Silencing of the DNA-repair MGMT gene via promoter methylation is presently the only clinically relevant predictive biomarker for patients with glioblastoma and, increasingly, a critical eligibility criterion for clinical trial participation.1,2 Consequently, National Comprehensive Cancer Network guidelines recommend testing all newly diagnosed glioblastomas.3 Promoter methylation status of MGMT is particularly important for clinical decision-making for patients who are elderly or frail, who are less able to tolerate multimodal therapy and for whom temozolomide can be withheld due to its limited benefit in MGMT-unmethylated cases.2 Herein we evaluate the national practice patterns of MGMT testing and identify potential factors associated with access to testing.
The National Cancer Database contains data on more than 70% of patients with newly diagnosed cancer in the US. With Partners HealthCare institutional review board approval, patients (≥40 years old) diagnosed with histologically confirmed glioblastoma, World Health Organization grade IV, between 2010 and 2016 were identified using International Classification of Diseases for Oncology, Third Edition coding and collaborative staging brain-specific variables.4 Only patients with complete data encoded for MGMT testing (38.2% of identified cases) from their diagnosing institution were included. Patient informed consent was waived by the institutional review board owing to the deidentified nature of the data analyzed in this study.
The primary outcome was receipt of MGMT promoter methylation testing. Lack of testing was defined as “test not done (test not ordered and not performed).” Univariable associations were assessed by Fisher exact or χ2 tests. Multivariable logistic regression was used to evaluate the associations between patients’ demographic and socioeconomic characteristics and testing, and between testing and receiving chemotherapy. Multivariable Cox regression was used to assess the association of testing with overall survival (OS). Stata, version 15.1 (StataCorp), was used for analyses (2-sided α = .05).
Out of a total of 12 830 patients evaluated, 56.9% with newly diagnosed glioblastoma received MGMT testing, increasing to 73.6% by 2016. Patients who were elderly, uninsured, insured through Medicaid, from poorer quartiles of households or low-population urban/rural areas, or diagnosed at community programs independently received less testing (Table 1). Among patients with Karnofsky Performance Scale (KPS) data (n = 1937), testing was more likely for favorable status (KPS ≥70; 1013/1474 [68.7%]) than poor status (KPS <70; 284/463 [61.3%]; P = .003). Patients who were Hispanic (52.5%) or Black non-Hispanic (52.5%) were less likely to be tested than those who were White non-Hispanic (57.3%) or Asian/Pacific Islander (56.5%; P = .01), but not independently so following multivariable adjustment.
Whereas 5618 patients out of 7303 (76.9%) with MGMT-tested glioblastoma received chemotherapy (2272/2936 [77.4%] of MGMT-methylated and 3346/4367 [76.6%] of MGMT-unmethylated cases), only 3739 (67.6%) untested patients received chemotherapy (Table 2). Lack of testing was associated with similar unadjusted OS as MGMT-unmethylated tumors and with an intermediate adjusted OS between MGMT-methylated and MGMT-unmethylated tumors.
Using US national data, we found that patients with newly diagnosed glioblastoma who were uninsured, insured through Medicaid, from poorer households or low-population urban or rural areas, or diagnosed at community hospitals were disproportionately less likely to receive MGMT testing. Although testing rates improved by 2016 across all settings—likely reflecting the growing awareness of the clinical importance of MGMT status (eg, NOA-08, Nordic-ISRCTN81470623, RTOG-0525) and its integration into national guidelines—testing still lagged for the aforementioned patient populations.1,2
Additionally, testing was underused for patients who were elderly or who had poor performance status, populations that would most benefit from MGMT testing-guided deescalation of combined therapy. These testing disparities appeared to influence patients’ management: patients who were untested received less chemotherapy and had intermediate adjusted survival between that of patients who were MGMT methylated and MGMT unmethylated, suggesting that untested glioblastomas comprise a mix of methylation statuses whose management could be improved by appropriate testing. Notable limitations included the database’s limited details about test types and timing.
The results of this study indicate that substantial socioeconomic and care setting disparities exist in the testing of this important biomarker for patients with glioblastoma. With MGMT status increasingly becoming a critical trial eligibility criterion, failure to test in a timely manner will compound existing barriers to patients’ access to clinical trials.5,6 Future studies are needed to define how these disparities in MGMT promoter methylation testing arise and to help develop strategies to ensure equitable access to quality oncologic care for patients with glioblastoma.
Accepted for Publication: July 29, 2020.
Corresponding Author: J. Bryan Iorgulescu, MD, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115 (email@example.com).
Published Online: October 22, 2020. doi:10.1001/jamaoncol.2020.4937
Author Contributions: Dr Iorgulescu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Smith, Iorgulescu.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Lamba, Smith, Reardon, Iorgulescu.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Smith, Iorgulescu.
Obtained funding: Iorgulescu.
Administrative, technical, or material support: Lamba, Iorgulescu.
Supervision: Smith, Ligon, Reardon, Iorgulescu.
Conflict of Interest Disclosures: Dr Aizer reported grants from Varian and personal fees from Novartis outside the submitted work. Dr Reardon reported grants from Acerta Pharmaceuticals, Incyte, Omniox, Tragara, and Midatech; grants and personal fees from Agenus, Celldex, EMD Serono, and Inovio; and personal fees from AbbVie, Advantagene, Amgen, Bayer, Bristol Myers Squibb, DelMar, Genentech/Roche, Merck, Merck KGaA, Monteris, Novocure, Oncorus, Oxigene, Regeneron, Stemline, and Taiho Oncology, Inc, outside the submitted work. Dr Iorgulescu reported salary support from the National Institutes of Health. No other disclosures were reported.
Funding/Support: Funding for this work was provided by the Conquer Cancer/American Society of Clinical Oncology Foundation (2020 Conquer Cancer Merit Award).
Role of the Funder/Sponsor: The Conquer Cancer/American Society of Clinical Oncology Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The National Cancer Database is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The Commission on Cancer’s National Cancer Database and the hospitals participating in the database are the source of the deidentified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.
Additional Contributions: The authors are indebted to Patrick Wen, MD (Dana-Farber Cancer Institute), for his sage insights and helpful discussions for this study; he was not compensated.
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