PTEN mutations predict benefit from tumor treating fields (TTFields) therapy in patients with recurrent glioblastoma

Dono, Antonio; Mitra, Sonali; Shah, Mauli; Takayasu, Takeshi; Zhu, Jay‐Jiguang; Tandon, Nitin; Esquenazi, Yoshua; Ballester, Leomar Y.

doi:10.1007/s11060-021-03755-1

Cited by 25 publications

(17 citation statements)

References 36 publications

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“…Correlations between genetic alternations and therapeutic efficacy have also been investigated in patients treated with TTFields [ 21 ]. There were undergoing trials of combinations of regiments as well, which were intended to facilitate the interaction between TTFields and other medical prescriptions [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Tumor Treating Fields Combine with Temozolomide for Newly Diagnosed Glioblastoma: A Retrospective Analysis of Chinese Patients in a Single Center

Chen

Song

et al. 2022

JCM

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Introduction: TTFields plus Temozolomide (TTFields/TMZ) extended survival versus TMZ alone in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. We have reported a retrospective analysis of newly diagnosed Chinese GBM patients who received TTFields/TMZ treatment and TMZ treatment from August 2018 to May 2021 in Huashan hospital in Shanghai. Methods: Overall survival (OS) and progression-free survival (PFS) curves were constructed using the Kaplan–Meier method. A Cox proportional hazards regression model, propensity score matched data, and inverse probability of treatment weighting (IPTW) based on propensity score were used to assess the effect of TTFields and account for confounding factors. Results: In the preliminary analysis, the median PFS in TTFields/TMZ group was 16 months (95% CI, 9.6–24.6) versus 11 months (95% CI, 9–12) in TMZ group (p < 0.05). Median overall survival was 21.8 months (95% CI, 17.4-NA) with TTFields/TMZ versus 15 months (HR = 0.43; 95% CI, 13–18) with TMZ alone. The multivariate analysis identified surgery type, STUPP scheme, IDH status, and TTFields use as favorable prognostic factors. After PSM adjustment, the variate among the groups was similar, except that the methylation rate of MGMT promoter remained high in the TMZ group (12 v 32 months; p = 0.011). Upon IPTW Survival analysis, TTFields was associated with a significantly lower risk of death (HR = 0.19 in OS; 95% CI, 0.09–0.41) and progression (HR = 0.35; 95% CI 0.14–0.9) compared with TMZ group. Conclusion: In the final analysis of our single-center Chinese patients with glioblastoma, adding TTFields to temozolomide chemotherapy resulted in statistically significant improvement in PFS and OS.

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Section: Introductionmentioning

confidence: 99%

Tumor Treating Fields Combine with Temozolomide for Newly Diagnosed Glioblastoma: A Retrospective Analysis of Chinese Patients in a Single Center

Chen

Song

et al. 2022

JCM

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“…Our modeling also indicates that using microfluidics to measure shear stress (τ) induced by TTFields and investigations into TTFields-induced alterations in transmembrane fenestration number, distribution, and size are pertinent to cancer research. Although exogenously imposed AEFs are not specifically tied to a singular signal transduction pathway in cancer cells, we have recently reported that phosphatase and tensin homolog (PTEN) mutations predict benefit from TTFields in patients with recurrent isocitrate dehydrogenase (IDH) wild-type GBM [90], which represents the first molecular biology-based predictor of responsiveness to TTFields therapy. PTEN is involved in maintaining mitotic spindle architecture and promoting chromosome alignment and segregation, functions overlapping with the postulated mechanism of action of TTFields [8,91,92].…”

Section: Discussionmentioning

confidence: 99%

Permeabilizing Cell Membranes with Electric Fields

Aguilar

Chang

et al. 2021

Cancers

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The biological impact of exogenous, alternating electric fields (AEFs) and direct-current electric fields has a long history of study, ranging from effects on embryonic development to influences on wound healing. In this article, we focus on the application of electric fields for the treatment of cancers. In particular, we outline the clinical impact of tumor treating fields (TTFields), a form of AEFs, on the treatment of cancers such as glioblastoma and mesothelioma. We provide an overview of the standard mechanism of action of TTFields, namely, the capability for AEFs (e.g., TTFields) to disrupt the formation and segregation of the mitotic spindle in actively dividing cells. Though this standard mechanism explains a large part of TTFields’ action, it is by no means complete. The standard theory does not account for exogenously applied AEFs’ influence directly upon DNA nor upon their capacity to alter the functionality and permeability of cancer cell membranes. This review summarizes the current literature to provide a more comprehensive understanding of AEFs’ actions on cell membranes. It gives an overview of three mechanistic models that may explain the more recent observations into AEFs’ effects: the voltage-gated ion channel, bioelectrorheological, and electroporation models. Inconsistencies were noted in both effective frequency range and field strength between TTFields versus all three proposed models. We addressed these discrepancies through theoretical investigations into the inhomogeneities of electric fields on cellular membranes as a function of disease state, external microenvironment, and tissue or cellular organization. Lastly, future experimental strategies to validate these findings are outlined. Clinical benefits are inevitably forthcoming.

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“…Studies were conducted to identify predictive biomarkers of the efficacy of the use of TTFields in GBM patients. A retrospective review of 149 patients with IDH wild-type rGBMs, of whom 29 were treated with TTFields, found that PTEN mutation might predict prolonged postprogression survival better in the TTFields-treated group than in the groups subjected to other treatments, whereas patients with PTEN wild-type rGBMs showed no improvements [ 109 ]. A recent genomic analysis revealed that molecular driver alterations in NF1, as well as wild-type PIK3CA and EGFR, were associated with improved response to TTFields [ 110 ].…”

Section: Clinical Studies Of Ttfields Treatment On Gbmsmentioning

confidence: 99%

Tumor-Treating Fields in Glioblastomas: Past, Present, and Future

Guo

Yang

et al. 2022

Cancers

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Tumor-treating fields (TTFields), a noninvasive and innovative therapeutic approach, has emerged as the fourth most effective treatment option for the management of glioblastomas (GBMs), the most deadly primary brain cancer. According to on recent milestone randomized trials and subsequent observational data, TTFields therapy leads to substantially prolonged patient survival and acceptable adverse events. Clinical trials are ongoing to further evaluate the safety and efficacy of TTFields in treating GBMs and its biological and radiological correlations. TTFields is administered by delivering low-intensity, intermediate-frequency, alternating electric fields to human GBM function through different mechanisms of action, including by disturbing cell mitosis, delaying DNA repair, enhancing autophagy, inhibiting cell metabolism and angiogenesis, and limiting cancer cell migration. The abilities of TTFields to strengthen intratumoral antitumor immunity, increase the permeability of the cell membrane and the blood–brain barrier, and disrupt DNA-damage-repair processes make it a promising therapy when combined with conventional treatment modalities. However, the overall acceptance of TTFields in real-world clinical practice is still low. Given that increasing studies on this promising topic have been published recently, we conducted this updated review on the past, present, and future of TTFields in GBMs.

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PTEN mutations predict benefit from tumor treating fields (TTFields) therapy in patients with recurrent glioblastoma

Cited by 25 publications

References 36 publications

Tumor Treating Fields Combine with Temozolomide for Newly Diagnosed Glioblastoma: A Retrospective Analysis of Chinese Patients in a Single Center

Tumor Treating Fields Combine with Temozolomide for Newly Diagnosed Glioblastoma: A Retrospective Analysis of Chinese Patients in a Single Center

Permeabilizing Cell Membranes with Electric Fields

Tumor-Treating Fields in Glioblastomas: Past, Present, and Future

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