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Molecular alterations associated with improved outcome in patients with glioblastoma treated with Tumor-Treating Fields

ABSTRACT: Abstract

Background

The genomic and overall biologic landscape of glioblastoma (GB) has become clearer over the past 2 decades, as predictive and prognostic biomarkers of both de novo and transformed forms of GB have been identified. The oral chemotherapeutic agent temozolomide (TMZ) has been integral to standard-of-care treatment for nearly 2 decades. More recently, the use of non-pharmacologic interventions, such as application of alternating electric fields, called Tumor-Treating Fields (TTFields), has emerged as a complementary treatment option that increases overall survival (OS) in patients with newly diagnosed GB. The genomic factors associated with improved or lack of response to TTFields are unknown.

Methods

We performed comprehensive genomic analysis of GB tumors resected from 55 patients who went on to receive treatment using TTFields, and compared results to 57 patients who received standard treatment without TTFields.

Results

We found that molecular driver alterations in NF1, and wild-type PIK3CA and epidermal growth factor receptor (EGFR), were associated with increased benefit from TTFields as measured by progression-free survival (PFS) and OS. There were no differences when stratified by TP53 status. When NF1, PIK3CA, and EGFR status were combined as a Molecular Survival Score, the combination of the 3 factors significantly correlated with improved OS and PFS in TTFields-treated patients compared to patients not treated with TTFields.

Conclusions

These results shed light on potential driver and passenger mutations in GB that can be validated as predictive biomarkers of response to TTFields treatment, and provide an objective and testable genomic-based approach to assessing response.

SUBMITTER: Pandey M

PROVIDER: S-EPMC9270729 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to treating glioblastoma; namely, tumor treating fields (TTFields). TTFields involves the delivery of alternating electric fields to the tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24?h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases.

Project description:BackgroundTo date, there has been no large-scale, real-world study of the health-related quality of life outcomes for patients using tumor treating fields (TTFields) therapy for glioblastoma (GBM) treatment.MethodsA survey was mailed to 2,815 patients actively using TTFields for treatment of GBM in the USA (n = 2,182) and Europe (n = 633). The survey included patient-reported demographic and clinical information, as well as EuroQol's EQ-5D-5L and visual analogue scale (EQ-VAS) overall health score.ResultsA total of 1,106 applicable patients responded to the survey (USA = 782 and Europe = 324), with a mean age of 58.6 years (SD = 12.3). The average time since diagnosis and time using TTFields were 21.5 months (SD = 25.1) and 13.5 months (SD = 13.2), respectively. Over 61% of patients had been diagnosed at least 1 year prior and 28.4% at least 2 years prior; 45 patients (4.2%) had been diagnosed at least 5 years prior. Progressed disease was reported in 307 patients, while 690 reported non-progressed disease. Regression analyses showed that GBM disease progression and older age had predictable negative associations (p < 0.001) with most EQ-5D-5L dimensions and the EQ-VAS. However, longer time since diagnosis was associated with improved self-care (p < 0.05), usual activities (p < 0.01), and EQ-VAS (p < 0.05) overall and in patients with progressed disease (p < 0.01, p < 0.05, and p < 0.01, respectively). Additionally, longer time using TTFields was associated with improved mobility (p < 0.05), self-care (p < 0.001), usual activities (p < 0.01), and EQ-VAS (p < 0.01) overall; with improved EQ-VAS in progression-free patients (p < 0.05); and with improved mobility (p < 0.05), self-care (p < 0.01), usual activities (p < 0.05), and EQ-VAS (p < 0.05) in patients with progressed disease.ConclusionThis is the largest real-world study of patient-reported quality of life in GBM and TTFields treatment to date. It shows unsurprising negative associations between quality of life and disease progression and older age, as well as more novel, positive associations between quality of life and longer time since diagnosis and time using TTFields therapy.

Project description:BackgroundGlioblastoma, one of the common tumors of the central nervous system (CNS), is prone to recurrence even after standard treatment protocols. As an innovative physiotherapy method emerging in recent years, the tumor treating fields (TTFields) technique has been approved for the treatment of glioblastoma due to its non-invasive and portable features. The purpose of this study is to visualize and analyze the scientific results and research trends in TTFields therapy for glioblastoma.MethodsPublications related to TTFields therapy for glioblastoma were searched in the Web of Science Core Collection (WoSCC) database in September 2022. A bibliometric and visual analysis of publications in this field was performed mainly using CiteSpace and R software for country/region, author, journal, reference and keyword.ResultsA total of 618 publications in this field were retrieved, and 248 were finally obtained according to the search criteria, including 159 articles (64.11%) and 89 reviews (37.89%). The cumulative number of publications increased year by year, with an average growth rate (AGR) of 28.50%. The test results of Pearson correlation coefficient showed a high positive correlation between publications and citations (r=0.937, p<0.001). The USA had the largest number of publications (123, 49.60%), followed by Germany (32, 12.90%) and China (30, 12.10%). As for the country/region collaborations, the USA cooperated most closely with other countries/regions, followed by Germany and China. The degree of collaboration (DC) between countries/regions was 25.81%. The institutions with the largest number of publications were Tel Aviv Univ (10), Harvard Med Sch (10) and Novocure Ltd (10). Moreover, Wong E (18) possessed the greatest number of publications, followed by Weinberg U (11) and Kirson E (10). The DC between authors was 97.58%. STUPP R (236) was the most cited author followed by KIRSON ED (164) and GILADI M (104). JOURNAL OF NEURO-ONCOLOGY (22) was the journal with the largest number of published publications (75), followed by FRONTIERS IN ONCOLOGY (15) and CANCERS (13). The top 10 keywords that occurred frequently included glioblastoma (156), tumor treating field (152), temozolomide (134), randomized phase III (48), brain (46), survivor (46), cancer (44), trial (42), alternating electric field (42) and radiotherapy (36). Furthermore, cluster analysis was performed on the basis of keyword co-occurrence, and finally 15 clusters were formed to determine the current research status and future development trend of TTFields therapy for glioblastoma.ConclusionTTFields has been increasingly known as the fourth novel physical anti-tumor therapy in addition to surgery, radiotherapy and anti-tumor drugs. Cooperation and communication between countries/regions need to be enhanced in future research. Several studies have demonstrated the therapeutic potential of TTFields in glioma, and its application alone or in combination with other treatments has become a current research hotspot.