The Christie School of Oncology: Christie Research Publications Repository
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Findings of the PROTIEUS trial pre-accrual quality assurance contouring assessment-the importance of the benchmark case
No full textImpact of dose to a novel cardiac avoidance area on cardiac mortality in 3,459 lung cancer patients receiving curative radiotherapy
No full textRadiotherapy results in decreased time to second cancer in children with Li Fraumeni syndrome
No full textLi Fraumeni syndrome (LFS) arising from germline TP53 mutation results in defective DNA repair and increased risk of multiple primary cancers beginning in childhood. Curative intent radiotherapy is often used to treat childhood cancer, but its impact on children with LFS has not been reviewed. We undertook a retrospective case-series review of 47 children with a solid cancer diagnosed age less than 16 years to assess time and survival after second cancer diagnosis. After radiotherapy for the first cancer diagnosis, median time to second primary cancer diagnosis was 13.3 years and median survival 9.7 years. Where no radiotherapy was received, median time to second primary cancer diagnosis was 25.1 years (χ2 = 14.8, P < .0001; Hazard Ratio = 7.9 [95% CI = 2.8 to 22.6]), and median survival of 29.2 years (χ2 = 12.5, P = .004, Hazard Ratio = 3.2 [95% CI = 1.5 to 6.6]). Radiotherapy for first cancer in children with LFS is associated with adverse outcomes and ought to be considered only in the absence of other potentially curative options. Where unavoidable, second cancer risks must be minimized
Randomized phase II dose optimization study of inobrodib (CCS1477), in combination with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma (RRMM)
No full textAPPROACH: Analysis of Proton versus Photon Radiotherapy in Oligodendroglioma and Assessment of Cognitive Health - study protocol paper for a phase III multicentre, open-label randomised controlled trial
No full textINTRODUCTION: Oligodendroglioma (ODG) is a rare type of brain tumour, typically diagnosed in younger adults and associated with prolonged survival following treatment. The current standard of care is maximal safe debulking surgery, radiotherapy (RT) and adjuvant procarbazine, lomustine and vincristine (PCV) chemotherapy. Patients may experience long-term treatment-related toxicities, with RT linked to impairments of neurocognitive function (NCF) and health-related quality of life (HRQoL). With proton beam therapy (PBT), radiation dose falls off sharply beyond the target with reduced normal brain tissue radiation doses compared with photon RT. Therefore, PBT might result in reduced radiation-induced toxicity compared with photon RT. METHODS AND ANALYSIS: APPROACH is a multicentre open-label phase III randomised controlled trial of PBT versus photon RT in patients with ODG, investigating the impact of PBT on long-term NCF measured using the European Organisation for Research and Treatment of Cancer (EORTC) Core Clinical Trial Battery Composite (CTB COMP). The trial will randomise 246 participants from 18 to 25 UK RT sites, allocated 1:1 to receive PBT or photon RT, with PBT delivered at one of the two UK PBT centres. Participants with grade 2 and grade 3 ODG will receive 54 Gy in 30 fractions and 59.4 Gy in 33 fractions, respectively, followed by 6×6-weekly cycles of PCV chemotherapy. The trial contains staged analyses, with an internal pilot for feasibility of recruitment at 12 months, early assessment of efficacy at 2 years, futility assessment and final primary endpoint comparison of NCF between arms at 5 years. Secondary endpoints include additional NCF, treatment compliance, acute and late toxicities, endocrinopathies, HRQoL, tumour response, progression-free survival and overall survival. ETHICS AND DISSEMINATION: Ethical approval was obtained from Newcastle North Tyneside REC (reference 22/NE/0232). Final trial results will be published in peer-reviewed journals and adhere to International Committee of Medical Journal Editors (ICMJE) guidelines. TRIAL REGISTRATION NUMBER: ISRCTN:13390479
Amivantamab in Participants With Advanced NSCLC and MET Exon 14 Skipping Mutations: Final Results From the CHRYSALIS Study
No full textINTRODUCTION: Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity. We assessed the safety and efficacy of amivantamab in participants with advanced NSCLC harboring primary MET exon 14 skipping mutations (METex14). METHODS: CHRYSALIS enrolled participants with METex14 NSCLC who progressed after or declined standard-of-care therapy. Participants received intravenous amivantamab weekly for 4 weeks and biweekly thereafter. Objective response rate, duration of response (DoR), clinical benefit rate, progression-free survival, overall survival, safety, and circulating tumor DNA were analyzed. RESULTS: Among 97 participants, 16 were treatment naive, 28 received prior treatment without MET therapies, and 53 received prior MET therapies. Objective response rate was 32% overall, 50% in treatment-naive participants, 46% in participants without prior MET therapies, and 19% in participants with prior MET therapies. In participants without prior MET therapies, amivantamab activity was observed regardless of co-occurring genomic alterations. Clinical benefit rate was 69% overall, 88% in treatment-naive participants, 64% in participants without prior MET therapies, and 66% in participants with prior MET therapies. Median DoR was 11.2 months; 61% (19/31) of the responders had DoR greater than or equal to 6 months. Median progression-free survival was 5.3 months (95% confidence interval, 4.3-7.0); median overall survival was 15.8 months (95% confidence interval, 14.6-not estimable). Most common adverse events were rash (79%) and infusion-related reactions (72%), most being grades 1 to 2 (52%). CONCLUSIONS: The safety profile was consistent with previous reports of amivantamab in EGFR-mutant NSCLC. Amivantamab demonstrated clinically meaningful and durable antitumor activity in participants with METex14 advanced NSCLC, including those who progressed on prior MET therapies
A Systematic Review of Deep Inspiration Breath Hold and Free Breathing in Proton Beam Therapy Plans for Breast Cancer Radiotherapy
No full textAIMS: To conduct a systematic review of breast cancer radiotherapy studies reporting a comparison of proton beam therapy (PBT) in deep inspiration breath hold (DIBH) and in free breathing (FB). METHODS AND MATERIALS: Studies comparing DIBH and FB proton beam therapy plans, in the same patient, published between 2015 and 2023 were included. Doses to organs at risk were compared between DIBH and FB plans. RESULTS: Nine papers were identified for inclusion, reporting on 97 patients in total. All plans were for left-sided treatment. Average weighted mean heart dose was 0.31 Gy for DIBH and 0.48 Gy for FB. Average weighted mean left lung dose was 5.27 Gy for DIBH and 4.80 Gy for FB. Average weighted mean near maximum/maximum left anterior descending artery dose was 6.49 Gy for DIBH and 8.74 Gy for FB. CONCLUSION: Based on the current literature, it does not appear that DIBH offers a marked dosimetric benefit to most breast cancer patients treated with PBT. However, the benefits of combining PBT and DIBH for individual breast RT patients cannot be excluded
Mutant p53 induces SH3BGRL expression to promote cell engulfment
No full textPreviously, we identified that mutant p53 expression in cancer cells promotes engulfment of neighbouring cancer cells to form cell-in-cell (CIC) structures. This process gave mutant p53 cells an advantage in tumour formation in mouse xenograft experiments. TP53 can be found mutated at nearly every amino acid in cancers and mutant p53 expression is associated with various GOF (Gain-of-function) processes, including cancer cell invasion, metastasis, stemness and drug resistance. In the current manuscript, we identified SH3BGRL (Src homology 3 binding glutamate rich protein like) as a mutant p53-regulated gene and investigated to what extent SH3BGRL expression and cell engulfment are responsible for mutant p53-dependent anchorage-independent growth and chemoresistance. We demonstrate that mutant p53 expression drives cell engulfment in which the mutant p53 host cell moves in the direction of the target internal cell to form CIC structures. This is therefore more reminiscent of cell engulfment rather than cell entosis, in which cells invade into host cells. Using NGS (Next Generation Sequencing), we identified novel target genes of mutant p53 and demonstrate that cell engulfment requires SH3BGRL expression. We generated mutant p53 and p53 KO cell lines that stably overexpressed SH3BGRL and determined that SH3BGRL promotes etoposide resistance in mutant p53 cells and anchorage-independent growth independent of mutant p53 expression. Through FACS sorting of pure cell engulfing (CIC) populations, we could also show that engulfing cells have an enhanced etoposide resistance. These data suggest that SH3BGRL and cell engulfment are required for certain GOFs of mutant p53
Integrating genetic polymorphisms and clinical data to develop predictive models for skin toxicity in breast cancer radiation therapy
No full textBACKGROUND: We aim to develop and validate predictive models for acute and late skin toxicity in breast cancer (BC) patients undergoing radiation therapy (RT). Models incorporate a genetic profile-comprising candidate single nucleotide polymorphisms (SNPs) in non-coding RNAs and previously reported toxicity-associated variants-combined with clinical variables. METHODS: The study involved 1979 BC patients monitored for two to eight years post-RT in a multi-centre study. We assessed acute (oedema/erythema) and late (atrophy/fibrosis) toxicity using logistic regression and Cox proportional hazards models. The cohort was divided into training and validation datasets. RESULTS: Six SNPs demonstrated to be predictors of acute (rs13116075, rs12565978, rs72550778 and rs7284767) and late toxicity (rs16837908 and rs61764370) either in the training or validation cohort. However, none of these SNPs were consistently associated with toxicity across both stages of analysis. The rs13116075, rs12565978 and rs16837908 were previously reported to be associated with RT toxicity. In the validation phase, SNP-based models showed limited predictive ability, with AUC values of 0.49 and c-index of 0.54 for acute and late toxicity, respectively. Models incorporating either clinical variables alone or in combination with SNPs achieved similar AUC and c-index values of ∼0.60 for acute and late toxicity, respectively. However, the combined model exhibited the highest predictive accuracy for acute and late toxicity, both in the training and the validation cohorts. CONCLUSIONS: Our findings highlight the importance of combining clinical data with genetic markers to enhance the accuracy of models predicting RT toxicity in BC
A phase II trial of mTORC1/2 inhibition in STK11 deficient non small cell lung cancer
No full textThere are no current stratified medicine options for STK11-deficient NSCLC. STK11 loss mediates mTORC activation, GLUT1 up-regulation and increased glycolysis. This metabolic reprogramming might represent a therapeutic vulnerability targetable with mTORC1/2 inhibition. In arm B2 of the National Lung Matrix Trial 54 patients with NSCLC received vistusertib, of which 49 were STK11-deficient (30 with KRAS mutation (B2D), 19 without (B2S)). Objective response (OR) and durable clinical benefit (DCB) rates with 95% credible intervals (CrI) were estimated from posterior probability distributions generated using Bayesian beta-binomial conjugate analysis. In B2D, 2 per-protocol patients obtained OR (estimated true OR rate (95%CrI) 9.8% (2.4-24.3). Estimates of true DCB rate (95%CrI): B2D 24.4% (11.1-42.3), B2S 14.6% (3.6-34.7). Overall, vistusertib cannot be recommended in this context. Longitudinal ctDNA analysis demonstrates enrichment of SMARCA4 mutations post-treatment. In vitro studies show adaptive resistance to mTORC1/2 inhibition via AKT reactivation. (NCT02664935, ISRCTN38344105, EudraCT 2014-000814-73, 10 June 2015)