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Annual Meeting Proceedings Part 1 - American Society of Clinical ...

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120s Central Nervous System Tumors<br />

2019 Poster Discussion Session (Board #7), Fri, 1:00 PM-5:00 PM and<br />

4:30 PM-5:30 PM<br />

IDH1 status and survival benefit from surgical resection <strong>of</strong> enhancing and<br />

nonenhancing tumor in malignant astrocytomas. Presenting Author: Daniel<br />

P. Cahill, Massachusetts General Hospital, Boston, MA<br />

Background: The value <strong>of</strong> maximal safe resection for malignant astrocytic<br />

gliomas (AA, WHO Grade III anaplastic astrocytoma and GBM, WHO Grade<br />

IV glioblastoma) has sometimes been controversial, because <strong>of</strong> confounding<br />

between measures <strong>of</strong> surgical resection and other prognostic factors.<br />

IDH1 gene mutations are associated with improved survival in glioma<br />

patients, and are thought to identify tumors with a distinct molecular<br />

evolutionary origin. We sought to determine the prognostic impact <strong>of</strong><br />

surgical resection on survival after controlling for IDH1 status in malignant<br />

astrocytomas. Methods: <strong>Clinical</strong> parameters including preoperative and<br />

postoperative MRI-based tumor volume were recorded prospectively on<br />

407 malignant astrocytoma patients – AA (n�157) and GBM (n�250).<br />

IDH1 status was assessed by sequencing and R132H-specific immunohistochemistry.<br />

Results: The measures <strong>of</strong> surgical resection associated with<br />

longer survival differed between IDH1 wild-type and mutant tumors. In<br />

multivariate analyses <strong>of</strong> IDH1 wild-type tumors (controlling for age,<br />

Karn<strong>of</strong>sky performance score, tumor location, and tumor grade), residual<br />

postoperative enhancement was associated with a median survival <strong>of</strong> 9.9<br />

mo vs. 17.4 mo with no enhancement (HR�1.73, 95% CI, 1.19-2.52,<br />

p�.004). Residual non-enhancing disease, however, was not associated<br />

with survival (scored as continuous volumetric cc, 95% CI 0.99-1.01,<br />

p�.608). These results are consistent with prior studies <strong>of</strong> GBM, which are<br />

largely IDH1 wild-type lesions (Lacroix et al., J Neurosurg 95:190-8,<br />

2001). In contrast, in IDH1 mutant tumors, both residual enhancing<br />

(HR�7.93, 95%CI 1.14-55.22, p�.037) and non-enhancing (HR�1.03,<br />

95% CI 1.01-1.05, p�.005) postoperative tumor burden were associated<br />

with worse survival. Conclusions: These data suggest surgical resection in<br />

malignant astrocytic gliomas may be individualized based on IDH1 genotype.<br />

IDH1 mutant tumors have a better baseline overall prognosis,<br />

therefore more aggressive surgery and tolerance <strong>of</strong> temporary peri-operative<br />

neurologic deficits can be weighed in an attempt to gain the additional<br />

survival benefit that appears to be associated with reducing non-enhancing<br />

tumor burden.<br />

2021 Poster Discussion Session (Board #9), Fri, 1:00 PM-5:00 PM and<br />

4:30 PM-5:30 PM<br />

MET and ALK in glioblastoma multiforme (GBM): Comparison <strong>of</strong> IHC and<br />

FISH. Presenting Author: Kimary Kulig, National Comprehensive Cancer<br />

Network, Fort Washington, PA<br />

Background: GBM, the most common and lethal malignant primary brain<br />

tumor in adults, has an overall one-year life expectancy <strong>of</strong> 33.7%.<br />

Personalized medicine on the basis <strong>of</strong> predictive biomarkers remains<br />

elusive in GBM; however a recent case report showed clinical improvement<br />

after treatment with a mesenchymal-epithelial transition (MET) inhibitor.<br />

The authors <strong>of</strong> that report ascribe clinical response to the MET inhibitor,<br />

but the drug is also an inhibitor <strong>of</strong> anaplastic lymphoma kinase (ALK). We<br />

explored the co-expression, gain, or amplification <strong>of</strong> both MET and ALK by<br />

IHC and FISH in GBM. Methods: A convenience sample <strong>of</strong> 56 available<br />

tumors from gross-resected GBM cases within the Duke Brain Tumor tissue<br />

bank was stained for MET using clone 8F11 (Leica) and for ALK using clone<br />

5A4 (Novocastra). FISH employed the LSI ALK (2p23) breakpointspanning<br />

dual-color DNA probe and the LSI D7S486 (MET)/CEP 7 dual<br />

color DNA probe (Vysis). Results: Of 56 GBM cases, MET was expressed in<br />

69.6% and ALK in 17.9% by IHC. By FISH, gain or amplification was found<br />

in 100% <strong>of</strong> cases for MET and in 48.2% for ALK. Co-expression <strong>of</strong> MET and<br />

ALK by IHC was 14.3% and 48.2% by FISH. Co-expression by either IHC or<br />

FISH was also 48.2%. OS estimation for this cohort is premature, with<br />

77% <strong>of</strong> patients still alive. Conclusions: MET and ALK are (co-)expressed in<br />

a significant proportion <strong>of</strong> GBM. IHC detection <strong>of</strong> MET and ALK did not<br />

correlate well with FISH results, suggesting that gene gain or amplification<br />

does not necessarily lead to abnormal MET and ALK protein expression or<br />

that IHC methods or antibodies used can be optimized. Prior studies<br />

reported MET amplification in GBM as low as 4%. Our study indicates that<br />

MET gain/amplification and protein expression may be much higher, having<br />

implications for MET-targeted therapy. Additionally, co-expression <strong>of</strong> ALK<br />

and MET has implications for dual inhibitors <strong>of</strong> these signaling pathways as<br />

well as resistance mechanisms. Our continued work will explore significance<br />

<strong>of</strong> MET and ALK as predictors <strong>of</strong> therapeutic response, with careful<br />

control for clinically relevant patient and disease characteristics.<br />

Biomarker IHC �<br />

FISH �<br />

(gain or amplification) IHC- FISH-<br />

MET 39 56 17 0<br />

ALK 10 27 46 29<br />

MET � ALK 8 27 15 0<br />

2020 Poster Discussion Session (Board #8), Fri, 1:00 PM-5:00 PM and<br />

4:30 PM-5:30 PM<br />

Genomic characterization <strong>of</strong> meningiomas. Presenting Author: Priscilla<br />

Kaliopi Brastianos, Dana-Farber Cancer Institute, Boston, MA<br />

Background: Understanding the genetic alterations in cancer has lead to<br />

groundbreaking discoveries in targeted therapies. Meningiomas are among<br />

the most common primary brain tumors, with approximately 18,000 new<br />

cases diagnosed annually. Though certain genes have been associated with<br />

the development <strong>of</strong> meningiomas, most notably the tumor suppressor gene<br />

neur<strong>of</strong>ibromatosis 2 (NF2), the genetic changes that drive meningiomas<br />

remain poorly understood. Our objective was to comprehensively characterize<br />

the somatic genetic alterations <strong>of</strong> meningiomas to gain insight into the<br />

molecular pathways that drive this disease. Methods: Fresh frozen specimens<br />

and paired blood were collected from 16 consented patients. DNA<br />

was extracted from regions <strong>of</strong> high tumor purity determined by evaluation <strong>of</strong><br />

H&E slides. Whole-genome sequencing from 10 tumor-normal pairs and<br />

whole-exome sequencing from 6 tumor-normal pairs was carried out. We<br />

performed an unbiased screen for point mutations, insertions-deletions,<br />

rearrangements and copy-number changes across the exomes and genomes.<br />

Recurrent (potential driver) events were then analyzed with<br />

additional algorithms for statistical significance. Results: Alterations in the<br />

NF2 gene were present in 9 <strong>of</strong> 16 patients. Multiple novel rearrangements<br />

and recurrent non-NF2 mutations were also identified in the cohort.<br />

Massive genomic rearrangement termed chromothripsis was observed in<br />

chromosome 1 in one sample, which has never previously been described in<br />

meningiomas, and represents a potentially new mechanism <strong>of</strong> malignant<br />

transformation in this tumor type. Conclusions: While NF2 mutations<br />

appear to drive a majority <strong>of</strong> these tumors, our analysis has uncovered<br />

additional potential driver genes in meningiomas, particularly in those<br />

tumors negative for NF2 alterations. To our knowledge, this is the first study<br />

to comprehensively characterize the totality <strong>of</strong> somatic genetic alterations<br />

in meningiomas, and brings us closer to the development <strong>of</strong> new therapeutic<br />

targets for this disease.<br />

2022 Poster Discussion Session (Board #10), Fri, 1:00 PM-5:00 PM and<br />

4:30 PM-5:30 PM<br />

Pilocytic astrocytomas in adults: A retrospective study <strong>of</strong> 125 patients.<br />

Presenting Author: Brett James Theeler, University <strong>of</strong> Texas M. D. Anderson<br />

Cancer Center, Houston, TX<br />

Background: Pilocytic astrocytomas (PAs) are rare primary brain tumors in<br />

adults. The natural history is poorly defined with the largest published<br />

series including only 30-40 patients. To better define clinical characteristics<br />

<strong>of</strong> adult PAs, we present an analysis <strong>of</strong> adult PAs at MD Anderson<br />

Cancer Center. Methods: We conducted an IRB-approved, retrospective<br />

chart review <strong>of</strong> patients �18 years diagnosed with PAs from 1990-2011 at<br />

our institution. Results: We identified 125 patients with a median age <strong>of</strong> 29<br />

(range 18-72y), female to male ratio <strong>of</strong> 1.7:1, and median follow-up <strong>of</strong> 62<br />

months. The most common anatomic locations were brainstem 22%,<br />

cerebellum 14%, intraventricular 14%, and cortical/lobar 14% (36% other<br />

locations). 21% <strong>of</strong> cases had an initial pathologic diagnosis discordant with<br />

neuropathologic review at our institution. Comorbidities included neur<strong>of</strong>ibromatosis<br />

type 1 (5 pts) and a history <strong>of</strong> asthma or autoimmune disease<br />

(14%). 38 patients had a gross total (GTR), 55 a sub-total resection (STR)<br />

and the remainder a biopsy. 62 patients were treated with radiotherapy<br />

(RT): 45 as adjuvant (adj), 17 at recurrence; 2 received RT in both adj and<br />

recurrent settings. 73 (58%) patients were stable after initial treatment<br />

(surgery �/- adj RT). Median progression free survivals (mPFS) based on<br />

upfront treatment as follows: GTR only (n�30) - not been reached, STR<br />

only (n�32) 226.6 months, GTR plus adj RT (n�8) 13.2 months, STR plus<br />

adj RT (n�23) is 52.4 months (p�0.026, logrank test for trend). At last<br />

follow-up, 77% <strong>of</strong> all patients were stable and 13% were deceased.<br />

Conclusions: This is the largest series <strong>of</strong> adult PAs reported to date.<br />

Extracerebellar location, slight female predominance, and history <strong>of</strong><br />

allergic/autoimmune disease were associations found in this cohort.<br />

Neuropathologic review is essential to avoid misdiagnosis. A significant<br />

subset <strong>of</strong> adult PAs behave more aggressively than expected for a grade I<br />

tumor with over 40% <strong>of</strong> patients experiencing recurrence after initial<br />

treatment. Adj RT following GTR or STR did not improve PFS, and a trend<br />

towards worse PFS with adj RT was observed although these analyzed<br />

subgroups were small. These results may help provide a framework for<br />

prospective studies in this tumor type.<br />

Visit abstract.asco.org and search by abstract for the full list <strong>of</strong> abstract authors and their disclosure information.

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