Publications by authors named "Janet S Graham"

9 Publications

  • Page 1 of 1

Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME-RT).

Radiat Oncol 2021 Aug 26;16(1):163. Epub 2021 Aug 26.

Institute of Cancer Sciences, Glasgow Royal Infirmary, University of Glasgow, Room 2.57, Level 2, New Lister Building, Glasgow, G31 2ER, UK.

Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response.

Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m oxaliplatin, 350 mg folinic acid and 400 mg/m bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m 5-FU infusion over 46-48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease.

Discussion: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020).
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http://dx.doi.org/10.1186/s13014-021-01888-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393812PMC
August 2021

Hypermutation In Pancreatic Cancer.

Gastroenterology 2017 01 15;152(1):68-74.e2. Epub 2016 Nov 15.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
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http://dx.doi.org/10.1053/j.gastro.2016.09.060DOI Listing
January 2017

Genomic analyses identify molecular subtypes of pancreatic cancer.

Nature 2016 Mar 24;531(7592):47-52. Epub 2016 Feb 24.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
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http://dx.doi.org/10.1038/nature16965DOI Listing
March 2016

Whole genomes redefine the mutational landscape of pancreatic cancer.

Nature 2015 Feb;518(7540):495-501

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
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http://dx.doi.org/10.1038/nature14169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523082PMC
February 2015

Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel.

BMC Clin Pathol 2014 23;14:35. Epub 2014 Jul 23.

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden G61 1QH, UK ; Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde NHS, Glasgow G51 4TF, UK.

Background: Pancreatico-biliary adenocarcinomas (PBA) have a poor prognosis. Diagnosis is usually achieved by imaging and/or endoscopy with confirmatory cytology. Cytological interpretation can be difficult especially in the setting of chronic pancreatitis/cholangitis. Immunohistochemistry (IHC) biomarkers could act as an adjunct to cytology to improve the diagnosis. Thus, we performed a meta-analysis and selected KOC, S100P, mesothelin and MUC1 for further validation in PBA resection specimens.

Methods: Tissue microarrays containing tumour and normal cores in a ratio of 3:2, from 99 surgically resected PBA patients, were used for IHC. IHC was performed on an automated platform using antibodies against KOC, S100P, mesothelin and MUC1. Tissue cores were scored for staining intensity and proportion of tissue stained using a Histoscore method (range, 0-300). Sensitivity and specificity for individual biomarkers, as well as biomarker panels, were determined with different cut-offs for positivity and compared by summary receiver operating characteristic (ROC) curve.

Results: The expression of all four biomarkers was high in PBA versus normal ducts, with a mean Histoscore of 150 vs. 0.4 for KOC, 165 vs. 0.3 for S100P, 115 vs. 0.5 for mesothelin and 200 vs. 14 for MUC1 (p < .0001 for all comparisons). Five cut-offs were carefully chosen for sensitivity/specificity analysis. Four of these cut-offs, namely 5%, 10% or 20% positive cells and Histoscore 20 were identified using ROC curve analysis and the fifth cut-off was moderate-strong staining intensity. Using 20% positive cells as a cut-off achieved higher sensitivity/specificity values: KOC 84%/100%; S100P 83%/100%; mesothelin 88%/92%; and MUC1 89%/63%. Analysis of a panel of KOC, S100P and mesothelin achieved 100% sensitivity and 99% specificity if at least 2 biomarkers were positive for 10% cut-off; and 100% sensitivity and specificity for 20% cut-off.

Conclusion: A biomarker panel of KOC, S100P and mesothelin with at least 2 biomarkers positive was found to be an optimum panel with both 10% and 20% cut-offs in resection specimens from patients with PBA.
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http://dx.doi.org/10.1186/1472-6890-14-35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112611PMC
July 2014

Adjuvant therapy in colon cancer.

Expert Rev Anticancer Ther 2012 Jan;12(1):99-109

Beatson West of Scotland Cancer Centre, Great Western Road, Glasgow, G12 0YN, Scotland, UK.

Huge advances have been made in the treatment of colon cancer over the last decade. Success has been most noticeable in stage IV disease - where careful selection of patients with small-volume disease for treatment with surgical resection ± perioperative chemotherapy has resulted in an improvement in survival of approximately 5-50%; and stage III - disease where the advent of 5-fluorouracil/oxaliplatin, as adjuvant treatment has also resulted in a significant prolongation in survival. Progression-free survival is now an established surrogate for overall survival, and has resulted in more timely reporting of adjuvant studies and therefore faster integration of promising agents into the clinic. Targeted agents, which have shown promise in the metastatic setting, are currently being examined in the adjuvant setting, although results so far are disappointing. Patients with high-risk stage II cancer remain a challenging group. They have a poorer prognosis than those with stage IIIA disease, and national and international guidance recommend offering chemotherapy after careful discussion of the pros and cons. Despite the fact that we have identified many of the biological features that make stage II disease higher risk, we still struggle to achieve the same improvement in survival for this subgroup compared with others. It may be that these patients required treatment with alternative regimens and predictive biomarkers would be particularly helpful.
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http://dx.doi.org/10.1586/era.11.189DOI Listing
January 2012

The promises and pitfalls of epigenetic therapies in solid tumours.

Eur J Cancer 2009 May 11;45(7):1129-1136. Epub 2009 Feb 11.

Department of Oncology and Ovarian Cancer Action Centre, Imperial College, Hammersmith Campus, Du Cane Road, W12 0NN London, UK. Electronic address:

Epigenetic inactivation of tumour suppressor genes, in contrast to gene mutations, can be modulated or reversed by small molecules. This has lead to several recent studies of drugs targeting epigenetic mechanisms as novel cancer therapies. So far, epigenetic therapies, including HDAC inhibitors and demethylating agents, show considerable activity in haematological malignancies, but their value in the treatment of solid tumours remains much more uncertain. This review will discuss some of the challenges that are expected in the treatment of solid tumours with epigenetic therapies and discuss approaches to overcome these obstacles. There is an increasing need for trials driven by pharmacodynamic biomarkers for these agents, which are aimed at finding the optimum biological dose rather than the maximal-tolerated dose, and also investigating their use in combination with cytotoxics--for example as chemosensitisers. Such trials already suggest that improved tumour delivery and specificity, with decreased normal tissue toxicity, will be required to take full advantage of this class of agents in solid tumours.
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http://dx.doi.org/10.1016/j.ejca.2009.01.003DOI Listing
May 2009

A multi-centre dose-escalation and pharmacokinetic study of diflomotecan in patients with advanced malignancy.

Cancer Chemother Pharmacol 2009 Apr 25;63(5):945-52. Epub 2008 Jul 25.

The Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 OYN, UK.

Purpose: Diflomotecan, a homocamptothecin, targets DNA topoisomerase I. Previous clinical trials have demonstrated a variable degree of dose limiting toxicity. The purpose of this study was to further evaluate the safety and pharmacokinetic profile of a range of diflomotecan doses administered intravenously.

Methods: Patients with advanced solid malignant tumours, refractory to standard therapies, with adequate haematologic, renal and hepatic function, received diflomotecan administered as a 20 min intravenous infusion every 21 days. Cohorts of six patients were recruited sequentially to one of three fixed starting dose groups-2, 4, or 7 mg, with drug administered by fixed-dose rather than dosing by body surface area. Pharmacokinetic analyses were performed on serial blood samples taken over the first 24 h after diflomotecan administration (cycles 1 and 2). Cytochrome P450 3A4 (CYP3A4) activity was determined by an erythromycin breath test (EBT) prior to diflomotecan administration in cycles 1 and 2.

Results: Thirteen patients, were treated with a starting dose of either 2 mg (n = 8) or 4 mg (n = 5) of diflomotecan. Dose limiting toxicities (DLTs) were observed in 1 patient in the 2 mg starting dose level (grade 4 neutropenia which lasted for 8 days), and in 2 of 5 patients enrolled at the 4 mg starting dose level (grade 4 neutropenia for 11 days; grade 4 neutropenia leading to withdrawal from the study), and no further dose escalation was performed. Pharmacokinetic analyses revealed a less than dose-proportional increase in diflomotecan and for the two metabolites BN80942 and P-20, with a magnitude of P-20 exposure similar to the parent drug. There was a high inter-patient variability in diflomotecan exposure similar to that observed with other camptothecin derivatives. One minor response was observed in a patient with oesophageal cancer.

Conclusions: Diflomotecan administered as a 20-min intravenous infusion 3-weekly is characterised by a variable pharmacokinetic profile. Alternative oral dosing schedules of diflomotecan have been shown to display a more predictable PK/PD and safety profile and should be selected for further evaluation in Phase II clinical trials.
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http://dx.doi.org/10.1007/s00280-008-0795-6DOI Listing
April 2009

Open-label, non-randomised, inter-individual dose escalation of ZK 304709 with the evaluation of safety, tolerability, pharmacokinetics, oral bioavailability and orientating efficacy after daily administration in patients with advanced cancer (7 d treatment and 14 d recovery).

Eur J Cancer 2008 Oct 22;44(15):2162-8. Epub 2008 Jul 22.

Cancer Research UK, Department of Medical Oncology, University of Glasgow, Glasgow G61 1BD, UK.

Purpose: The primary objectives of this study were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of ZK 304709, a novel multi-targeted growth inhibitor (MTGI(trade mark)), in man. Secondary end-points included safety evaluation, tolerability, pharmacokinetic profiling and assessment of response using standard and novel surrogate pharmacodynamic end-points.

Materials And Methods: Patients (n=40) with advanced solid malignancies were treated with ZK 304709, administered orally once daily for 7 d with 14 d recovery. Doses were escalated in sequential cohorts of three patients with expansion to 6-7 patients should a dose-limiting toxicity occur.

Results: ZK 304709 was safely administered up to 360mg. However, above 90mg blood concentrations increased only slightly. As this dose was not deemed likely to result in meaningful pharmacologic or clinical activity, the trial was stopped before the MTD was ascertained. It was therefore not possible to make a reliable assessment of efficacy or pharmacodynamic end-points.

Conclusions: Due to the lack of further increment in blood concentrations above a dose of 90mg, which was felt from previous animal studies to be unlikely to result in meaningful pharmacologic or clinical activity, this study was stopped early.
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http://dx.doi.org/10.1016/j.ejca.2008.06.006DOI Listing
October 2008
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