hypothesized that next-generation sequencing can be used to guide treatment recommendations within a clinically acceptable time frame following surgery for patients with recurrent glioblastoma.<b>Experimental Design:</b> We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome- ...[more]

PMID: 29074604

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Project description:BackgroundChemotherapy-resistant cancer stem cells (CSC) may lead to tumor recurrence in glioblastoma (GBM). The poor prognosis of this disease emphasizes the critical need for developing a treatment stratification system to improve outcomes through personalized medicine.MethodsWe present a case series of 12 GBM and 2 progressive anaplastic glioma cases from a single Institution prospectively treated utilizing a CSC chemotherapeutics assay (ChemoID) guided report. All patients were eligible to receive a stereotactic biopsy and thus undergo ChemoID testing. We selected one of the most effective treatments based on the ChemoID assay report from a panel of FDA approved chemotherapy as monotherapy or their combinations for our patients. Patients were evaluated by MRI scans and response was assessed according to RANO 1.1 criteria.ResultsOf the 14 cases reviewed, the median age of our patient cohort was 49 years (21-63). We observed 6 complete responses (CR) 43%, 6 partial responses (PR) 43%, and 2 progressive diseases (PD) 14%. Patients treated with ChemoID assay-directed therapy, in combination with other modality of treatment (RT, LITT), had a longer median overall survival (OS) of 13.3 months (5.4-NA), compared to the historical median OS of 9.0 months (8.0-10.8 months) previously reported. Notably, patients with recurrent GBM or progressive high-grade glioma treated with assay-guided therapy had a 57% probability to survive at 12 months, compared to the 27% historical probability of survival observed in previous studies.ConclusionsThe results presented here suggest that the ChemoID Assay has the potential to stratify individualized chemotherapy choices to improve recurrent and progressive high-grade glioma patient survival.Importance of the studyGlioblastoma (GBM) and progressive anaplastic glioma are the most aggressive brain tumor in adults and their prognosis is very poor even if treated with the standard of care chemoradiation Stupp's protocol. Recent knowledge pointed out that current treatments often fail to successfully target cancer stem cells (CSCs) that are responsible for therapy resistance and recurrence of these malignant tumors. ChemoID is the first and only CLIA (clinical laboratory improvements amendment) -certified and CAP (College of American Pathologists) -accredited chemotherapeutic assay currently available in oncology clinics that examines patient's derived CSCs susceptibility to conventional FDA (Food and Drugs Administration) -approved drugs. In this study we observed that although the majority of our patients (71.5%) presented with unfavorable prognostic predictors (wild type IDH-1/2 and unmethylated MGMT promoter), patients treated with ChemoID assay-directed therapy had an overall response rate of 86% and increased median OS of 13.3 months compared to the historical median OS of 9.1 months (8.1-10.1 months) previously reported [1] suggesting that the ChemoID assay may be beneficial in personalizing treatment strategies.

Project description:BACKGROUND:Despite the well described heterogeneity in glioblastoma (GBM), treatment is standardized, and clinical trials investigate treatment effects at population level. Genomics-driven oncology for stratified treatments allow clinical decision making in only a small minority of screened patients. Addressing tumor heterogeneity, we aimed to establish a clinical translational protocol in recurrent GBM (recGBM) utilizing autologous glioblastoma stem cell (GSC) cultures and automated high-throughput drug sensitivity and resistance testing (DSRT) for individualized treatment within the time available for clinical application. RESULTS:From ten patients undergoing surgery for recGBM, we established individual cell cultures and characterized the GSCs by functional assays. 7/10 GSC cultures could be serially expanded. The individual GSCs displayed intertumoral differences in their proliferative capacity, expression of stem cell markers and variation in their in vitro and in vivo morphology. We defined a time frame of 10 weeks from surgery to complete the entire pre-clinical work-up; establish individualized GSC cultures, evaluate drug sensitivity patterns of 525 anticancer drugs, and identify options for individualized treatment. Within the time frame for clinical translation 5/7 cultures reached sufficient cell yield for complete drug screening. The DSRT revealed significant intertumoral heterogeneity to anticancer drugs (p?<?0.0001). Using curated reference databases of drug sensitivity in GBM and healthy bone marrow cells, we identified individualized treatment options in all patients. Individualized treatment options could be selected from FDA-approved drugs from a variety of different drug classes in all cases. CONCLUSIONS:In recGBM, GSC cultures could successfully be established in the majority of patients. The individual cultures displayed intertumoral heterogeneity in their in vitro and in vivo behavior. Within a time frame for clinical application, we could perform DSRT in 50% of recGBM patients. The DSRT revealed a remarkable intertumoral heterogeneity in sensitivity to anticancer drugs in recGBM that could allow tailored therapeutic options for functional precision medicine.

Project description:Abstract BACKGROUND: Glioblastoma (GBM) is the most aggressive primary brain tumor that virtually always recurs with no established standard therapy at recurrence. Median survival after recurrence is 7-12 months. Selective internal radiation therapy (SIRT) with Yttrium-90 (Y90) glass microspheres (TheraSphere™, Boston Scientific, Marlborough, MA) is an FDA approved standard treatment for hepatocellular carcinoma, and represents a novel strategy to treat regionally localized brain tumors. We are conducting a first-in-human clinical trial (under IDE) using Y90 microspheres modified to treat tumors in the brain. The goal of selectively delivering Y90 intra-arterially is to achieve higher tumoral absorbed doses while limiting non-target exposure. DESIGN: The primary objective is to evaluate the safety of Y90 microspheres treatment. Target enrollment is 12 patients at 5 participating medical centers. Key inclusion criteria include: 1st or 2nd recurrence of GBM , size 1-5cm, located in the non-dominant hemisphere in a non-eloquent region, accessible neurovascular anatomy for single intra-arterial treatment based on a diagnostic cerebral angiogram. After consent, patients will undergo screening angiography and imaging that be reviewed by the trial steering committee to determine treatment suitability. Treatment consists of Y90 microspheres administered intra-arterially to deliver 40Gy ± 10% to the treatment volume. Post-administration Y90 PET and MRI images allow assessment of dose distribution and acute safety. Following overnight admission, patients will be followed as outpatients weekly x 4, and then monthly up to month 6. Primary endpoints include treatment-related limiting toxicities, dose limiting toxicity defined as non-hematological toxicities ≥ grade 3, CNS toxicity ≥ grade 3 (eg. symptomatic ischemia or edema) related to non-target embolization, occurring through 30 days post procedure. Secondary endpoints include: treatment-related serious adverse events, change in post-treatment neurological function, technical success, objective response rate, progression-free survival, and overall survival. The study is registered with clinicaltrials.gov, number: NCT05303467.

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Prospective Feasibility Trial for Genomics-Informed Treatment in Recurrent and Progressive Glioblastoma.

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Prospective Feasibility Trial for Genomics-Informed Treatment in Recurrent and Progressive Glioblastoma.

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