Neuro-Oncology (December 2018): Molecular Oncology Tumor Boards

ASCO University
Dec 05, 2018 10:00 AM

Participant Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented every other month with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. Jason Huse (Molecular Pathologist from MD Anderson Cancer Center) and Arati Desai (Medical Oncologist from the University of Pennsylvania).

Do you have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

Participants are encouraged to leave comments and post questions about the case in order to generate a wide discussion among the cancer care community. You can also receive email notifications when new comments are posted by clicking the “Follow this Conversation” option located at the bottom of this page.

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Comments

16106

ASCO University
Re: Neuro-Oncology (December 2018): Molecular Oncology Tumor Boards
Dec 05, 2018 10:01 AM

Patient Case #1

A 42-year-old right-handed man presented with several weeks of mild cognitive and personality changes followed by a new onset generalized seizure which brought him to urgent medical attention. MRI of the brain demonstrated a large non-enhancing mass centered in the left frontal lobe, with involvement of the corpus callosum.  He underwent craniotomy with resection of the majority of the lesion, though with measurable small volume residual disease.  Pathology demonstrated grade II oligodendroglioma.  A GFAP stain highlighted neoplastic cells.  P53 weakly stained a subset of tumor nuclei.  Immunohistochemistry was positive for IDH R132H mutation and demonstrated that ATRX expression was retained.  1p/19q was co-deleted by FISH.  MGMT promoter methylation was positive by pyrosequencing.  Next generation sequencing confirmed the IDH R132H mutation and also revealed mutations in CIC and TERT.  

Post-operatively, he initiated radiation to a total dose of 5400 cGy in 30 fractions, followed by six cycles of adjuvant PCV (procarbazine, CCNU, vincristine) chemotherapy. 

16111

ASCO University
Re: Neuro-Oncology (December 2018): Molecular Oncology Tumor Boards
Dec 05, 2018 10:01 AM

Discussion Questions

1. What histopathological and/or molecular features, if any, are prognostic for this patient’s diagnosis?

2. What are the optimal testing methods for IDH mutation, MGMT methylation status, and 1p/19q deletional status?

3. What is the preferred treatment strategy for low grade oligodendroglioma with this molecular profile?

16121

Re: Neuro-Oncology (December 2018): Molecular Oncology Tumor Boards
Dec 10, 2018 12:14 PM

Course Faculty Response (Dr. Huse)

1. As summarized in the most recent WHO update for the classification of primary brain tumors, histopathological features designating astrocytic versus oligodendroglial lineage do not carry particularly strong prognostic significance in and of themselves.  Frank necrosis and microvascular proliferation, in their designation of glioblastoma (GBM), are still important.  However, those features are not apparent in this patient’s resection.  More important is the IDH-mutant status of this tumor, as assessed by immunostaining for IDH1 R132H (the most common glioma-associated IDH mutation).  IDH mutation designates more indolently evolving astrocytomas and oligodendrogliomas (WHO grades II and III), while IDH-wild type status in diffuse gliomas of adulthood most often portends aggressive biological behavior, on the order of GBM (WHO grade IV), even in the absence of GBM-associated histopathology.  In this particular case, retained nuclear ATRX immunopositivity and loss of chromosome 1p and 19q by FISH (1p/19q codeletion) are consistent with an integrated diagnosis of oligodendroglioma, IDH-mutant and 1p/19q-codeleted, WHO grade II, as are the additional mutations in CIC and TERT.  This diagnosis carries with it the most favorable prognosis of all diffuse gliomas normally arising in adults.  The prognostic significance of MGMT promoter methylation in IDH-mutant oligodendroglioma is unclear, contrasting with the biomarker’s established role in the stratification of GBM.

2. IDH mutational testing can be performed using a variety of methodologies.  Immunohistochemistry for the most common glioma-associated IDH mutational variant (IDH1 R132H), is often the first test of choice in pathology labs, given its ease of assessment and low cost.  In cases of frank GBM, a negative IDH1 R132H immunostaining result effectively excludes IDH mutation with 99% specificity in patients aged 55 or older, given the low incidence of IDH mutations in this population as a whole.  Sequencing methodologies, either focused approaches or more expansive next-generation sequencing panels, are also frequently and employed to assess IDH1 and IDH2 and are the gold standard for effectively excluding mutations in clinical samples.  MGMT methylation is primarily assessed by either methylation-specific PCR (quantitative or nonquantitative) or pyrosequencing in most clinical labs.  Finally, 1p/19q codeletion is determined by either fluorescence in situ hybridization (FISH) or PCR-based analyses in most clinical settings.  However, it should be emphasized that since neither of these methods assesses whole arm loss of chromosomes 1p and 19q, both are prone to false positive results in the absence of careful interpretation.  Despite its lack of widespread usage, cytogenomic array represents the most effective methodology to detect whole arm 1p/19q codeletion.  Next-generation sequencing platforms that extensively sample genes on 1p and 19q can also be adapted to provide interpretable copy number information.

16126

ASCO University
Re: Neuro-Oncology (December 2018): Molecular Oncology Tumor Boards
Dec 10, 2018 12:16 PM

Course Faculty Response (Dr. Desai)

3.This case highlights a 42 year old man with IDH mutated, 1p/19q co-deleted grade II oligodendroglioma with measurable residual disease post-operatively.  The RTOG 9802 trial was practice-defining in this realm (Buckner J, et al. New Eng J Med, 2016).  A phase 3 trial evaluating 251 patients with histologically defined grade II glioma who were classified as high risk by age ≥40 years and/or residual disease following initial surgery, the study randomized participants to radiation alone to a total dose of 54 cGy in 30 fractions over 6 weeks as compared to radiation followed by six cycles of PCV (procarbazine, CCNU, vincristine) chemotherapy. Both median overall survival and progression free survival were significantly prolonged in the group receiving radiation with chemotherapy as compared to those receiving radiation alone (OS: 13.3 years vs. 7.8 years, PFS: 10.4 years vs. 4.0 years).  The trial predated current WHO pathologic classification schema.  

Critically, the overall survival difference with radiation and sequential chemotherapy was only statistically significant in the oligodendroglioma (HR 0.43, p=.009) and oligoastrocytoma (HR 0.56, p=0.05) subgroups, with disproportionately favorable impact in patients whose tumors harbored IDH1 R132H mutations (HR 0.42, p=0.02). Data from both the EORTC 26951 (Van Den Bent, et al. J Clin Oncol, 2013) and RTOG 9402 (Cairncross G, et al. J Clin Oncol, 2013) trials for anaplastic oligodendrogliomas validate these findings of a long-term survival benefit for patients who received radiation and PCV chemotherapy as compared to radiation alone, in particular for  those patients whose tumors were 1p/19q co-deleted and IDH mutated (Cairncross G, et al. Cancer J, 2008).  

In RTOG 9802, as expected, Grade 3 or greater toxicity was more commonly observed in the PCV arm, reported as largely due to constitutional symptoms, myelosuppression, gastrointestinal symptoms, and hepatic function abnormalities.  Though the trial called for six adjuvant PCV cycles, the authors report that only 56% of patients received chemotherapy as per protocol, with a median number of cycles as three for procarbazine, four for CCNU, and four for vincristine.  In EORTC 26951, only 30% of patients completed six planned cycles of therapy with a median number of three PCV cycles administered and with discontinuation most commonly for hematologic toxicity or tumor progression.  While radiation and PCV chemotherapy represents the evidence-based choice in this scenario, concerns regarding side effects and complexity of the regimen as well as questions regarding additional benefit and CNS penetration of vincristine continue to circulate.  Alternative systemic therapy considerations include PC (procarbazine, CCNU alone) or temozolomide, though without similar caliber prospective supportive data at this time.

16131

ASCO University
Re: Neuro-Oncology (December 2018): Molecular Oncology Tumor Boards
Dec 10, 2018 12:18 PM

Patient Case #2

A 55-year-old right-handed woman presented with unrelenting headaches and fatigue, prompting neuroimaging.  MRI of the brain demonstrated a non-enhancing, infiltrative neoplasm involving the left superior frontal gyrus, extending posteromedially to the cingulate gyrus.  She underwent craniotomy and gross total resection of her tumor.  Pathology was reported as diffuse astrocytoma, WHO grade II.  The Ki-67 labeling index in tumor cell nuclei measured approximately 3%.  IDH R132H was negative by immunohistochemistry and next generation sequencing analysis did not detect mutations in either IDH1 or IDH2, although mutations in TP53 were identified.  MGMT promoter methylation was positive by pyrosequencing.  Post-operatively, she received radiation to 5400 cGy in 30 fractions, with concurrent temozolomide 75 mg/m2/day, followed by adjuvant temozolomide to 12 cycles.  

She was monitored serially, initially with clinical and radiographic stability, but approximately two years after initial diagnosis, she developed a new 2 cm enhancing lesion adjacent to her initial resection cavity.  She underwent a second craniotomy and gross total resection of this lesion.  Pathology now demonstrated glioblastoma, WHO grade IV, with similar molecular features to those seen in her initial resection.

16136

ASCO University
Re: Neuro-Oncology (December 2018): Molecular Oncology Tumor Boards
Dec 10, 2018 12:18 PM

Discussion Questions

1.Would the diagnosis of “astrocytoma, WHO grade II” that this patient received following her initial resection be appropriate under the revised WHO 2016 classification system?  What additional information should be provided if available?

2.What is the impact of these reported molecular features on this patient’s prognosis and treatment choice?


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