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BACKGROUND: This study aims to investigate the relationship between cancer cachexia and oropharyngeal dysphagia (OD) in patients with head and neck cancer (HNC) prior to chemoradiotherapy or bioradiotherapy (CRT/BRT).METHODS: A prospective cohort study with patients with HNC undergoing CRT/BRT (2018-2021) was conducted. Body composition and skeletal muscle function were evaluated using bioelectrical impedance analysis, handgrip strength, and the short physical performance battery (SPPB). The M. D. Anderson Dysphagia Inventory (MDADI), Eating Assessment Tool (EAT)-10 questionnaire, and patient characteristics were collected. A standardized videofluoroscopic swallowing study was offered to patients.RESULTS: Sixty-six patients were included. Twenty-six patients scored EAT-10 ≥ 3 and seventeen were cachectic. ACE-27 score >1, cachexia, abnormal SPPB-derived repeated chair-stand test, lower MDADI scores, and higher overall stage grouping showed potential predictive value (p ≤ 0.10) for EAT-10 ≥ 3. Using multivariable regression analysis, only cachexia remained a significant predictor of EAT-10 ≥ 3 (HR 9.000 [95%CI 2.483-32.619], p = 0.001).CONCLUSION: Cachexia independently predicted the presence of patient-reported OD.

Objective As preservation of cognitive functioning increasingly becomes important in the light of ameliorated survival after intracranial tumor treatments, identification of eloquent brain areas would enable optimization of these treatments. Methods This cohort study enrolled adult intracranial tumor patients who received neuropsychological assessments pre-irradiation, estimating processing speed, verbal fluency and memory. Anatomical magnetic resonance imaging scans were used for multivariate voxel-wise lesion-symptom predictions of the test scores (corrected for age, gender, educational level, histological subtype, surgery, and tumor volume). Potential effects of histological and molecular subtype and corresponding WHO grades on the risk of cognitive impairment were investigated using Chi square tests. P-values were adjusted for multiple comparisons (p Results A cohort of 179 intracranial tumor patients was included [aged 19–85 years, median age (SD) = 58.46 (14.62), 50% females]. In this cohort, test-specific impairment was detected in 20–30% of patients. Higher WHO grade was associated with lower processing speed, cognitive flexibility and delayed memory in gliomas, while no acute surgery-effects were found. No grading, nor surgery effects were found in meningiomas. The voxel-wise analyses showed that tumor locations in left temporal areas and right temporo-parietal areas were related to verbal memory and processing speed, respectively. Interpretation Patients with intracranial tumors affecting the left temporal areas and right temporo-parietal areas might specifically be vulnerable for lower verbal memory and processing speed. These specific patients at-risk might benefit from early-stage interventions. Furthermore, based on future validation studies, imaging-informed surgical and radiotherapy planning could further be improved.

Purpose Reduced temporal muscle thickness (TMT) has recently been postulated as a prognostic imaging marker and an objective tool to assess patients frailty in glioblastoma. Our aim is to investigate the correlation of TMT and systemic muscle loss to confirm that TMT is an adequate surrogate marker of sarcopenia in newly diagnosed glioblastoma patients. Methods TMT was assessed on preoperative MR-images and skeletal muscle area (SMA) was assessed at the third lumbar vertebra on preoperative abdominal CT-scans. Previous published TMT sex-specific cut-off values were used to classify patients as ‘patient at risk of sarcopenia’ or ‘patient with normal muscle status’. Correlation between TMT and SMA was assessed using Spearman’s rank correlation coefficient. Results Sixteen percent of the 245 included patients were identified as at risk of sarcopenia. The mean SMA of glioblastoma patients at risk of sarcopenia (124.3 cm2, SD 30.8 cm2) was significantly lower than the mean SMA of patients with normal muscle status (146.3 cm2, SD 31.1 cm2, P P < .001), and a strong association in the patients at risk of sarcopenia (Spearman’s rho 0.678, P Conclusion Our results confirm the use of TMT as a surrogate marker of total body skeletal muscle mass in glioblastoma, especially in frail patients at risk of sarcopenia. TMT can be used to identify patients with muscle loss early in the disease process, which enables the implementation of adequate intervention strategies.

BACKGROUND: Definitive concomitant cisplatin-based chemoradiotherapy (CRT) is the current gold standard for most patients with advanced stage head and neck squamous cell carcinoma (HNSCC) of the pharynx and larynx. Since previous meta-analysis on CRT outcomes in HNSCC have been reported, advances have been made in radiotherapy techniques and clinical management, while HPV-status has been identified as a strong confounding prognostic factor in oropharyngeal cancer. Here, we present real-world outcome data from a large multicenter cohort of HPV-negative advanced stage HNSCC treated with CRT using contemporary IMRT-based techniques.METHOD: Retrospective data were collected from a multicenter cohort of 513 patients treated with definitive concurrent platinum-based CRT with curative intent between January 2009 and August 2017. Only patients with HPV-negative advanced stage (III-IV) HNSCC were included. A prognostic model for outcome was developed based on clinical parameters and compared to TNM.RESULTS: Nearly half of the 513 patients (49%) had an oropharyngeal tumor, often locally advanced (73.3% T3-T4b) and with involvement of the regional lymph nodes (84%). Most patients (84%) received cisplatin as single agent. 66% received the planned number of cycles and 75% reached a cumulative cisplatin dose of ≥200 mg/m2. Locoregional control was achieved in 324 (63%) patients during follow-up, and no association with tumor sites was observed (p = 0.48). Overall survival at 5 year follow-up was 47%, with a better survival for laryngeal cancer (p = 0.02) compared to other sites. A model with clinical variables (gender, high pre-treatment weight loss, N2c/N3-stage and CONCLUSION: Despite advances in clinical management, more than a third of patients with HPV-negative HNSCC do not complete CRT treatment protocols due to cisplatin toxicity. A model that consists of clinical variables and treatment parameters including cisplatin dose provided the strongest association with overall survival. Since cisplatin toxicity is a major obstacle in completing definitive CRT, the development of alternative and less toxic radiosensitizers is therefore warranted to improve treatment results. The association of RT-boost technique with distant metastasis is an important finding and requires further study.

Purpose Prior to radiotherapy combined with chemotherapy (CRT) or biotherapy (BRT) for oropharyngeal squamous cell carcinoma (OPSCC), teeth with poor prognosis that pose a risk for post-RT osteoradionecrosis (ORN) are removed. The effect of tooth loss on body weight loss and tube feeding (TF) dependency during CRT/BRT is unknown. This study aimed to evaluate the effect of incomplete dentition, tooth extractions prior to CRT/BRT, and the subsequent loss of functional units on (1) weight loss during CRT/BRT and (2) the need for TF during CRT/BRT for OPSCC. Methods OPSCC patients treated with CRT/BRT between 2013 and 2016 were included in this retrospective cohort study. Dental status was determined during the dental assessment at first visit and after tooth extractions prior to the start of CRT/BRT. Weight loss during CRT/BRT was scored dichotomously, comparing weight loss > 5% to stable or increased weight. Potential factors associated with weight loss were identified, including patient, tumor, and treatment characteristics. Results Seventy-seven OPSCC patients were included. Forty patients (52%) experienced weight loss > 5% during CRT/BRT. Extractions were performed in 66% of the OPSCC patients. The mean number of extracted teeth was 4.1 ± 5.6 per patient. Tooth extractions prior to CRT/BRT were associated with weight loss > 5% during CRT/BRT (HR 1.130 (95% CI 1.011–1.262), p = 0.031). None of the dental status-related parameters showed any significant associative value for TF during CRT/BRT. Conclusions Pre-CRT/BRT tooth extractions intended to reduce the risk of ORN, are a risk factor for weight loss during CRT/BRT for OPSCC. Trial registration number This study was approved by the medical ethics committee of the MUMC + (METC 2020–1589) on July 28, 2020.

Flow chart of patients with BRCA1/2 alterations submitted to the study team between September 2016 and December 2019, and reasons for drop-out, rejection or screen failure. Abbreviations: VUS = Variant of Unknown Significance, LOH = Loss of Heterozygosity.

Supplementary Figure from Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Purpose:Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers.Experimental Design:In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks).Results:Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup.Conclusions:Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.

Supplementary Table from Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

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Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers. Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks). Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup. Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.

Paraneoplastic neurological syndromes (PNS) can manifest with every type of malignancy. A well-known syndrome is myasthenia gravis (MG) in combination with thymomas. No association between primary brain tumors and neuromuscular disorders has been described. Here, we present a case of a 65-year-old patient who developed MG, following an uncomplicated, gross-total resection of a glioblastoma. To our knowledge, this is the first case describing the onset of MG during the early postoperative phase after glioblastoma resection. Current criteria of PNS are insufficient when the neurological syndrome is diagnosed at the time of a malignancy or shortly thereafter and should be revisited.

Background & aims: Patients who receive chemoradiotherapy or bioradiotherapy (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often experience high toxicity rates interfering with oral intake, causing tube feeding (TF) dependency. International guidelines recommend gastrostomy insertion when the expected use of TF exceeds 4 weeks. We aimed to develop and externally validate a prediction model to identify patients who need TF > 4 weeks and would benefit from prophylactic gastrostomy insertion. Methods: A retrospective multicenter cohort study was performed in four tertiary head and neck cancer centers in the Netherlands. The prediction model was developed using data from University Medical Center Utrecht and the Netherlands Cancer Institute and externally validated using data from Maastricht University Medical Center and Radboud University Medical Center. The primary endpoint was TF dependency >4 weeks initiated during CRT/BRT or within 30 days after CRT/BRT completion. Potential predictors were extracted from electronic health records and radiotherapy dose-volume parameters were calculated. Results: The developmental and validation cohort included 409 and 334 patients respectively. Multi variable analysis showed predictive value for pretreatment weight change, texture modified diet at baseline, ECOG performance status, tumor site, N classification, mean radiation dose to the contralateral parotid gland and oral cavity. The area under the receiver operating characteristics curve for this model was 0.73 and after external validation 0.62. Positive and negative predictive value for a risk of 90% or higher for TF dependency >4 weeks were 81.8% and 42.3% respectively. Conclusions: We developed and externally validated a prediction model to estimate TF-dependency >4 weeks in LAHNSCC patients treated with CRT/BRT. This model can be used to guide personalized decision-making on prophylactic gastrostomy insertion in clinical practice. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Objectives During all stages of oncologic diseases, pain is still a major problem. The Numeric Rating Scale (NRS) is one of the most frequently used tools for pain assessment, although interpretation is difficult. The main objective of this study is to compare two types of pain evaluation scales: NRS versus (non) acceptable pain evaluation scale. The secondary aim is to analyze a 10% sample of patients indicating non acceptable pain more in-depth. Methods To assess the pain evaluation scales, a prospective observational study, with a nested retrospective in-depth exploration, was conducted. One-year data of patients visiting the outpatient clinic of the oncology center of a university hospital were used. Besides the pain scores of all patients, a 10% sample of patients indicating non acceptable pain was analyzed more in-depth. Results During 1 year, a total of 37,580 patients registered at the outpatient clinic, of whom approximately 10% indicated non acceptable pain. The mean NRS of patients indicating non acceptable pain was 6.5 (n = 2153). For patients indicating acceptable pain, the mean NRS was 1.6 (n = 21,010). Although the presence of pain recorded in the patient record increased substantially over the year, the percentage of reported interventions only slightly increased. Conclusion The (non) acceptable pain evaluation seems a valuable addition to the NRS for assessing pain among patients with cancer. As interpretation of the NRS appears to be difficult, using the (non) acceptable pain evaluation is recommended. Moreover, creating awareness among specialists to discuss pain has a positive effect on the amount of pain discussed during consultation.

OBJECTIVE: Around 40% of oncology patients receive inadequate pain treatment. A previous study reported pain interventions for only 70% of patients who reported unacceptable pain at the self-service registration desk. The aim of this study is to gain insight in reasons for the absence of pain intervention among oncology patients who reported unacceptable pain.METHODS: In this mixed methods study, 20 patients visiting the oncology outpatient clinic were selected via patient record assessment and interviewed about their perceived reasons for absence of pain intervention.RESULTS: The reasons mentioned by the patients for absence of pain intervention included reluctance of the patient to discuss pain, no treatment preferred by the patient, focus of the physician on treatment of the disease, pain treatment difficult or impossible, and the perception that pain is an inevitable consequence of the cancer treatment. Almost 50% of the patients considered the physician responsible for the absence of pain intervention.CONCLUSION: In conclusion, a variety of reasons for absence of pain intervention are reported by patients, including patient-related and health professional-related reasons. Improvements can be made by promoting regular discussion of pain during hospital visits and empowerment of patients.

A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.

Introduction: Glioblastoma (GBM) is the most common malignant primary brain tumour which has, despite extensive treatment, a median overall survival of 15 months. Radiomics is the high-throughput extraction of large amounts of image features from radiographic images, which allows capturing the tumour phenotype in 3D and in a non-invasive way. In this study we assess the prognostic value of CT radiomics for overall survival in patients with a GBM. Materials and methods: Clinical data and pre-treatment CT images were obtained from 218 patients diagnosed with a GBM via biopsy who underwent radiotherapy +/- temozolomide between 2004 and 2015 treated at three independent institutes (n = 93, 62 and 63). A clinical prognostic score (CPS), a simple radiomics model consisting of volume based score (VPS), a complex radiomics prognostic score (RPS) and a combined clinical and radiomics (C + R)PS model were developed. The population was divided into three risk groups for each prognostic score and respective Kaplan-Meier curves were generated. Results: Patient characteristics were broadly comparable. Clinically significant differences were observed with regards to radiation dose, tumour volume and performance status between datasets. Image acquisition parameters differed between institutes. The cross-validated c-indices were moderately discriminative and for the CPS ranged from 0.63 to 0.65; the VPS c-indices ranged between 0.52 and 0.61; the RPS cindices ranged from 0.57 to 0.64 and the combined clinical and radiomics model resulted in c-indices of 0.59-0.71. Conclusion: In this study clinical and CT radiomics features were used to predict OS in GBM. Discrimination between low-, middle- and high-risk patients based on the combined clinical and radiomics model was comparable to previous MRI-based models. (c) 2021 The Author(s). Published by Elsevier B.V. Radiotherapy and Oncology 160 (2021) 132-139 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background Previous studies have recognized temporal muscle thickness (TMT) as a prognostic marker in glioblastoma, but clinical implementation is hampered due to studies’ heterogeneity and lack of established cutoff values. The aim of this study was to assess the validity of recent proposed sex-specific TMT cutoff values in a real-world population of genotyped primary glioblastoma patients. Methods We measured TMT in preoperative MR images of 328 patients. Sex-specific TMT cutoff values were used to divide patients into “at risk of sarcopenia” or “normal muscle status”. Kaplan-Meier analyses and stepwise multivariate Cox-Regression analyses were used to assess the association with overall survival (OS) and progression-free survival (PFS). The association with occurrence of complications and discontinuation of glioblastoma treatment was investigated using odds ratios (OR). Results Patients at risk of sarcopenia had a significantly higher risk of progression and death than patients with normal muscle status, which remained significant in the multivariate analyses (OS HR = 1.437; 95%CI: 1.046–1.973; P = .025 and PFS HR = 1.453; 95%CI: 1.037–2.036; P = .030). Patients at risk of sarcopenia also had a significantly higher risk of early discontinuation of treatment (OR = 2.45; 95%CI: 1.011–5.952; P = .042) and a significantly lower chance of receiving second-line treatment (OR = 0.23; 95%CI: 0.09–0.60; P = .001). There was no association with the occurrence of complications. Conclusions Our study confirms external validity of the use of proposed sex-specific TMT cutoff values as an independent prognostic marker in newly diagnosed glioblastoma patients. This simple, noninvasive marker could improve patient counseling and aid in treatment decision processes or trial stratification.

Gliomas are the most frequent primary tumors of the brain. They can be divided into grade II-IV astrocytomas and grade II-III oligodendrogliomas, based on their histomolecular profile. The prognosis and treatment is highly dependent on grade and well-identified prognostic and/or predictive molecular markers. Multi-parametric MRI, including diffusion weighted imaging, perfusion, and MR spectroscopy, showed increasing value in the non-invasive characterization of specific molecular subsets of gliomas. Radiolabeled amino-acid analogues, such as 18F-FET, have also been proven valuable in glioma imaging. These tracers not only contribute in the diagnostic process by detecting areas of dedifferentiation in diffuse gliomas, but this technique is also valuable in the follow-up of gliomas, as it can differentiate pseudo-progression from real tumor progression. Since multi-parametric MRI and 18F-FET PET are complementary imaging techniques, there may be a synergistic role for PET-MRI imaging in the neuro-oncological imaging of primary brain tumors. This could be of value for both primary staging, as well as during treatment and follow-up.

Purpose Evidence-based guidelines on how to prevent or treat cetuximab-related skin reactions are lacking and multiple care and management strategies are used. The main purpose of the present study is to gain information about the different skincare products being used against skin reactions in metastatic colorectal cancer (mCRC) and recurrent/metastatic (R/M) or locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) patients treated with cetuximab. Methods An open-label, prospective observational study conducted in the Netherlands. The occurrence of skin reactions and the care and management options taken were documented for 16 weeks, starting from the first administration of cetuximab. Results A total of 103 patients were included in 7 hospitals. 38 patients (37%) developed a grade ≥ 2 skin reaction. Eighty-six patients could be analysed for the primary endpoint (73.3% males, mean age 62.4 years, n = 44 LA SCCHN, n = 16 R/M SCCHN, n = 26 mCRC). The most frequently used skin products at some point during the observation period were moisturizing products (70%), systemic antibiotics (64%), topical antibiotics (58%), lipid-regenerating (28%) and other topical products (28%). The overall use of products gradually increased from baseline to week 6–10, reducing by week 16. Hospital protocols were the primary reason (> 50%) for choice of the skincare products and medications. Conclusion A variety of skin care products and antibiotics were commonly used. Only few patients developed severe cutaneous reactions. For patients, the occurrence of skin reactions did not influence their willingness to continue cetuximab therapy.

Highlights • Early changes in hypoxia could be a promising biomarker to identify patients with unfavorable prognosis. • Large differences were found between baseline and week 2 hypoxia PET signal. • Neither baseline nor week 2 static parameters were associated with worse OS and local PFS., Introduction The presence of hypoxia in head-and-neck squamous cell carcinoma is a negative prognostic factor. PET imaging with [18F] HX4 can be used to visualize hypoxia, but it is currently unknown how this correlates with prognosis. We investigated the prognostic value of [18F] HX4 PET imaging in patients treated with definitive radio(chemo)therapy (RTx). Materials and methods We analyzed 34 patients included in two prospective clinical trials (NCT01347281, NCT01504815). Static [18F] HX4 PET-CT images were collected, both pre-treatment (median 4 days before start RTx, range 1–16), as well as during RTx (median 13 days after start RTx, range 3–17 days). Static uptake at both time points (n = 33 pretreatment, n = 28 during RTx) and measured changes in hypoxic fraction (HF) and hypoxic volume (HV) (n = 27 with 2 time points) were analyzed. Univariate cox analyses were done for local progression free survival (PFS) and overall survival (OS) at both timepoints. Change in uptake was analyzed by comparing outcome with Kaplan-Meier curves and log-rank test between patients with increased and decreased/stable hypoxia, similarly between patients with and without residual hypoxia (rHV = ratio week 2/baseline HV with cutoff 0.2). Voxelwise Spearman correlation coefficients were calculated between normalized [18F] HX4 PET uptake at baseline and week 2. Results Analyses of static images showed no prognostic value for [18F] HX4 uptake. Analysis of dynamic changes showed that both OS and local PFS were significantly shorter (log-rank P

Background Chemoradiation or bioradiation treatment (CRT/BRT) of locally advanced head and neck squamous cell carcinoma (LAHNSCC) comes with high toxicity rates, often leading to temporary tube feeding (TF) dependency. Cachexia is a common problem in LAHNSCC. Yet changes in body composition and muscle weakness during CRT/BRT are underexplored. Strong evidence on the effect of TF on body composition during treatment is lacking. The aim of this cohort study was to assess (i) the relationship of fat-free mass index (FFMI) and handgrip strength (HGS) with CRT/BRT toxicity and outcome, (ii) body composition in patients treated with chemoradiation (cisplatin) vs. bioradiation (cetuximab), and (iii) the effect of the current TF regime on body composition and muscle strength. Methods Locally advanced head and neck squamous cell carcinoma patients treated with CRT/BRT between January 2013 and December 2016 were included (n = 137). Baseline measurements of body composition (bioelectrical impedance analysis) and HGS were performed. Toxicity grades (Common Terminology Criteria for Adverse Events) were scored. In a subset of 69 patients, weight loss, body composition, and HGS were additionally assessed during and after CRT/BRT. TF was initiated according to the Dutch guidelines for malnutrition. Results In this cohort (68% male, mean age 59 +/- 8 years), the incidence of baseline muscle wasting, defined as FFMI

Prior to radiotherapy combined with chemotherapy (CRT) or biotherapy (BRT) for oropharyngeal squamous cell carcinoma (OPSCC), teeth with poor prognosis that pose a risk for post-RT osteoradionecrosis (ORN) are removed. The effect of tooth loss on body weight loss and tube feeding (TF) dependency during CRT/BRT is unknown. This study aimed to evaluate the effect of incomplete dentition, tooth extractions prior to CRT/BRT, and the subsequent loss of functional units on (1) weight loss during CRT/BRT and (2) the need for TF during CRT/BRT for OPSCC.OPSCC patients treated with CRT/BRT between 2013 and 2016 were included in this retrospective cohort study. Dental status was determined during the dental assessment at first visit and after tooth extractions prior to the start of CRT/BRT. Weight loss during CRT/BRT was scored dichotomously, comparing weight loss 5% to stable or increased weight. Potential factors associated with weight loss were identified, including patient, tumor, and treatment characteristics.Seventy-seven OPSCC patients were included. Forty patients (52%) experienced weight loss 5% during CRT/BRT. Extractions were performed in 66% of the OPSCC patients. The mean number of extracted teeth was 4.1 ± 5.6 per patient. Tooth extractions prior to CRT/BRT were associated with weight loss 5% during CRT/BRT (HR 1.130 (95% CI 1.011-1.262), p = 0.031). None of the dental status-related parameters showed any significant associative value for TF during CRT/BRT.Pre-CRT/BRT tooth extractions intended to reduce the risk of ORN, are a risk factor for weight loss during CRT/BRT for OPSCC.This study was approved by the medical ethics committee of the MUMC + (METC 2020-1589) on July 28, 2020.

Purpose:To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type.Patients and Methods:Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive off-label drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model.Results:Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types.Conclusions:These data indicate that using PARPis is a promising treatment strategy for patients with non–BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

Background: Glioblastoma is the most prevalent and severe type of malignant brain tumor in adults. Although the genetic make-up initiating glioblastoma is increasingly better understood, a better understanding in the mechanisms that drive its evolution, heterogeneity and therapy resistance may reveal new directions for therapy development. To get better insights into glioblastoma evolution, we analyzed and de-convoluted transcriptomes of primary and recurrent glioblastoma resections. Material and Methods: Matching primary and secondary resections from n=185 glioblastoma patients were collected as part of EORTC Study 1542. The study was extended with tumor pairs from n=51 patients from the international GLASS study. The datasets were subjected to differential and deconvolution analysis using in-house algorithms. Results: When mapping the tumor samples into a reduced Glioblastoma Intrinsic Transcriptional Subtype space, we visualized subtype traversal, indicating that the CL subtype most often switches. As we found no more transitions from MES to other subtypes than to be expected by chance, we concluded that MES is an end-state. On average, tumor cell percentages decreased from ~67% to ~50% mostly due to an increase in TAM/microglia. Differential expression analysis was performed with correction for tumor cell percentages. While expression of most known oncogenes did not change considerably over time, marker genes of TAM/microglia, neurons and oligodendrocytes were up-regulated whereas endothelial cell markers were down-regulated over time. Furthermore, a cluster of ~30 extracellular matrix-associated genes increase significantly over time. A signature representing the gene-set was significantly associated with poor survival; high signatures were in particular associated to survival in secondary resections (P = 6.613e-06, Kaplan-Meier estimator). This suggests that the increase of extracellular matrix expression fulfils an important role in glioblastoma evolution. Conclusion: Using a large cohort, we interrogated changes in the glioblastoma transcriptome over time and found that in particular the composition of the tumor and its environment changes. The tumor cell percentage drops, suggesting more invasion or recruitment of non-malignant cells or a combination of both. This change is independent of an increase in the prognostic increase in extracellular matrix expression. Citation Format: Youri Hoogstrate, Kaspar Draaisma, Santoesha A. Ghisai, Iris de Heer, Levi van Hijfte, Wouter Coppieters, Melissa Kerkhof, Astrid Weyerbrock, Marc Sanson, Ann Hoeben, Slávka Lukacova, Giuseppe Lombardi, Sieger Leenstra, Monique Hanse, Ruth Fleischeuer, Colin Watts, Joseph McAbee, Nicos Angelopoulos, Thierry Gorlia, Vassilis Golfinopoulos, Johan M. Kros, Vincent Bours, Martin J. van den Bent, Pierre A. Robe, Pim J. French. Transcriptional evolution of glioblastoma reveals changes in bulk composition, mesenchymal sub-type as end-state, and a prognostic association with increased extracellular matrix gene expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6140.

Introduction: Both HPV-positive and -negative head and neck squamous cell carcinoma (HNSCC) often show activation of the PI3K/AKT/mTOR pathway, due to, amongst others, PI3KCA mutations, PTEN loss, or receptor tyrosine kinase activation. In HPV-negative tumors, CDKN2A (p16) inactivation or CCND1 (cyclin D1) amplification frequently occurs resulting in sustained cyclin dependent kinase (CDK) 4/6 activation. The aim of our study was to investigate the efficacy of PI3K/AKT/mTOR pathway inhibitors (PI3Ki) (alpelisib, buparlisib and gedatolisib) and CDK4/6 inhibitors (CDKi) (palbociclib and ribociclib) in HPV-positive and -negative HNSCC cell lines. Methods: The efficacy of the inhibitors was assessed using MTT assays and changes in PI3K and Cyclin D1/CDK pathway protein expression were determined by Western blotting. Cell cycle analysis was performed with flow cytometry and apoptosis was assessed by Annexin-V staining. Changes in cell metabolism were assessed by Seahorse XF assays. Results: Both HPV-positive and -negative HNSCC cell lines were highly sensitive to the PI3Ki (Gedatolisib, IC50 5-30 nM > Buparlisib, IC50 0.6-3.6 µM > Alpelisib, IC50 3-23 µM). In general, PI3Ki decreased pathway activity, resulted in moderate cell cycle arrest and apoptosis, and decreased oxidative and glycolytic metabolism. CDKi were particularly effective in blocking HPV-negative cell line growth (Palbociclib, IC50 0.5-2 µM > Ribociclib, IC50 4-7 µM). CDK inhibition showed decreased pRb expression and G1 cell cycle arrest, whereas apoptosis was not induced. Conclusion: PI3Ki and CDKi efficiently inhibit their respective pathways and HNSCC cell growth in vitro, the latter only in HPV-negative cell lines. Whereas PI3Ki especially show an effect on oxidative and glycolytic metabolism, CDKi particularly lead to cell cycle arrest. Further research should elucidate whether these inhibitors may be effective therapeutic agents in HNSCC patients. Citation Format: Imke Demers, Femke Verhees, Dion Leegemaate, Robin Jacobs, Ann Hoeben, Frank Hoebers, Bernd Kremer, Ernst-Jan Speel. PI3K/AKT/mTOR pathway and CDK4/6 inhibitors efficiently inhibit cell growth of HPV-positive and HPV-negative head and neck squamous cell carcinoma in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2573.

e18027 Background: Response rates of immune checkpoint inhibitor (ICI) therapy for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are relatively low. This study evaluates the predictive and prognostic value of weight loss and changes in body composition prior to and during ICI therapy in R/M HNSCC. Methods: This retrospective multicenter cohort study enrolled ninety-eight patients. Patient, tumor and treatment characteristics were retrieved from health records, including neutrophil and platelet-lymphocyte-ratio (NLR and PLR). Cachexia was defined according to the international consensus (Fearon et al. 2011). Skeletal muscle (SM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were evaluated on baseline and follow-up computed tomography scans at the third lumbar vertebrae level. Univariable and multivariable regression analysis were performed for six months progression free survival (PFS6m) and overall survival (OS). Results: Thirty-four patients (35%) experienced significant early weight loss (> 2%) during the first six weeks of therapy. This subgroup presented a significantly higher NLR and PLR at baseline. NLR and PLR were significantly correlated with VAT and SAT index. Independent predictors of PFS6m were lower world health organization performance status (WHO PS) (HR 0.16 [95% CI 0.04-0.54] p = 0.003), higher baseline SAT index (HR 1.045 [95% CI 1.02-1.08] p = 0.003), and early weight loss < 2% (HR 0.85 [95% CI 0.74-0.98] p = 0.03). WHO PS and baseline cachexia in combination with > 2% early weight loss were independent predictors of OS (HR 2.09 [95% CI 1.11-3.92] p = 0.02, HR 2.18 [95% CI 1.13-4.21] p = 0.02). Conclusions: The combination of cachexia at baseline and weight loss during the first six weeks of ICI therapy is associated with worse OS in HNSCC patients treated with ICI therapy. Patients with early weight loss during ICI treatment show an increase in systemic inflammation. The mechanism of how adipose tissue interferes with ICI response needs further investigation.

Patient-derived cancer organoids have taken a prominent role in pre-clinical and translational research and have been generated for most common solid tumors. Cancer organoids have been shown to retain key genetic and phenotypic characteristics of their tissue of origin, tumor subtype and maintain intratumoral heterogeneity and therefore have the potential to be used as predictors for individualized treatment response. In this review, we highlight studies that have used cancer organoids to compare the efficacy of standard-of-care and targeted combination treatments with clinical patient response. Furthermore, we review studies using cancer organoids to identify new anti-cancer treatments using drug screening. Finally, we discuss the current limitations and improvements needed to understand the full potential of cancer organoids as avatars for clinical management of cancer therapy.

Personalized medicine (PM) or precision medicine in oncology is an emerging approach for tumor treatment and prevention that takes into account inter- and intra-tumor variability in genes, tumor (immune) environment, and lifestyle and morbidities of each person diagnosed with cancer [...]

PURPOSE: The immunocytokine L19-IL2 delivers interleukin-2 to the tumor by exploiting the selective L19-dependent binding of extradomain B of fibronectin on tumor blood vessels. In preclinical models, L19-IL2 has been shown to enhance the local and abscopal effects of radiation therapy. The clinical safety of L19-IL2 monotherapy has been established previously. In this study, the safety and tolerability of L19-IL2 after stereotactic body radiation therapy (SBRT) was assessed.METHODS AND MATERIALS: Patients with oligometastatic solid tumors received radical SBRT to all visible metastases. Within 1 week after SBRT, intravenous L19-IL2 using a 3 + 3 dose escalation design was administered. Safety and tolerability were analyzed as the primary endpoint using the Common Terminology Criteria for Adverse Events 4.03 scoring system, with progression-free and overall survival as secondary endpoints.RESULTS: A total of 6 patients in 2 L19-IL2 dose levels were included. The 15 million International Units (Mio IU) dose level was well tolerated with no dose-limiting toxicity. The most frequently reported adverse events were chills, noninfectious fever, fatigue, edema, erythema, pruritus, nausea/vomiting, and cough and dyspnea. Blood analysis revealed abnormalities in liver function tests, anemia, hypoalbuminemia, and hypokalemia. At the second dose level (ie, 22.5 Mio IU), which is the recommended dose for L19-IL2 monotherapy, all 3 included patients experienced dose-limiting toxicity but recovered without sequelae. We documented 2 long-term progression-free responders, both having non-small cell lung cancer as primary tumor.CONCLUSIONS: Based on the results of this phase 1 clinical trial, the recommended phase 2 dose for SBRT combined with L19-IL2 is 15 Mio IU. The therapeutic efficacy of this combination is currently being evaluated in the multicentric EU-funded phase 2 clinical trial, ImmunoSABR.

Treatment of glioblastoma xenografts with chloroquine results in macroautophagy/autophagy inhibition, resulting in a reduction of tumor hypoxia and sensitization to radiation. Preclinical data show that EGFRvIII-expressing glioblastoma may benefit most from chloroquine because of autophagy dependency. This study is the first to explore the safety, pharmacokinetics and maximum tolerated dose of chloroquine in combination with radiotherapy and concurrent daily temozolomide in patients with a newly diagnosed glioblastoma. This study is a single-center, open-label, dose-finding phase I trial. Patients received oral chloroquine daily starting one week before the course of chemoradiation (temozolomide 75 mg/m2/d) until the end of radiotherapy (59.4 Gy/33 fractions). Thirteen patients were included in the study (n = 6: 200 mg, n = 3: 300 mg, n = 4: 400 mg chloroquine). A total of 44 adverse events, possibly related to chloroquine, were registered including electrocardiogram QTc prolongation, irreversible blurred vision and nausea/vomiting resulting in cessation of temozolomide or delay of adjuvant cycles. The maximum tolerated dose was 200 mg chloroquine. Median overall survival was 16 months (range 2–32). Median survival was 11.5 months for EGFRvIII- patients and 20 months for EGFRvIII+ patients. A daily dose of 200 mg chloroquine was determined to be the maximum tolerated dose when combined with radiotherapy and concurrent temozolomide for newly diagnosed glioblastoma. Favorable toxicity and promising overall survival support further clinical studies. Abbreviations: AE: adverse events; CQ: chloroquine; DLT: dose-limiting toxicities; EGFR: epidermal growth factor receptor; GBM: glioblastoma; HCQ: hydroxychloroquine; IDH1/2: isocitrate dehydrogenase (NADP(+)) 1/2; MTD: maximum tolerated dose; CTC: National Cancer Institute Common Toxicity Criteria; MGMT: O-6-methylguanine-DNA methyltransferase; OS: overall survival; po qd: per os quaque die; SAE: serious adverse events; TMZ: temozolomide; WHO: World Health Organization

Glioblastoma (GBM) is the most malignant primary brain tumor for which no curative treatment options exist. Non-invasive qualitative (Visually Accessible Rembrandt Images (VASARI)) and quantitative (radiomics) imaging features to predict prognosis and clinically relevant markers for GBM patients are needed to guide clinicians. A retrospective analysis of GBM patients in two neuro-oncology centers was conducted. The multimodal Cox-regression model to predict overall survival (OS) was developed using clinical features with VASARI and radiomics features in isocitrate dehydrogenase (IDH)-wild type GBM. Predictive models for IDH-mutation, 06-methylguanine-DNA-methyltransferase (MGMT)-methylation and epidermal growth factor receptor (EGFR) amplification using imaging features were developed using machine learning. The performance of the prognostic model improved upon addition of clinical, VASARI and radiomics features, for which the combined model performed best. This could be reproduced after external validation (C-index 0.711 95% CI 0.64–0.78) and used to stratify Kaplan–Meijer curves in two survival groups (p-value &lt, 0.001). The predictive models performed significantly in the external validation for EGFR amplification (area-under-the-curve (AUC) 0.707, 95% CI 0.582–8.25) and MGMT-methylation (AUC 0.667, 95% CI 0.522–0.82) but not for IDH-mutation (AUC 0.695, 95% CI 0.436–0.927). The integrated clinical and imaging prognostic model was shown to be robust and of potential clinical relevance. The prediction of molecular markers showed promising results in the training set but could not be validated after external validation in a clinically relevant manner. Overall, these results show the potential of combining clinical features with imaging features for prognostic and predictive models in GBM, but further optimization and larger prospective studies are warranted.

Summary Tumor-educated platelets (TEPs) are potential biomarkers for cancer diagnostics. We employ TEP-derived RNA panels, determined by swarm intelligence, to detect and monitor glioblastoma. We assessed specificity by comparing the spliced RNA profile of TEPs from glioblastoma patients with multiple sclerosis and brain metastasis patients (validation series, n = 157; accuracy, 80%; AUC, 0.81 [95% CI, 0.74–0.89; p < 0.001]). Second, analysis of patients with glioblastoma versus asymptomatic healthy controls in an independent validation series (n = 347) provided a detection accuracy of 95% and AUC of 0.97 (95% CI, 0.95–0.99; p < 0.001). Finally, we developed the digitalSWARM algorithm to improve monitoring of glioblastoma progression and demonstrate that the TEP tumor scores of individual glioblastoma patients represent tumor behavior and could be used to distinguish false positive progression from true progression (validation series, n = 20; accuracy, 85%; AUC, 0.86 [95% CI, 0.70–1.00; p < 0.012]). In conclusion, TEPs have potential as a minimally invasive biosource for blood-based diagnostics and monitoring of glioblastoma patients., Graphical Abstract, Highlights TEP RNA enables blood-based brain tumor diagnostics TEP RNA is dynamic throughout anti-tumor treatment TEP RNA may be employed for therapy monitoring, Sol et al. show that tumor-educated platelets (TEPs) can be employed for detection of glioblastoma. Glioblastoma TEP RNA profiles can be differentiated from patients with metastatic brain cancer or MS. Furthermore, the tumor signals in TEPs are dynamic, indicating that TEPs can be employed for blood-based therapy monitoring.

BACKGROUND & AIMS: Chemoradiation and bioradiation (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often comes with high toxicity rates, interfering with oral intake and leading to temporary tube feeding (TF) dependency. High-quality scientific evidence for indicators of prophylactic gastrostomy insertion is not available. The aim of this retrospective cohort study was to develop a prediction model to identify patients who need prophylactic gastrostomy insertion, defined as the expected use of TF for at least four weeks.METHODS: Four-hundred-fifty LAHNSCC patients receiving CRT/BRT with curative intent between 2013 and 2016 were included in the study. Primary outcome was TF-dependency for four weeks or longer. Patient, tumor, and treatment characteristics were extracted from the medical records and their effects on the use of TF were analyzed using univariable and multivariable analysis. The prediction model was internally validated using bootstrapping techniques.RESULTS: Sixty-five percent (294/450 patients) required TF for four weeks or longer. Variables included in the model were: body mass index and adjusted diet at start of CRT/BRT, percentage weight change at baseline, World Health Organization performance status, tumor subsite, TNM-classification, CRT/BRT, mean radiation dose on the contralateral submandibular and parotid gland. The corrected Area Under the Curve after internal validation was 72.3%, indicating good discriminative properties of the prediction model.CONCLUSIONS: We developed and internally validated a prediction model that is intended to estimate TF-dependency for at least four weeks in LAHNSCC patients treated with CRT/BRT. This model can be used as a tool to support personalized decision making on prophylactic gastrostomy insertion.

We proposed a pooling-based radiomics feature selection method and showed how it would be applied to the clinical question of predicting one-year survival in 130 patients treated for glioma by radiotherapy. The method combines filter, wrapper and embedded selection in a comprehensive process to identify useful features and build them into a potentially predictive signature. The results showed that non-invasive CT radiomics were able to moderately predict overall survival and predict WHO tumour grade. This study reveals an associative inter-relationship between WHO tumour grade, CT-based radiomics and survival, that could be clinically relevant.

PURPOSE Precision medicine trials in glioblastoma (GBM) are often conducted at tumor recurrence. However, second surgeries for recurrent GBM are not routinely performed, and therefore, molecular data for trial inclusion are predominantly derived from the primary sample. This study aims to establish whether molecular targets change during tumor progression and, if so, whether this affects precision medicine trial design. MATERIALS AND METHODS We collected 186 pairs of primary-recurrent GBM samples from patients receiving chemoradiotherapy with temozolomide and sequenced approximately 300 cancer genes. MGMT, TERT, and EGFRvIII status was individually determined. RESULTS The molecular profile of our cohort was identical to that of other GBM cohorts ( IDH wild-type [WT], 95%; EGFR amplified, approximately 50%), indicating that patients amenable to second surgery do not represent a specific molecular subtype. Molecular events in IDH WT GBMs were stable in approximately 80% of events, but changes in mutation status were observed for all examined genes (range, approximately 90% and 60% for TERT and EGFR mutations, respectively), and such changes strongly affected targeted trial size and design. A similar pattern of GBM driver instability was observed within MGMT promoter–methylated tumors. MGMT promoter methylation status remained prognostic at tumor recurrence. The observation that hypermutation at GBM recurrence was rare (8%) and not correlated with outcome was relevant for immunotherapy-based treatments. CONCLUSION This large cohort of matched primary and recurrent IDH WT tumors establishes the frequency of GBM driver instability after chemoradiotherapy with temozolomide. This allows per gene or pathway calculation of trial size at tumor recurrence, using molecular data of the primary tumor only. We also identify genes for which repeat surgery is necessary because of low mutation retention rate.