Predictive factors of radioiodine ablation success: results from a MEDIRAD prospective clinical study for thyroid cancer.

OBJECTIVE: Serum thyroglobulin measurements are used in the long-term management of patients with differentiated thyroid cancer following thyroidectomy and radioiodine therapy. The use of predictive biomarkers, such as post-operative stimulated thyroglobulin levels and absorbed dose, may help to identify patients at risk of disease recurrence or an unsuccessful initial treatment. METHODS: Differentiated thyroid cancer patients treated with 1.1 or 3.7 GBq of radioiodine using recombinant human thyrotropin stimulation or thyroid hormone withdrawal were recruited into observational clinical studies in France, Germany and the UK with aligned study endpoints (MEDIRAD). The maximum absorbed dose to the thyroid remnant was determined and compared to post-operative stimulated thyroglobulin with respect to its ability to predict ablation success. Radioiodine therapy success was defined as unstimulated or stimulated thyroglobulin level of <0.2 or <1.0 ng/mL 9-12 months post-radioiodine. RESULTS: Ninety-four patients had follow-up data and negative antithyroglobulin antibody tests. Seventy-eight patients (83%) were deemed excellent biochemical responders. Post-operative thyroglobulin and maximum absorbed dose predicted ablation success with receiver operating characteristic area under the curves of 0.83 ± 0.05 (P < 0.001) and 0.64 ± 0.08 (P = 0.12). A dose-response relationship between maximum absorbed dose and ablation success was found for patients with a post-operative stimulated thyroglobulin of ≥1 ng/mL. CONCLUSIONS: Predictions of ablation success using post-operative stimulated thyroglobulin or the absorbed dose to the thyroid remnant could inform personalisation of management of differentiated thyroid cancer and identify patients where further treatments or more intensive follow-up are required. Patients with a post-operative stimulated Tg of <1 ng/mL likely do not benefit from radioiodine

Pilot of lifestyle InterventiON to reducE brEast cancer Risk (PIONEER): the development, implementation and lessons from a randomised controlled study

This thesis describes current understanding of fixed and modifiable breast cancer risk factors. It goes on to describe the development and results of a randomised controlled pilot study to reduce breast cancer risk through lifestyle change, as well as describing the experience of running a preventative therapy clinic. It also discusses the lessons learnt through running a lifestyle change pilot study to reduce breast cancer risk, and improvements which could be made to future studies

Standardization of radiation therapy to Inguinal and Pelvic Lymph Nodes in Locally Advanced Cancer of the Penis, as Defined by the International Penile Advanced Cancer Trial (InPACT).

PURPOSE: InPACT addresses the optimal management of locally advanced penile cancer, aiming to prospectively evaluate the relative benefits and sequencing of surgery, chemotherapy, and chemoradiotherapy. At trial inception, radiation therapy protocols for this rare cancer lacked consistency and standardization, necessitating multicenter, international collaboration to develop comprehensive radiation therapy planning, delivery, and quality assurance guidelines. METHODS AND MATERIALS: InPACT has 2 main aims; to establish the efficacy of neoadjuvant chemotherapy or chemoradiotherapy in patients with macroscopically-involved inguinal nodes. Second, to compare prophylactic pelvic lymph node dissection plus chemoradiation to the inguinal and pelvic fields versus chemoradiation alone in patients whose inguinal node histology predicts a high risk of occult pelvic node involvement. The primary outcome measure for the trial is survival time. An international group was convened to achieve consensus on radiation therapy contouring, planning, dose, fractionation, and delivery for this rare cancer. These guidelines have been used throughout the conduct of the trial to date and form part of the radiation therapy quality assurance for each participating center. RESULTS: International consensus radiation therapy guidelines were established, encompassing risk status assessment and indications for each treatment region based on radiological and pathologic risk status of nodal basins. Guidance provides a nodal contouring atlas, addresses prepubic fat coverage, and specifies dose fractionation for both neoadjuvant and adjuvant settings, including recommendations for macroscopic disease. Trial recruitment is ongoing. Oncological and toxicity outcomes will be reported in due course. CONCLUSIONS: The InPACT radiation therapy guidelines offer a step toward international consensus on contouring for inguino-pelvic radiation therapy in penile cancer

A Phase I Clinical Trial of Intrahepatic Artery Delivery of TG6002 in Combination with Oral 5-Fluorocytosine in Patients with Liver-Dominant Metastatic Colorectal Cancer.

PURPOSE: Effective treatment for patients with metastatic cancer is limited, particularly for those with colorectal cancer with metastatic liver lesions, in which accessibility to numerous tumors is essential for favorable clinical outcomes. Oncolytic viruses (OV) selectively replicate in cancer cells; however, direct targeting of inaccessible lesions is limited when using conventional intravenous or intratumoral administration routes. PATIENTS AND METHODS: We conducted a multicenter, dose-escalation, phase I study of vaccinia virus, TG6002, via intrahepatic artery (IHA) delivery in combination with the oral prodrug 5-fluorocytosine to 15 patients with metastatic colorectal cancer. RESULTS: Successful IHA delivery of replication-competent TG6002 was achieved, as demonstrated by the virus within tumor biopsies. Functional transcription of the FCU1 transgene indicates viral replication within the tumor, with higher plasma 5-fluorouracil associated with patients receiving the highest dose of TG6002. IHA delivery of TG6002 correlated with a robust systemic peripheral immune response to the virus with activation of peripheral blood mononuclear cells, associated with a proinflammatory cytokine response and release of calreticulin, potentially indicating immunogenic cell death. Gene Ontology analyses of differentially expressed genes reveal a significant immune response at the transcriptional level in response to treatment. Moreover, an increase in the number and frequency of T-cell receptor clones against both cancer antigens and neoantigens, with elevated functional activity, may be associated with improved anticancer activity. Despite these findings, no clinical efficacy was observed. CONCLUSIONS: In summary, these data demonstrate the delivery of OV to tumor via IHA administration, associated with viral replication and significant peripheral immune activation. Collectively, the data support the need for future studies using IHA administration of OVs

Mesothelin-Targeting Armoured CAR-T Cells for Malignant Pleural Mesothelioma

Second and third generation chimeric antigen receptor (CAR)-T cells have shown significant clinical benefit in haematological malignancies, which has not yet been observed in solid tumours. Malignant pleural mesothelioma (MPM) is a highly aggressive tumour with limited treatment options and poor patient prognosis, largely attributed to the tumour-specific tumour microenvironment (TME). In these highly immunosuppressive tumours, mesothelin-targeting CAR-T cells (M11-CAR-T cells) have shown limited clinical benefit so far. Previously, combining M11-CAR-T cells with an anti-transforming growth factor-β (TGF-β) antibody has augmented their effect preclinically, owing to inhibition of immunosuppressive functions of TGF-β in the TME. This project aims to develop a CAR-T cell therapy for MPM, using the M11-CAR with downstream secretion of TGF-β inhibitory peptides (M11-β-CAR), ultimately aiming to augment M11-CAR-T cell efficacy in the context of MPM. To test this, M11-β-CAR constructs were cloned and assessed in vitro and in vivo for their function in MPM tumours and reduction of immunosuppression in the TME. The M11-β-CAR-T cells were significantly more functional than conventional M11-CAR-T cells both in vitro and in vivo. In immunocompetent MPM mouse models, the M11-β-CAR was shown to significantly inhibit tumour growth, increase proliferation and function of endogenous tumour-infiltrating lymphocytes (TILs), and significantly increased the levels of neutrophils in the tumour. The increase in neutrophils was also determined to be required for the function of the M11-β-CAR-T cells and were found to be capable of spontaneous tumour killing in responding tumours. This research is important as it will highlight the potential of M11-β-CAR-T cells in increasing CAR-T cell efficacy through limiting immunosuppression in the TME of MPM and enabling TME remodelling. The findings of this research will have an impact on treating other immunosuppressive solid tumours with armoured CAR-T cell therapy

A large-scale retrospective study in metastatic breast cancer patients using circulating tumour DNA and machine learning to predict treatment outcome and progression-free survival.

Monitoring levels of circulating tumour-derived DNA (ctDNA) provides both a noninvasive snapshot of tumour burden and also potentially clonal evolution. Here, we describe how applying a novel statistical model to serial ctDNA measurements from shallow whole genome sequencing (sWGS) in metastatic breast cancer patients produces a rapid and inexpensive predictive assessment of treatment response and progression-free survival. A cohort of 149 patients had DNA extracted from serial plasma samples (total 1013, mean samples per patient = 6.80). Plasma DNA was assessed using sWGS and the tumour fraction in total cell-free DNA estimated using ichorCNA. This approach was compared with ctDNA targeted sequencing and serial CA15-3 measurements. We identified a transition point of 7% estimated tumour fraction to stratify patients into different categories of progression risk using ichorCNA estimates and a time-dependent Cox Proportional Hazards model and validated it across different breast cancer subtypes and treatments, outperforming the alternative methods. We used the longitudinal ichorCNA values to develop a Bayesian learning model to predict subsequent treatment response with a sensitivity of 0.75 and a specificity of 0.66. In patients with metastatic breast cancer, a strategy of sWGS of ctDNA with longitudinal tracking of tumour fraction provides real-time information on treatment response. These results encourage a prospective large-scale clinical trial to evaluate the clinical benefit of early treatment changes based on ctDNA levels

Barriers to publishing early phase clinical trials: the oncologists' perspective.

INTRODUCTION: Findings from early phase studies are not always placed in the public domain. This study aims to explore why many early phase clinical oncology studies are not published, as well as identify the potential barriers investigators encountered in the publication process. METHODS: Semi-structured interviews were conducted among investigators with experience in early phase clinical oncology studies. Interviews were analyzed using reflexive thematic analysis. RESULTS: Twenty-one investigators were interviewed. The majority worked in Europe (n = 13), while other investigators were based in North America (n = 4), Asia (n = 2) or Oceania (n = 2). We identified three reasons why investigators believed publishing early phase clinical trial results was important: (1) there is an ethical and moral responsibility; (2) there should be no loss of knowledge to society; and (3) there should be no waste of resources. Four main barriers in the publication process of early phase clinical trials were identified: (1) practical barriers (eg, an increased complexity of number of trials/trial sites), (2) insufficient resources (eg, money, time and human), (3) limited motivation (eg, limited intrinsic motivation of the investigator or limited prospect of return for the sponsor), and (4) inadequate collaboration (eg, different interests between industry partners and investigators). Finally, five major stakeholders were identified that can potentially contribute to improving the publication process: (1) journal editors, (2) sponsors, (3) investigators, (4) regulatory bodies, and (5) society. Investigator suggestions for improving this process, for each stakeholder, are presented. CONCLUSIONS: This study highlights the barriers experienced in publishing early phase clinical trials. Recognizing and acknowledging these barriers is crucial to devise effective strategies to improve the publishing and public sharing of early phase clinical trials

Replication Stress Is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors.

Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma subtype that is driven by the EWS-WT1 chimeric transcription factor. The prognosis for DSRCT is poor, and major advances in treating DSRCT have not occurred for over two decades. To identify effective therapeutic approaches to target DSRCT, we conducted a high-throughput drug sensitivity screen in a DSRCT cell line assessing chemosensitivity profiles for 79 small-molecule inhibitors. DSRCT cells were sensitive to PARP inhibitors (PARPi) and ataxia-telangiectasia and Rad3-related inhibitors (ATRi), as monotherapies and in combination. These effects were recapitulated using multiple clinical PARPi and ATRi in three biologically distinct, clinically relevant models of DSRCT, including cell lines, a patient-derived xenograft-derived organoid model, and a cell line-derived xenograft mouse model. Mechanistically, exposure to a combination of PARPi and ATRi caused increased DNA damage, G2-M checkpoint activation, micronuclei accumulation, replication stress, and R-loop formation. EWS-WT1 silencing abrogated these phenotypes and was epistatic with exogenous expression of the R-loop resolution enzyme RNase H1 in reversing sensitivity to PARPi and ATRi monotherapies. The combination of PARPi and ATRi also induced EWS-WT1-dependent cell-autonomous activation of the cyclic GMP-AMP synthase-stimulator of IFN genes innate immune pathway and cell-surface expression of PD-L1. Taken together, these findings point toward a role for EWS-WT1 in generating R-loop-dependent replication stress that leads to a targetable vulnerability, providing a rationale for the clinical assessment of PARPi and ATRi in DSRCT. Significance: EWS-WT1, the unique oncogenic driver of desmoplastic small round cell tumors, confers sensitivity to PARP and ATR inhibitors, supporting the potential of these drugs in treating patients with this aggressive sarcoma subtype

NSD2-epigenomic reprogramming and maintenance of plasma cell phenotype in t(4;14) myeloma.

Overexpression of the H3K36 histone methyltransferase NSD2 in t(4;14) multiple myeloma (MM) is an early, oncogenic event, and understanding its impact on genomic organisation and expression is relevant to understanding MM biology. We performed epigenetic, transcriptional and phenotypic profiling of the t(4;14) KMS11 myeloma cell line and its isogenic translocation knock out (TKO) to characterise the sequelae of NSD2 overexpression. We found a marked global impact of NSD2 on gene expression and DNA organisation implicating cell identity genes; notably the early lymphocyte regulator, LAIR1 and MM cell surface markers, including CD38, a classical marker of plasma cells which was reduced in TKO cells. Plasma cell transcription factors such as PRDM1, IRF4 and XBP1 were unaffected, suggesting a downstream direct gene effect of NSD2 on cell identity. Changes in cell surface markers suggest an altered surface immunophenotype. Our findings suggest a role for NSD2 in maintaining MM cell identity, with potential implications for future therapeutic strategies based on targeting of NSD2

DEK::NUP214 acts as an XPO1-dependent transcriptional activator of essential leukemia genes.

The t(6;9)(p22.3;q34.1) translocation/DEK::NUP214 fusion protein defines a distinct subgroup of younger AML patients classified as a separate disease entity by the World Health Organization. DEK is a nuclear factor with multifunctional roles, including gene regulation, while its fusion partner, NUP214, plays a pivotal role in nuclear export by interacting with transport receptors such as XPO1. However, the precise mechanism by which DEK::NUP214 drives leukemia remains unclear. A comprehensive multi-omics comparison of 57 AML primary samples (including whole genome sequencing, targeted sequencing, transcriptomics, and drug screening with >500 compounds) revealed that t(6;9) cases display a selective response to XPO1 inhibitors (Selinexor & Eltanexor) and a distinct transcriptomic signature characterized by the overexpression of FOXC1 and HOX genes that are key leukemia mediators. CUT&RUN experiments demonstrated the direct binding of DEK::NUP214 to the promoters of FOXC1 and HOXA/B clusters. Strikingly, the expression of these genes and the binding of DEK::NUP214 to their regulatory regions were selectively reduced upon XPO1 inhibition in t(6;9) cells. Altogether, these results identified a novel function of DEK::NUP214 as an XPO1-dependent transcriptional activator of key leukemia drivers and provide a rationale to explore the use of XPO1 inhibitors in this patient population