Human gliomas present as heterogeneous disease and are graded via the World Health Organization (WHO) classification system using traditional histopathology techniques. Tumor grade is used to guide treatment and establish prognosis.
Treatment plans are different for patients diagnosed with WHO grade 2, 3, or 4 gliomas (see Table I; van den Bent, 2010).
| Table I: Treatment Plans by Tumor Type | |
|---|---|
| Tumor type | Standard of care |
| Oligodendroglial tumors | Initial mngt with upfront chemotx widely accepted, regardless of grade |
| Low grade gliomas | RT 45-55 Gy, higher dosages of RT correlate with toxicity, unproven role for upfront chemotx alone |
| Grade III tumors | RT 60 Gy, value of adjuvant chemotx and of combined chemotx-RT unproven |
| GBM | Combined chemotx-RT (60 Gy) with TMZ |
It is widely recognized and well-documented that clinically significant inter-observer and intra-observer variation exists in the histological diagnosis of glioma. For example, one study evaluated a systematic series on a cohort of 500 brain tumor patients and found some degree of disagreement in 43% of cases. (Bruner, et al). A prospective study on 244 cases reviewed by 4 neuro-pathologists reported a diagnostic inter-observer variability rate of 48% with the first review (Coons, et al).
This clinically significant variation poses an issue for optimizing treatment plans for two reasons:
- In most cases, histopathology does not adequately represent tumor biology; and
- There is significat variation in actual overall outcomes within each grade.
| Table II: Overall Survival by Grade Overall Survival (weeks) |
|||
|---|---|---|---|
| Grade | 25th Percentile | Median | 75th Percentile |
| II | 365 | 780 | 864 |
| III | 87 | 244 | 718 |
| GBM | 37 | 68 | 123 |
To illustrate the effect this discrepancy can have, consider a patient with a histopathology grade 2 whose molecular biology profile suggests a prognosis more similar to a grade 3 tumor. In this case, the patient would be under-treated relative to their grade assigned prognostic risk.
Cancer-specific DNA methylation changes are hallmarks of human cancers. CpG island hypermethylation has been shown to serve as biomarkers in cancer, for prognosis or prediction of response to therapy, and to monitor cancer recurrence. A CpG island methylation phenotype (CIMP) was first identified and characterized in colorectal cancer. DNA methylation alterations have also been reported in gliomas. In particular, several studies have noted differences in methylation between primary and secondary GBMs.
The DecisionDx-LGG methylation profile assay was discovered and developed by Dr. Kenneth Aldape and Kristin Diefes at The University of Texas M. D. Anderson Cancer Center in Houston and exclusively licensed to Castle Biosciences Inc.
