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P53, EGFR, and PTEN as markers of diagnosis and prognosis in patients with anaplastic glioma enrolled in NCCTG clinical trials

Reviewer: Ryan Smith, MD
OncoLink
Ultima Vez Modificado: 31 de mayo del 2003

Presenter: J.C. Buckner
Presenter's Affiliation: NCCTG
Type of Session: Scientific

Background

• The NCCTG has previously reported survival differences in patients with high grade gliomas.
• Median survival times were 52 mo, 19 mo, 16 mo, and 11 mo for grade 3 oligoastrocytomas (OA3), anaplastic astrocytomas (AA), grade 4 oligoastrocytomas (OA4), and glioblastoma multiforme (GBM), respectively.
• 2 yr survivals are 82%, 45%, 32%, and 13% for grade 3 oligoastrocytomas, anaplastic astrocytomas, grade 4 oligoastrocytomas, and glioblastoma multiforme, respectively.
• In addition to histology and grade (the most influential prognostic factors), age and performance status were also prognostic for outcome
• These same patients were analyzed for many different genetic scenarios to determine their prognostic significance

Materials and Methods

• Patients were obtained from (all) prospective trials using radiation therapy and nitrosourea-based chemotherapy
• Unfortunately, none of the studies showed increased efficacy over other modalities
• Tissue from 197 patients (14%) were analyzed to assess genetic markers
• Many markers were evaluated, though those that were prognostic included EGFR amplification (by FISH analysis), p53 mutation (by PCR), and PTEN alterations (by FISH and PCR).
• Patient selection variables were also studied to determine if the patients whose tissue was analyzed differed from the population as a whole

Results

• Proportionally less patients with GBM were analyzed compared to the population as a whole. This was planned as there was an abundance of GBM cases in the trials studied.
• There were proportionally more patients analyzed with AA than in the population as a whole
• p53 mutations were much more common in grade 3 tumors (35% vs 10%)
• EGFR amplification was more common in grade 4 tumors (43% vs. 19%)
• PTEN alterations were never seen in OA3 and much more common in GBMs (33%)

Author's Conclusions

• p53 mutation is associated with grade 3 tumors, younger patients, and a better prognosis
• EGFR amplification is associated with grade 4 tumors, older patients, and a worse prognosis
• PTEN was found infrequently, but was more common in grade 4 tumors-especially GBM, and never seen in OA3. This may explain the worse prognosis of AA vs. OA3

Clinical/Scientific Implications

There has long been a partitioning of outcome in patients with high grade gliomas. One of the most influential predictors of outcome is histology, with tumors with an oligodendroglioma component faring better and those tumors that are less anaplastic faring better. However, subgroups have been identified that have better survival, respond to radiation therapy, and respond to chemotherapeutic regimens. A likely component of these tumors are differing genetic mutations that have led to their carcinogenesis. This study indicates that, indeed, specific mutations may be responsible for the differing outcomes, with histology being a secondary consequence. Obviously, the opposite may be true, leading to acceptance of the classical view that histology reigns supreme over all of the prognostic factors. However, the overall occurrence of these mutations are all <50% and the sample size of the OA patients are very small. Therefore, though this can be settled using data from a much larger population in a prospective manner, it is difficult to draw definitive conclusions of these patients from this study alone. However, given the poor prognosis of patients with high grade gliomas and the associated nihilism that has developed in the oncology community because of this, genetic investigations such as these are important steps to attempt to tailor therapies specifically to certain patient groups. Therapies designed to target specific mutations may finally start to improve outcomes in these patients.

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