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Pretreatment and on-treatment ctDNA and tissue biomarkers predict recurrence in patients with stage IIIB-D/IV melanoma treated with adjuvant immunotherapy: CheckMate 915.
No full textPURPOSE: CheckMate 915 (NCT03068455) compared adjuvant nivolumab monotherapy versus combination nivolumab+ipilimumab in patients with resected stage III/IV melanoma. This exploratory analysis was performed to identify biomarkers that correlate with benefit from adjuvant immunotherapy. PATIENTS AND METHODS: 1,844 patients received nivolumab 480 mg every 4 weeks or nivolumab 240 mg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks. Tumor and peripheral biomarkers were evaluated, including tumor-informed circulating tumor DNA (ctDNA) at postresection baseline and on-treatment, for their association with recurrence-free survival and distant metastases-free survival. RESULTS: Biomarker analyses were conducted in 60-96% of the intention-to-treat population. ctDNA positivity at baseline (seen in 16.2% of patients) and on-treatment was associated with higher risk of recurrence than ctDNA negativity (HR, 1.97; 95% CI, 1.57 to 2.46), with a high specificity (87%) and modest sensitivity (39%). ctDNA status, tumor mutational burden (TMB) status (TMB < or ≥350 mutations/tumor) and interferon gamma-RNA signature score (< or ≥median) evaluated together, as well as ctDNA status with tumor CD8 or cell programmed death ligand 1 expression, were more predictive of survival than ctDNA alone. Tumor bulk RNA-seq expression patterns identified gene expression at baseline associated with recurrence. CONCLUSIONS: This study represents the largest assessment of ctDNA and other baseline tumor and peripheral biomarkers for predicting recurrence-free survival in patients with resected melanoma receiving adjuvant immunotherapy. ctDNA alone and in combination with more established biomarkers predicted recurrence-free and distant metastasis-free survival and has potential utility for assessing and monitoring the risk of recurrence in patients with resected melanoma treated with immunotherapy in the adjuvant setting. TRIAL REGISTRATION NUMBER: NCT03068455
Testing a 5-fraction Simultaneous Integrated Boost in Radiotherapy for Breast Cancer: The UK FAST-Forward Boost Trial Opens to Recruitment.
No full textEvaluation of the Role of Stereotactic Body Radiotherapy (SBRT) in Advanced Breast Cancer
No full textBackground: Stereotactic body radiotherapy (SBRT) delivers excellent local control (LC) with minimal toxicity in oligometastatic breast cancer (OMBC). However, randomised controlled trials have produced conflicting survival outcomes, leaving uncertainty about which patients benefit most from SBRT. This thesis evaluates the role of SBRT in OMBC and aims to identify the subgroups most likely to benefit. Methods: A retrospective analysis compares 10-year outcomes of metachronous versus synchronous OMBC treated with SBRT. The PERSPECTIVE study explores patients’ perspectives on SBRT for OMBC, while an international survey explores clinicians’ perspectives. The utility of Contrast Clearance Analysis (CCA) MRI was evaluated in distinguishing treatment effects from active brain metastases post-SRS, where standard contrast-enhanced MRI findings were equivocal. The TRAK-ER SBRT sub-study investigates circulating tumour DNA (ctDNA) changes before and after SBRT and the risk of early disease progression in OMBC. It also investigates whether whole-body MRI (WBMRI) detects further metastases compared to standard imaging. Results: SBRT offers 2-year LC rates of over 85%, comparable for synchronous and metachronous OMBC. In the PERSPECTIVE study, patients prioritised extension of life but would consider SBRT for its LC and durable pain relief benefits. The clinician survey demonstrates that most clinicians consider SBRT for the treatment of metachronous and synchronous OMBC and highlight LC as a key future trial endpoint. CCA appears to add value to standard contrast-enhanced MRI for distinguishing treatment-related effects from active disease. The ongoing TRAK-ER SBRT sub-study has opened to recruitment in the UK and France.Conclusions: SBRT provides excellent LC for synchronous and metachronous OMBC. Patients and clinicians support the use of SBRT for OMBC and consistently rate LC as a key priority. CCA offers additional diagnostic value in differentiating treatment effects from active disease post-SRS. The TRAK-ER sub-study aims to provide insights into the role of ctDNA analysis and WBMRI in identifying OMBC patients most likely to benefit from SBRT
Accuracy of continuous glucose monitoring during noncardiac surgery: a prospective, blinded observational multicentre cohort study.
No full textBACKGROUND: Hyperglycaemia after noncardiac surgery is rarely detected outside of the critical care environment, yet occurs commonly and is associated with excess complications including infections and myocardial injury. Systematic, prospectively collected data regarding the accuracy of continuous glucose monitoring commenced immediately before surgery and throughout the early perioperative period are lacking. METHODS: We prospectively enrolled patients aged >50 yr undergoing noncardiac surgery who required at least 24 h of hospital stay. We used real-time continuous glucose monitoring (Dexcom G7 sensor, placed in the upper outer arm) (Dexcom, San Diego, CA, USA) with reference values from arterial blood glucose measurements by amperometry. The primary outcome was the overall mean difference (bias) before surgery, at end of surgery, and 24 h after surgery (Bland-Altman analysis). Secondary outcomes included the mean absolute relative difference and surveillance error grid analyses. RESULTS: We compared paired blood (73% arterial) and continuous glucose monitoring glucose values at each prespecified timepoint in 118 participants (64/118 [54%] female; mean age: 66 [range: 51-89] yr; 25% with diabetes mellitus). The overall bias between continuous glucose monitoring and blood glucose from measurements at each of the three timepoints in the first 24 h after induction of anaesthesia was 0.38 mM (95% confidence interval [95% CI]: 0.23-0.53; n=340 paired readings). Bias decreased from before the start of surgery (1.08 mM [95% CI: 0.87-1.29]; n=116) to 0.15 mM at the end of surgery (95% CI: -0.15 to 0.46; n=113). Mean absolute relative difference ranged from 12.0% to 18.3%. Error grid analyses found that >98% continuous glucose monitoring values were within acceptable risk ranges. CONCLUSIONS: The accuracy of state-of-the-art continuous glucose monitoring is sufficient for perioperative use and could enhance perioperative surveillance of dysglycaemia. CLINICAL TRIAL REGISTRATION: ISRCTN46862025
Structural insights into lipid membrane binding by human ferlins.
No full textFerlins are ancient membrane proteins with a unique architecture, and play central roles in crucial processes that involve Ca2+-dependent vesicle fusion. Despite their links to multiple human diseases and numerous functional studies, a mechanistic understanding of how these multi-C2 domain-containing proteins interact with lipid membranes to promote membrane remodelling and fusion is currently lacking. Here we obtain near-complete cryo-electron microscopy structures of human myoferlin and dysferlin in their Ca2+- and lipid-bound states. We show that ferlins adopt compact, ring-like tertiary structures upon membrane binding. The top arch of the ferlin ring, composed of the C2C-C2D region, is rigid and exhibits only little variability across the observed functional states. In contrast, the N-terminal C2B and the C-terminal C2F-C2G domains cycle between alternative conformations and, in response to Ca2+, close the ferlin ring, promoting tight interaction with the target membrane. Probing key domain interfaces validates the observed architecture, and informs a model of how ferlins engage lipid bilayers in a Ca2+-dependent manner. This work reveals the general principles of human ferlin structures and provides a framework for future analyses of ferlin-dependent cellular functions and disease mechanisms
Radiation-induced extracellular matrix remodelling drives prognosis and predicts radiotherapy response in muscle-invasive bladder cancer
No full textMultimodal characterisation of the longitudinal radiation-induced changes in the immune landscape of primary breast cancers
No full textDespite ongoing interest in combining radiotherapy (RT) with immunotherapy in breast cancer
management, there is a lack of understanding of the e=ect of RT alone on the in situ tumour
microenvironment (TME) and anti-tumour immune response. Utilising a unique dataset of clinical
samples from the PRADA and Neo-RT trials, which tested neoadjuvant RT (NART) in primary breast
cancer patients, this thesis sought to characterise longitudinal in situ and systemic immunoradiobiological
changes.
Assessment of stromal tumour-infiltrating lymphocytes (sTILs) using both manual and deep learningbased
methods suggested that NART contributes to a significant and long-term loss of lymphocytes
from the TME, mirrored by systemic lymphodepletion. However, associations between sTILs and
patient outcomes suggested complex underlying immune biology within the irradiated TME. To further
understand the phenotypic composition and spatial distribution of these sTILs, two multiplex
immunofluorescence panels were applied and revealed significant enrichment of Granzyme B+ cells
among sTILs following NART, as well as di=erences in changes to CD20+ B-cell and FoxP3+ Treg
representation between responders and non-responders during NART. On-treatment enrichment of
immune hotspot-related cellular neighbourhoods within the TME also associated with better response
to treatment. In parallel, characterisation of the T-cell receptor (TCR) repertoire showed that early
NART-induced changes to clustering and clonotype abundance in the tumour associated with better
response.
Altogether this thesis presents novel experimental data to address the existing knowledge gap of how
RT itself a=ects the in situ breast TME, at clinically pertinent RT dose-fractionations, and importantly
suggests that longitudinal radiation-induced immune dynamics may associate with eventual
response to treatment. This work thus contributes valuable insights to the ongoing discussion of how
the immunomodulatory e=ects of RT can be optimally and rationally used for synergistic
combinations with immunomodulatory agents, in this new era of breast cancer immunotherapy
Modulating Redox Biology to Improve Radiation Responses.
No full textRedox biology plays an important role in cancer progression and therapy resistance. Tumor cells maintain elevated levels of reactive oxygen species to support proliferation while upregulating antioxidant defences to avoid oxidative cell death. Radiotherapy, a standard treatment for over half of all cancer patients, relies on the generation of reactive oxygen species and adequate oxygen availability for efficacy. However, hypoxic tumor microenvironments and enhanced antioxidant systems contribute significantly to radioresistance. This redox imbalance, which is characteristic of tumor cells, presents a therapeutic opportunity where modifying redox biology may sensitise tumors to radiation and promote cell death. In this review, we examine how redox signalling supports tumor survival and highlight emerging clinical strategies that target redox pathways to overcome resistance and improve radiotherapy outcomes
Camizestrant in Combination with Three Globally Approved CDK4/6 Inhibitors in Women with ER+, HER2- Advanced Breast Cancer: Results from SERENA-1.
No full textPURPOSE: This trial investigated the safety and tolerability of camizestrant with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in women with estrogen receptor-positive, HER2- advanced breast cancer. PATIENTS AND METHODS: SERENA-1 (NCT03616587) is a phase I, multipart, open-label study in women with refractory estrogen receptor-positive, HER2- advanced breast cancer. Patients received oral once-daily camizestrant 75 or 150 mg plus abemaciclib; camizestrant 75, 150, or 300 mg plus palbociclib; or camizestrant 75 mg plus ribociclib 400 or 600 mg. Safety/tolerability, pharmacokinetics, efficacy, and impact on estrogen receptor 1 mutation ctDNA were assessed. RESULTS: By September 16, 2024 (data cutoff), 53 patients had received camizestrant plus abemaciclib, 78 camizestrant plus palbociclib, and 60 camizestrant plus ribociclib. Patients had a median of 2 (range, 0-7) prior regimens for advanced disease; 83% had received a prior CDK4/6i and 59% prior fulvestrant. The most common treatment-emergent adverse events for camizestrant 75 mg (phase III dose) plus each CDK4/6i were diarrhea [with abemaciclib (87.5%)] and neutropenia [with palbociclib (80%) and ribociclib (32.1% for 400 mg and 53.1% for 600 mg)]. The median camizestrant tmax was ∼4 hours postdose across combinations, with an estimated half-life of 9.5 to 17 hours. No clinically meaningful drug-drug interactions were evident. In this heavily pretreated population, CBR24 was 49.5% and the median progression-free survival was 7.4 months (95% confidence interval, 5.3-9.3), with antitumor activity across all combinations, including patients previously treated with CDK4/6i and/or fulvestrant, with or without estrogen receptor 1 mutation. CONCLUSIONS: Camizestrant is well tolerated, with antitumor activity in combination with CDK4/6i. These results support the evaluation of camizestrant 75 mg plus standard CDK4/6i doses in phase III trials
The synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types.
No full textMetastatic uveal melanoma is an aggressive disease with limited effective therapeutic options. To comprehensively map monogenic and digenic dependencies, we performed CRISPR-Cas9 screening in ten extensively profiled human uveal melanoma cell line models. Analysis involved genome-wide single-gene and combinatorial paired-gene CRISPR libraries. Among our 76 uveal melanoma-specific essential genes and 105 synthetic lethal gene pairs, we identified and validated the CDP-diacylglycerol synthase 2 gene (CDS2) as a genetic dependency in the context of low CDP-diacylglycerol synthase 1 gene (CDS1) expression. We further demonstrate that CDS1/CDS2 forms a synthetic lethal interaction in vivo and reveal that CDS2 knockout results in the disruption of phosphoinositide synthesis and increased cellular apoptosis and that re-expression of CDS1 rescues this cell fitness defect. We extend our analysis using pan-cancer data, confirming increased CDS2 essentiality in diverse tumor types with low CDS1 expression. Thus, the CDS1/CDS2 axis is a therapeutic target across a range of cancers