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  • Chemotherapy for advanced gallbladder cancer (GBC): a systematic review and meta-analysis

    Azizi, Alexander; Lamarca, Angela; McNamara, Mairead G; Valle, Juan W; Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, United Kingdom; Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Cambridge (2021)
    Background: The benefit from chemotherapy, specifically for patients with gallbladder cancer (GBC), has been poorly explored since GBC is mostly studied jointly with other biliary tract cancers (BTC). Methods: Eligible studies reporting outcome of palliative systemic chemotherapy for advanced GBC were identified through MEDLINE, cross-referencing and conferences (PROSPERO-CRD42019155745). Meta-analysis of proportions and calculation of pooled weighted means were performed. Results: 58 eligible studies (n = 1,986 patients); cisplatin/gemcitabine (33% of patients), gemcitabine/oxaliplatin (14%) or gemcitabine monotherapy (9%). Estimated pooled overall radiological response rate(ORR), and pooled weighted mean progression-free (PFS) and overall survivals (OS) were 23.2% (95%-CI 20.0-26.5) (I2: 52.5% (p < 0.001)), 4.8 months (95%-CI 4.3-5.2) and 8.3 months (95%CI 7.6-8.9), respectively. Patients with non-GBC BTCs achieved a lower ORR than GBC [odds ratio 0.65 (95% CI, 0.50-0.84)]. Conclusions: GBC benefit from chemotherapy differs from other BTCs, with shorter PFS/OS despite higher ORR; new treatment options are urgently required for management of advanced GBC.
  • Stereotactic radiation for lung cancer: a practical approach to challenging scenarios

    Andruska, N.; Stowe, H. B.; Crockett, Cathryn; Liu, W.; Palma, D.; Faivre-Finn, Corinne; Badiyan, S. N.; Washington University School of Medicine, St Louis, MO, USA (2021)
    Stereotactic body radiation therapy (SBRT) is an effective and well-tolerated treatment for medically inoperable patients with early-stage non-small cell lung carcinoma (NSCLC). SBRT is a noninvasive treatment involving the delivery of ablative radiation doses with high precision over the course of a few treatments. Relative to conventionally fractionated radiation, SBRT achieves superior local control and survival. SBRT utilization has increased dramatically over the past 15 years and is currently considered the standard-of-care in cases of inoperable early-stage NSCLC. It is being increasingly applied to more complex patient populations at higher risk of treatment-related toxicity. In these more complex patients, there is an increasing need to balance patient and treatment factors in selecting the optimal patients for SBRT. Here we review several challenging clinical scenarios commonly encountered in thoracic multidisciplinary tumor boards.
  • Biases in study design, implementation, and data analysis that distort the appraisal of clinical benefit and ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scoring

    Gyawali, B.; de Vries, E. G. E.; Dafni, U.; Amaral, T.; Barriuso, Jorge; Bogaerts, J.; Calles, A.; Curigliano, G.; Gomez-Roca, C.; Kiesewetter, B.; et al. (2021)
    Background: The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated, widely used tool developed to score the clinical benefit from cancer medicines reported in clinical trials. ESMO-MCBS scores assume valid research methodologies and quality trial implementation. Studies incorporating flawed design, implementation, or data analysis may generate outcomes that exaggerate true benefit and are not generalisable. Failure to either indicate or penalise studies with bias undermines the intention and diminishes the integrity of ESMO-MCBS scores. This review aimed to evaluate the adequacy of the ESMO-MCBS to address bias generated by flawed design, implementation, or data analysis and identify shortcomings in need of amendment. Methods: As part of a refinement of the ESMO-MCBS, we reviewed trial design, implementation, and data analysis issues that could bias the results. For each issue of concern, we reviewed the ESMO-MCBS v1.1 approach against standards derived from Helsinki guidelines for ethical human research and guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, the Food and Drugs Administration, the European Medicines Agency, and European Network for Health Technology Assessment. Results: Six design, two implementation, and two data analysis and interpretation issues were evaluated and in three, the ESMO-MCBS provided adequate protections. Seven shortcomings in the ability of the ESMO-MCBS to identify and address bias were identified. These related to (i) evaluation of the control arm, (ii) crossover issues, (iii) criteria for non-inferiority, (iv) substandard post-progression treatment, (v) post hoc subgroup findings based on biomarkers, (vi) informative censoring, and (vii) publication bias against quality-of-life data. Conclusion: Interpretation of the ESMO-MCBS scores requires critical appraisal of trials to understand caveats in trial design, implementation, and data analysis that may have biased results and conclusions. These will be addressed in future iterations of the ESMO-MCBS.
  • Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

    Dingemans, A. C.; Früh, M.; Ardizzoni, A.; Besse, B.; Faivre-Finn, Corinne; Hendriks, L. E.; Lantuejoul, S.; Peters, S.; Reguart, N.; Rudin, C. M.; et al. (2021)
  • EHA/ESMO clinical practice guidelines for the management of malignant lymphoma: recommendations for the second phase of the COVID-19 pandemic

    Dreyling, M.; Aurer, I.; Federico, M.; Jerkeman, M.; Kersten, M. J.; Linton, Kim M; Mey, U.; Tilly, H.; Buske, C.; Department of Medicine III, LMU Hospital, Munich, Germany (2021)
  • A European network for teenagers and young adults with cancer

    Bozovic-Spasojevic, I.; Balsat, M.; Blondeel, A.; Castleton, Anna; De Munter, J.; Gamble, A. S.; Kienesberger, A.; Konsoulova-Kirova, A. A.; Rizvi, K.; Schneider, C.; et al. (2021)
  • Dosimetric predictors of radiotherapy-induced lymphocytopenia in lung cancer

    Joseph, N.; Choudhury, Ananya; Ministry of Health, Colombo, Sri Lanka; Sri Lanka Cancer Research Group, Maharagama, Sri Lanka. (2021)
  • Retrograde radiological gastrostomy technique and retrograde stent placement in a completely occluded cervical esophagus

    Bi, Yixi; Edwards, Derek; Mullan, Damian; Laasch, Hans-Ulrich; Radiology, The Christie Hospital, Manchester (2021)
    Malignant obstruction of the cervical esophagus presents some anatomical and technical challenges when considering radiologic or endoscopic intervention. This case report describes the failure of antegrade access to place a gastrostomy tube and stent due to complete luminal occlusion from an esophageal tumor. The ultrasound-guided percutaneous gastric puncture was performed to achieve retrograde pneumodistension to allow radiologic gastrostomy insertion. Subsequently, the cervical esophagus was retrogradely cannulated via insertion of a guidewire from the gastrostomy site. A distal release esophageal stent was then inserted over the wire and deployed from the mouth in an antegrade manner. However, due to the unpredictable proximal shortening of distal release stents, this stent was eventually shortened and displaced so that it no longer covered the top of the tumor stricture, and further antegrade access failed. Once more, a retrograde access approach was adopted via the gastrostomy stoma, a guidewire and catheter were passed retrogradely through the original stent and out through the mouth. A distal release stent system was then inserted in a retrograde manner via the gastrostomy stoma, effectively making it a proximal release stent which enabled more precise positioning of the stent above the tumor. Palliation was achieved until death, and beyond expected mean survival.
  • Lenvatinib in patients with advanced grade 1/2 pancreatic and gastrointestinal neuroendocrine tumors: results of the Phase II TALENT Trial (GETNE1509)

    Capdevila, J.; Fazio, N.; Lopez, C.; Teulé, A.; Valle, Juan W; Tafuto, S.; Custodio, A.; Reed, N.; Raderer, M.; Grande, E.; et al. (2021)
    Purpose: Approved systemic therapies for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown limited capacity to reduce tumor burden and no antitumor activity after progression to targeted agents (TAs). We investigated the efficacy and safety of lenvatinib in patients with previously treated advanced GEP-NETs. Patients and methods: This was a multicenter, single-arm, open-label, phase II trial with two parallel cohorts ( identifier: NCT02678780) involving 21 institutions in 4 European countries. Eligible patients had histologically confirmed advanced grade 1-2 pancreatic (panNET) or GI (GI-NET) NETs with documented tumor progression after treatment with a TA (panNET) or somatostatin analogs (GI-NET). Patients were treated with lenvatinib 24 mg once daily until disease progression or treatment intolerance. The primary end point was overall response rate by central radiology review. Secondary end points included progression-free survival, overall survival, duration of response, and safety. Results: Between September 2015 and March 2017, a total of 111 patients were enrolled, with 55 (panNET) and 56 (GI-NET) patients in each cohort. The median follow-up was 23 months. The overall response rate was 29.9% (95% CI, 21.6 to 39.6): 44.2% (panNET) and 16.4% (GI-NET). The median (range) duration of response was 19.9 (8.4-30.8) and 33.9 (10.6-38.3) months in the panNET and GI-NET groups, respectively. The median progression-free survival was 15.7 months (95% CI, 14.1 to 19.5). The most common adverse events were fatigue, hypertension, and diarrhea; 93.7% of patients required dose reductions or interruptions. Conclusion: We report the highest centrally confirmed response reported to date with a multikinase inhibitor in advanced GEP-NETs, with a particularly strong response in the panNET cohort. This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other TAs, suggesting the potential value of lenvatinib in the treatment of advanced GEP-NETs.
  • Liver embolisation for patients with neuroendocrine neoplasms: systematic review induced lymphocytopenia in lung cancer

    Kanabar, R.; Barriuso, Jorge; McNamara, Mairead G; Mansoor, Was; Hubner, Richard A; Valle, Juan W; Lamarca, Angela; Manchester Medical School, The University of Manchester, Manchester, (2021)
    Background: Liver embolisation is one of the treatment options available for patients diagnosed with neuro-endocrine neoplasms (NEN). It is still uncertain whether the benefits of the various types of embolisation treatments truly outweigh the complications in NENs. This systematic review assesses the available data relating to liver embolisation in patients with NENs. Methods: Eligible studies (identified using MEDLINE-PubMed) were those reporting data on NEN patients who had undergone any type of liver embolisation. The primary end points were best radiological response and symptomatic response; secondary end-points included progression-free survival (PFS), overall survival (OS) and toxicity. Results: Of 598 studies screened, 101 were eligible: 16 were prospective (15.8%). The eligible studies included a total of 5,545 NEN patients, with a median of 39 patients per study (range 5-214). Pooled rate of partial response was 36.6% (38.9% achieved stable disease) and 55.2% of patients had a symptomatic response to therapy when pooled data were analysed. The median PFS and OS were 18.4 months (95% CI 15.5-21.2) and 40.7 months (95% CI 35.2-46.2) respectively. The most common toxicities were found to be abdominal pain (48.8%) and nausea (48.1%). Outcome did not significantly vary depending on the type of embolisation performed. Conclusion: Liver embolisation provides adequate symptom relief for patients with carcinoid syndrome and is also able to reach partial response in a significant proportion of patients and a reasonable PFS. Quality of studies was limited, highlighting the need of further prospective studies to confirm the most suitable form of liver embolisation in NENs.
  • Robust deep learning-based segmentation of glioblastoma on routine clinical mri scans using sparsified training

    Eijgelaar, R. S.; Visser, M.; Müller, D. M. J.; Barkhof, F.; Vrenken, H.; van Herk, Marcel; Bello, L.; Conti Nibali, M.; Rossi, M.; Sciortino, T.; et al. (2020)
    Purpose: To improve the robustness of deep learning-based glioblastoma segmentation in a clinical setting with sparsified datasets. Materials and methods: In this retrospective study, preoperative T1-weighted, T2-weighted, T2-weighted fluid-attenuated inversion recovery, and postcontrast T1-weighted MRI from 117 patients (median age, 64 years; interquartile range [IQR], 55-73 years; 76 men) included within the Multimodal Brain Tumor Image Segmentation (BraTS) dataset plus a clinical dataset (2012-2013) with similar imaging modalities of 634 patients (median age, 59 years; IQR, 49-69 years; 382 men) with glioblastoma from six hospitals were used. Expert tumor delineations on the postcontrast images were available, but for various clinical datasets, one or more sequences were missing. The convolutional neural network, DeepMedic, was trained on combinations of complete and incomplete data with and without site-specific data. Sparsified training was introduced, which randomly simulated missing sequences during training. The effects of sparsified training and center-specific training were tested using Wilcoxon signed rank tests for paired measurements. Results: A model trained exclusively on BraTS data reached a median Dice score of 0.81 for segmentation on BraTS test data but only 0.49 on the clinical data. Sparsified training improved performance (adjusted P < .05), even when excluding test data with missing sequences, to median Dice score of 0.67. Inclusion of site-specific data during sparsified training led to higher model performance Dice scores greater than 0.8, on par with a model based on all complete and incomplete data. For the model using BraTS and clinical training data, inclusion of site-specific data or sparsified training was of no consequence. Conclusion: Accurate and automatic segmentation of glioblastoma on clinical scans is feasible using a model based on large, heterogeneous, and partially incomplete datasets. Sparsified training may boost the performance of a smaller model based on public and site-specific data.Supplemental material is available for this article.Published under a CC BY 4.0 license.
  • How to manage atrial fibrillation secondary to ibrutinib

    Essa, H.; Lodhi, Taha; Dobson, R.; Wright, D.; Lip, G. Y. H.; Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool Heart & Chest Hospital, Liverpool, (2021)
    Atrial fibrillation (AF) is the most common cardiac arrhythmia and a significant cause of cardiovascular morbidity and mortality worldwide (1). Ibrutinib is a covalent irreversible inhibitor of Bruton’s tyrosine kinase (BTK) used in the treatment of B-cell cancers such as chronic lymphocytic leukemia and mantle cell lymphoma. It is estimated that up to 16% of patients develop ibrutinibinduced AF, which can be a therapy-limiting side effect. The mechanisms are not clear but may relate to direct inhibition of BTK, which is expressed in cardiac tissue (2). In this primer, we use a clinical case of a patient with chronic lymphocytic leukemia to demonstrate the challenges and management considerations of AF secondary to ibrutinib.
  • From BRCA1 to polygenic risk scores: mutation-associated risks in breast cancer-related genes

    Woodward, E. R.; van Veen, E. M.; Evans, D Gareth R; Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, (2021)
    Background: There has been huge progress over the last 30 years in identifying the familial component of breast cancer. Summary: Currently around 20% is explained by the high-risk genes BRCA1 and BRCA2, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes ATM and CHEK2. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. Key-Messages: There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as CDH1 and TP53, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.
  • Prognostic significance of genome-wide DNA methylation profiles within the randomised, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma

    Tesileanu, C. M. S.; van den Bent, M. J.; Sanson, M.; Wick, W.; Brandes, A. A.; Clement, P. M.; Erridge, S. C.; Vogelbaum, M. A.; Nowak, A. K.; Baurain, J. F.; et al. (2021)
    Background: Survival in patients with IDH1/2 mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients. Methods: The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumour classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using one of two glioma-tailored NGS panels. The primary endpoint was overall survival measured from date of randomization. Results: Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumours. Of these, 432 tumours were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazards model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication. Conclusion: Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification
  • The promise of proton beam therapy for oesophageal cancer: a systematic review of dosimetric and clinical outcomes

    Nicholas, O.; Prosser, S.; Mortensen, H. R.; Radhakrishna, Ganesh; Hawkins, M. A.; Gwynne, S. H.; South West Wales Cancer Centre, Swansea, UK; Swansea University Medical School, Swansea, UK (2021)
    Aims: Due to its physical advantages over photon radiotherapy, proton beam therapy (PBT) has the potential to improve outcomes from oesophageal cancer. However, for many tumour sites, high-quality evidence supporting PBT use is limited. We carried out a systematic review of published literature of PBT in oesophageal cancer to ascertain potential benefits of this technology and to gauge the current state-of-the-art. We considered if further evaluation of this technology in oesophageal cancer is desirable. Materials and methods: A systematic literature search of Medline, Embase, Cochrane Library and Web of Science using structured search terms was carried out. Inclusion criteria included non-metastatic cancer, full articles and English language studies only. Articles deliberating technical aspects of PBT planning or delivery were excluded to maintain a clinical focus. Studies were divided into two sections: dosimetric and clinical studies; qualitatively synthesised. Results: In total, 467 records were screened, with 32 included for final qualitative synthesis. This included two prospective studies with the rest based on retrospective data. There was heterogeneity in treatment protocols, including treatment intent (neoadjuvant or definitive), dose, fractionation and chemotherapy used. Compared with photon radiotherapy, PBT seemed to reduce dose to organs at risk, especially lung and heart, although not for all reported parameters. Toxicity outcomes, including postoperative complications, were reduced compared with photon radiotherapy. Survival outcomes were reported to be at least comparable with photon radiotherapy. Conclusion: There is a paucity of high-quality evidence supporting PBT use in oesophageal cancer. Wide variation in intent and treatment protocols means that the role and 'gold-standard' treatment protocol are yet to be defined. Current literature suggests significant benefit in terms of toxicity reduction, especially in the postoperative period, with comparable survival outcomes. PBT in oesophageal cancer holds significant promise for improving patient outcomes but requires robust systematic evaluation in prospective studies.
  • Indications and outcomes for repeat cytoreductive surgery and heated intra-peritoneal chemotherapy in peritoneal surface malignancy

    Sutton, Paul A; O'Dwyer, Sarah T; Barriuso, Jorge; Aziz, Omer; Selvasekar, Chelliah; Renehan, Andrew G; Wilson, Malcolm S; Colorectal and Peritoneal Oncology Centre, The Christie Hospital, UK (2021)
    Introduction: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is offered in specialist centres as a treatment for peritoneal surface tumours. Despite its demonstrated efficacy, intra-abdominal recurrence occurs in 31-57% of patients. The aim of this study is to review the early and long-term outcomes in patients who undergo repeat CRS/HIPEC. Materials and methods: A retrospective review of a prospectively maintained database of patients who had undergone repeat CRS/HIPEC for appendiceal neoplasms and colorectal peritoneal metastases (CRPM) from 2003 to 2019 was performed at a single specialist centre. Data pertaining to both short term outcomes and survival were evaluated. Results: Of 1259 patients who had undergone CRS/HIPEC, 84(6.7%) underwent repeat surgery: 45(53.6%) had pseudomyxoma peritonei (PMP) secondary to low grade appendiceal mucinous neoplasms (LAMN), 21(25.0%) had appendix carcinoma and 18(21.4%) had CRPM. Demographics, intra-operative findings and short-term outcomes were comparable across tumour types and between procedures. Median (95% CI) interval between procedures was 22.7(18.9-26.6) months and was comparable between tumour types. Median (95%CI) overall survival was not reached for the cohort overall or for those with PMP, but was 61.0(32.6-89.4) months for those with appendix cancer and 76.9(47.4-106.4) months for CRPM (p=<0.001). Survival was favourable in the PMP group (HR [95%CI] 0.044 [0.008-0.262]; p = 0.000) and unfavourable in the CC2-3 at index CRS procedure group (HR [95%CI] 25.612 [2.703-242.703]; p = 0.005). Conclusion: Our findings demonstrate that repeat cytoredutive surgery with HIPEC can result in favourable survival, especially for patients with PMP when complete cytoreduction is achieved at index operation. We recommend that detailed patient assessment is performed through an expert multidisciplinary team meeting (MDT).
  • Immune infiltrate diversity confers a good prognosis in follicular lymphoma

    Tsakiroglou, A. M.; Astley, S.; Dave, M.; Fergie, M.; Harkness, E.; Rosenberg, A.; Sperrin, M.; West, Catharine M L; Byers, R.; Linton, Kim M; et al. (2021)
    Background: Follicular lymphoma (FL) prognosis is influenced by the composition of the tumour microenvironment. We tested an automated approach to quantitatively assess the phenotypic and spatial immune infiltrate diversity as a prognostic biomarker for FL patients. Methods: Diagnostic biopsies were collected from 127 FL patients initially treated with rituximab-based therapy (52%), radiotherapy (28%), or active surveillance (20%). Tissue microarrays were constructed and stained using multiplex immunofluorescence (CD4, CD8, FOXP3, CD21, PD-1, CD68, and DAPI). Subsequently, sections underwent automated cell scoring and analysis of spatial interactions, defined as cells co-occurring within 30 μm. Shannon's entropy, a metric describing species biodiversity in ecological habitats, was applied to quantify immune infiltrate diversity of cell types and spatial interactions. Immune infiltrate diversity indices were tested in multivariable Cox regression and Kaplan-Meier analysis for overall (OS) and progression-free survival (PFS). Results: Increased diversity of cell types (HR = 0.19 95% CI 0.06-0.65, p = 0.008) and cell spatial interactions (HR = 0.39, 95% CI 0.20-0.75, p = 0.005) was associated with favourable OS, independent of the Follicular Lymphoma International Prognostic Index. In the rituximab-treated subset, the favourable trend between diversity and PFS did not reach statistical significance. Conclusion: Multiplex immunofluorescence and Shannon's entropy can objectively quantify immune infiltrate diversity and generate prognostic information in FL. This automated approach warrants validation in additional FL cohorts, and its applicability as a pre-treatment biomarker to identify high-risk patients should be further explored. The multiplex image dataset generated by this study is shared publicly to encourage further research on the FL microenvironment.
  • Outcomes of curative-intent radiotherapy in non-small cell lung cancer (NSCLC) patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD)

    Tang, C.; Mistry, H.; Bayman, Neil A; Chan, Clara; Cobben, David; Faivre-Finn, Corinne; Harris, Maggie A; Kennedy, Jason; Pemberton, Laura S; Price, Gareth J; et al. (2021)
    Outcomes of non-small cell lung cancer (NSCLC) patients with chronic obstructive pulmonary disease (COPD n = 587) and interstitial lung disease (ILD n = 34) treated with curative-intent radiotherapy were retrospectively investigated. Presence of ILD but not decreased forced expiratory volume in 1-second correlated with poor overall survival. Increased breathlessness and oxygen requirements after radiotherapy were observed in severe/very severe COPD and ILD.
  • First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors

    Falchook, G.; Infante, J.; Arkenau, H. T.; Patel, M. R.; Dean, Emma J; Borazanci, E.; Brenner, A.; Cook, Natalie; Lopez, J.; Pant, S.; et al. (2021)
    Background: We conducted a first-in-human dose-escalation study with the oral FASN inhibitor TVB-2640 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), as monotherapy and with a taxane. Methods: This completed open-label outpatient study was conducted at 11 sites in the United States and United Kingdom. Patients with previously-treated advanced metastatic solid tumors and adequate performance status and organ function were eligible. TVB-2640 was administered orally daily until PD. Dose escalation initially followed an accelerated titration design that switched to a standard 3 + 3 design after Grade 2 toxicity occurred. Disease-specific cohorts were enrolled at the MTD. Statistical analyses were primarily descriptive. Safety analyses were performed on patients who received at least 1 dose of study drug. ( identifier NCT02223247). Findings: The study was conducted from 21 November 2013 to 07 February 2017. Overall, 136 patients received TVB-2640, 76 as monotherapy (weight-based doses of 60 mg/m2 to 240 mg/m2 and flat doses of 200 and 250 mg) and 60 in combination, (weight-based doses of 60 mg/m2 to 100 mg/m2 and flat dose of 200 mg) (55 paclitaxel, 5 docetaxel). DLTs with TVB-2640 were reversible skin and ocular effects. The MTD/RP2D was 100 mg/m2. The most common TEAEs (n,%) with TVB-2640 monotherapy were alopecia (46; 61%), PPE syndrome (35; 46%), fatigue (28; 37%), decreased appetite (20; 26%), and dry skin (17; 22%), and with TVB-2640+paclitaxel were fatigue (29 ; 53%), alopecia (25; 46%), PPE syndrome (25; 46%), nausea (22; 40%), and peripheral neuropathy (20; 36%). One fatal case of drug-related pneumonitis occurred with TVB-2640+paclitaxel; no other treatment-related deaths occurred. Target engagement (FASN inhibition) and inhibition of lipogenesis were demonstrated with TVB-2640. The disease control rate (DCR) with TVB-2640 monotherapy was 42%; no patient treated with monotherapy had a complete or partial response (CR or PR). In combination with paclitaxel, the PR rate was 11% and the DCR was 70%. Responses were seen across multiple tumor types, including in patients with KRASMUT NSCLC, ovarian, and breast cancer. Interpretation: TVB-2640 demonstrated potent FASN inhibition and a predictable and manageable safety profile, primarily characterized by non-serious, reversible adverse events affecting skin and eyes. Further investigation of TVB-2640 in patients with solid tumors, particularly in KRASMUT lung, ovarian, and breast cancer, is warranted.
  • Genomic profile of advanced breast cancer in circulating tumour DNA

    Kingston, B.; Cutts, R. J.; Bye, H.; Beaney, M.; Walsh-Crestani, G.; Hrebien, S.; Swift, C.; Kilburn, L. S.; Kernaghan, S.; Moretti, L.; et al. (2021)
    The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities.

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