A new prognostic classification may help clinical decision-making in glioblastoma
Columbus, Ohio – New research shows that taking molecular variables into account will improve the prognostic classification of the lethal brain cancer called glioblastoma (GBM).
The study was led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
Published in the journal JAMA Oncology, the study found that adding significant molecular biomarkers to the existing GBM classification system improves the prognostic classification of GBM patients who have been treated with radiation and the drug temozolomide.
The current model has been used internationally for nearly two decades and is based on clinical variables alone. It was created before the introduction of temozolomide, which, along with radiation, is the current standard of care for GBM.
The new, refined classification was derived using samples from 452 GBM patients treated with radiation and temozolomide. It includes such key molecular markers as MGMT- and c-MET-protein expression, along with clinical variables including age, performance status, extent of resection and neurological function.
The researchers validated the model in an independent group of 196 patients.
"Our study has established and independently validated a novel molecular classification of glioblastoma, perhaps the most aggressive of all human malignancies," says principal investigator Arnab Chakravarti, MD, chair and professor of Radiation Oncology and co-director of the Brain Tumor Program.
"The revised model offers a more accurate assessment of prognostic groups in GBM patients who have been treated with radiation and temozolomide.
"We believe that incorporating c-MET and MGMT protein expression enhances the prognostic classification of glioblastoma patients over and above the traditional clinical variables, and that it will improve clinical decision making," says Chakravarti, who is also the Max Morehouse Chair in Cancer Research at Ohio State. "Furthermore, the inclusion of MGMT protein provides insight into the potential for resistance to radiation and temozolomide."
More than 11,880 new cases of GBM were estimated to occur in 2015, with overall survival averaging 12 to 15 months.
The five-year survival rate for GBM is 5 percent in the United States. However, a small subset of patients experiences longer survival, which suggests the presence of underlying tumor differences and the need for a better prognostic classification model.
For this study, Chakravarti and his colleagues used tissue samples obtained from the clinical trial RTOG 0525 (Clinicaltrials.gov identifier NCT00304031), a phase III trial that compared standard adjuvant temozolomide with a dose-dense schedule in patients with newly diagnosed GBM.
The researchers analyzed expression levels of 22 proteins for prognostic significance of overall survival.
Key technical findings include:
- Higher MGMT protein level was significantly associated with decreased MGMT promoter methylation and vice-versa;
- MGMT protein expression had greater prognostic value for overall survival compared with MGMT promoter methylation;
- The new model significantly improves outcome stratification over both the current model and over MGMT promoter methylation.
"There is a critical need for a more refined, molecularly based classification of glioblastoma in this era of temozolomide therapy," Chakravarti says. "Our model can be used to stratify GBM patients for future clinical studies on the global level."
Other researchers involved in this study were Erica HlavinBell, Joseph P. McElroy, Aline P. Becker, Andrea L. Salavaggione, The Ohio State University; Stephanie L. Pugh, Minhee Won, MA, NRG Oncology Statistics and Data Management Center, Philadelphia; Mark R. Gilbert, National Institutes of Health; Minesh Mehta, University of Maryland Medical Systems, now with Miami Cancer Institute; Alexander C. Klimowicz, University of Calgary; Anthony Magliocco, Moffitt Cancer Center; Markus Bredel, University of Alabama; Pierre Robe, Utrecht Cancer Center, Netherlands; Anca-L. Grosu, University of Freiburg, Germany; Roger Stupp, University Hospital Zurich, Switzerland; Walter Curran Jr, Emory University; Jill S. Barnholtz-Sloan, Case Western Reserve University; Kenneth Aldape, Paul D. Brown, MD Anderson Cancer Center; Deborah T. Blumenthal, Tel-Aviv Sourasky Medical Center, Israel; Jon Glass, Thomas Jefferson University Hospital, Philadelphia; Luis Souhami, McGill University Health Centre, Montreal; R. Jeffrey Lee, Intermountain Medical Center, Murray, Utah; David Brachman, Arizona Oncology Services Foundation; John Flickinger, UPMC-Shadyside Hospital, Pittsburgh.
About the OSUCCC – James
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 47 National Cancer Institute-designated Comprehensive Cancer Centers and one of only a few centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer drugs sponsored by NCI. As the cancer program's 308-bed adult patient-care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet designation, the highest honor an organization can receive for quality patient care and professional nursing practice. At 21 floors with more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care. For more information, please visit cancer.osu.edu.