The Christie School of Oncology: Christie Research Publications Repository
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A Novel Functional-Discriminant Approach Outperforms EUD-Based Modelling in Identifying Radioinduced Toxicity Patterns
No full textCholangiocarcinoma Targeted Therapies: Mechanisms of Action and Resistance
No full textCholangiocarcinoma is an aggressive bile duct malignancy with heterogeneous genomic features. Although most patients receive standard-of-care chemotherapy/immunotherapy, genomic changes that can be targeted with established or emerging therapeutics are common. Accordingly, precision medicine strategies are transforming the next-line treatment for patient subsets. Hotspot IDH1 mutations and activating fibroblast growth factor receptor 2 fusions occur frequently, and small-molecule inhibitors against these alterations are US Food and Drug Administration approved. Translational and basic science studies have elucidated the mechanisms of response and resistance in cholangiocarcinoma, providing insights into these targets that extend to other cancers. Additional US Food and Drug Administration-approved and National Comprehensive Cancer Network guideline-recommended treatments for recurrent genomic changes include BRAF inhibition (BRAF-V600E) and trastumazab deruxtecan (human epidermal growth factor receptor 2 amplification). Furthermore, ongoing clinical trials show promising results with KRAS inhibition (KRAS-codon 12 mutations), PRTM5 inhibition, alone or with methylthioadenosine inhibition (5-methylthioadenosine phosphorylase deletion), and murine double minute 2 inhibition (murine double minute 2 amplification). Despite these advances, the rate, depth, and duration of response to each treatment need improvement. Moreover, many patients do not have currently targetable genotypes. This review examines the clinical efficacy and mechanisms of resistance associated with these treatments, as well as insights into the molecular and biological effects of pathway activation and inhibition, based on study of patient samples and preclinical models. It also explores strategies to overcome resistance and possible precision medicine approaches for additional patient subsets
Thyroidectomy with or without postoperative radioiodine for patients with low-risk differentiated thyroid cancer in the UK (IoN): a randomised, multicentre, non-inferiority trial
No full textBACKGROUND: Patients with differentiated thyroid cancer can often be treated with postoperative radioiodine (also called radioiodine ablation) after total thyroidectomy. The IoN trial was designed to assess whether recurrence-free survival was non-inferior after no ablation compared with ablation in patients with low-risk differentiated thyroid cancer. METHODS: IoN was a multicentre, non-inferiority, phase 3 randomised trial conducted at 33 UK cancer centres. Eligible patients had complete (R0) resection following total thyroidectomy; stage pT1, pT2, pT3 (according to Tumour, Node, Metastasis staging version 7 [TNM7]), or pT3a (according to TNM8) disease; and N0, Nx, or N1a disease. Participants were randomly assigned (1:1) by minimisation, using a central electronic system, to have either 1·1 GBq ablation or no ablation, following thyroidectomy. Stratification factors were centre, age, T stage, and nodal status. Patients had annual neck ultrasound scans and 6-monthly serum thyroglobulin measurements. The primary endpoint was 5-year recurrence-free survival, defined by the absence of locoregional recurrent or persistent structural disease, distant metastases, or death from thyroid cancer. Non-inferiority was assessed with a margin of 5 percentage points. Per-protocol and intention-to-treat (ITT) analyses were done for the primary endpoint, and safety was analysed in the per-protocol population. The trial is registered with ClinicalTrials.gov (NCT01398085), ISRCTN (ISRCTN80416929), and EUDRACT (2011-000144-21), and is still in active follow-up. FINDINGS: We recruited 504 patients (including 390 [77%] female patients and 114 [23%] male patients) between June 26, 2012 and March 18, 2020 and randomly assigned 251 to receive no ablation and 253 to receive ablation (ITT population). 249 patients in the no ablation group did not have ablation and 231 in the ablation group had ablation (per-protocol population). Median follow-up was 6·8 years (IQR 5·6-8·6) in the no ablation group and 6·6 years (4·8-8·5) in the ablation group; 17 recurrences (eight in the no ablation group and nine in the ablation group; ITT population) occurred during follow-up. 5-year recurrence-free rates were 97·9% (95% CI 96·1-99·7) in the no ablation group versus 96·3% (93·9-98·7) in the ablation group in the ITT analysis, and 97·9% (96·1-99·7) versus 96·9% (94·7-99·1) in the per-protocol analysis. The 5-year absolute risk difference was 0·5 percentage points (95% CI -2·2 to 3·2, p(non-inferiority)=0·033; ITT analysis), showing that non-inferiority was reached. The observed recurrence rate was higher among patients with pT3 or pT3a tumours (four [9%] of 46 patients overall with pT3 or pT3a tumours vs 13 [3%] of 458 with pT1 or pT2 tumours), or N1a tumours (six [13%] of 47 with N1a vs 11 [2%] of 457 with N0 or Nx), but they were similar among those who did not receive ablation. Adverse events were similar between the groups, the most common being fatigue (63 [25%] of 249 in the no ablation group vs 65 [28%] of 231 in the ablation group), lethargy (34 [14%] vs 32 [14%]), and dry mouth (24 [10%] vs 21 [9%]), and there were no treatment-related deaths. INTERPRETATION: The IoN trial shows that ablation (or postoperative radioiodine) can be avoided for patients with pT1, pT2, and N0 or Nx tumours with no adverse features. Many patients with low-risk differentiated thyroid cancer worldwide can safely avoid postoperative radioiodine and its related hospitalisation and side-effects, which in turn results in lower health-care costs. FUNDING: Cancer Research UK
A human model to deconvolve genotype-phenotype causations in lung squamous cell carcinoma
No full textTractable, patient-relevant models are needed to investigate cancer progression and heterogeneity. Here, we report an alternative in vitro model of lung squamous cell carcinoma (LUSC) using primary human bronchial epithelial cells (hBECs) from three healthy donors. The co-operation of ubiquitous alterations (TP53 and CDKN2A loss) and components of commonly deregulated pathways including squamous differentiation (SOX2), PI3K signalling (PTEN) and the oxidative stress response (KEAP1) is investigated by generating hBECs harbouring cumulative alterations. Our analyses confirms that SOX2-overexpression initiates early preinvasive LUSC stages, and co-operation with the oxidative stress response and PI3K pathways to drive more aggressive phenotypes, with expansion of cells expressing LUSC biomarkers and invasive properties. This cooperation is consistent with the classical LUSC subtype. Importantly, we connect pathway dysregulation with gene expression changes associated with cell-intrinsic processes and immunomodulation. Our approach constitutes a powerful system to model LUSC and unravel genotype-phenotype causations of clinical relevance
Final results of ANICCA-Class II, a single arm, open-label phase II trial assessing nivolumab in tissue-specific class II expressing metastatic microsatellite stable colorectal cancer, with a parallel assessment of the immunoscore-immune checkpoint as a predictive biomarker for single-agent anti-PD-1
No full textBackground Neutralization of interferon (IFN)-gamma abrogates the efficacy of anti-programmed death-ligand 1 (PD-(L)1) checkpoint inhibitors. Most epithelial cells do not constitutively express major histocompatibility complex (MHC) class II but can be induced to do so by IFN-gamma. Inducible tumor-specific MHC class II (tsMHC-II) underlies responsiveness to anti-PD-(L)1. Retrospective studies show that tsMHC-II positivity associates with improved outcomes in patients treated with anti-PD-(L)1. The ANICCA-Class II single-arm Bayesian phase II trial prospectively explored whether positive tsMHC-II status could be a useful selection marker for anti-programmed cell death protein-1 (PD-1) in proficient mismatch repair colorectal cancer (pMMR CRC). In parallel, we retrospectively evaluated the potential predictive power of immunoscore-immune checkpoint (IS-IC) for outcome with single-agent immune checkpoint blockade. Methods Patients with histologically confirmed locally advanced/metastatic pMMR CRC with >1% MHC class II expression, Eastern Cooperative Oncology Group performance status 0-2, aged >= 18 years were eligible. Participants received 480 mg nivolumab every 28 days for up to 24 cycles. The primary outcome was durable clinical benefit (DCB) defined as participants remaining progression-free at their third trial-specific scan since treatment start (ie, at approximately 27 weeks). Secondary outcomes included progression-free survival time (PFS) and overall survival time (OS). Results 35 participants were treated: 65.7% of participants' cancers were tsMHC-II >= 5%. 3/35 patients achieved DCB (8.6%), estimating the true DCB rate (R) of 11% (95% credible interval 3% to 22%) with 0.002 probability that the true DCBR was >30%, below the required 0.5 to warrant further research. The higher tsMHC-II cut-point >= 5% was not more useful in predicting duration of disease stabilization. All three participants who achieved DCB had no evidence of liver metastases (LM); DCBR 23.1% in those without versus 0% in those with LM. PFS and OS were significantly greater in those without LM. There was no evidence that IS-IC high predicted for prolonged time on treatment or improved tumor growth inhibition. Conclusions In pMMR CRC, tsMHC-II positivity fails to identify a subset of patients with metastatic pMMR CRC obtaining potentially meaningful benefit from single-agent anti-PD-1. Although numbers are limited, there is no clear evidence that IS-IC is predictive of outcome with single-agent anti-PD-1. The poor outcome in those with LM underscores the need for therapies that overcome the systemic immunosuppression driven by LM
Circulating tumour cells are a prognostic indicator in advanced high-grade serous ovarian cancer and are associated with platelets and immune cells following dissemination
No full textBACKGROUND: Circulating tumour cells (CTCs) are rare yet crucial biomarkers with significant prognostic potential across different cancer types. However, their role in high-grade serous ovarian cancer (HSGC) is not well defined. To capture the full spectrum of CTCs found in HGSC, we employed an EpCAM independent enrichment technique in patients with advanced HGSC and investigated the prognostic value and molecular signatures of these rare cells. METHODS: CTC enumeration was performed in 43 newly diagnosed patients with HGSC using Parsortix® CTC enrichment and benchmarked against a metastatic breast cancer (MBC) cohort for which the device is FDA approved. CTCs were also isolated from the ovarian vein of patients with HGSC during primary cytoreductive surgery. CTCs were assessed as prognostic markers in patients with HGSC. FACS single cell sorting and scRNAseq was performed on CTCs isolated from the ovarian vein. RESULTS: CTCs isolated using Parsortix® enrichment in HGSC ranged between 1-22 cells/7.5 ml blood. Concordance was seen between Parsortix® enrichment and CellSearch® enumeration in patients with MBC (R(2) = 0.8786). CTC clusters were isolated from the ovarian vein (P = 0.0195) and were cloaked in platelets/immune cells. Detection of CTCs in patients with HGSC was predictive of a poorer progression free survival (P = 0.0183). Patients with CTCs were found to have increased serum levels of CD73 (P = 0.0311). scRNAseq of CTCs isolated from the ovarian vein identified enrichment in genes associated with immune signalling. CONCLUSIONS: Peripheral CTCs isolated from patients with HGSC were predictors of a poor prognosis. The ovarian vein was found to be a rich source of disseminating CTC clusters in HGSC. Further studies are warranted to investigate the utility of CTCs as markers of neoadjuvant chemotherapy response as well as for longitudinal monitoring. Molecular analysis of CTCs in HGSCs reveals a potential role of the immune system in CTC-mediated haematogenous metastasis
Response to letter Re: 'Consolidation thoracic radiotherapy after chemoimmunotherapy in ES-SCLC: A multicentric retrospective analysis'
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