Gastrointestinal adenocarcinoma incidence and survival trends in South Australia, 1990–2017

Background; Aims: Globally, there has been a concerning rise in the incidence of young-onset cancers. The aim of this study was to provide trends in the incidence and survival of gastrointestinal adenocarcinomas (oesophagus, stomach, pancreas, and colorectal) in South Australia over a 27-year period. Methods: This is a cross-sectional analysis of a prospective longitudinal database including all cases of gastrointestinal adenocarcinomas prospectively reported to the South Australian (State) Cancer Registry from 1990 to 2017. Results: A total of 28,566 patients diagnosed with oesophageal, stomach, pancreatic, or colorectal adenocarcinoma between 1990 and 2017 were included in the study. While the overall incidence for gastrointestinal adenocarcinomas in individuals >50 years has decreased since 2000 (IRR of 0.97 (95% CI 0.94–1.00; p = 0.06)) compared to 1990–1999, the rate amongst individuals aged 18–50 has significantly increased (IRR 1.41 (95% CI 1.27–1.57; p < 0.001)) during the same reference time period. Although noted in both sexes, the rate of increase in incidence was significantly greater in males (11.5 to 19.7/100,000; p < 0.001). The overall survival from adenocarcinomas across all subsites improved in the >50-year cohort in the last decade (HR 0.89 (95% CI 0.86–0.93; p < 0.001)) compared to 1990–1999. In individuals aged 18–50 years, there has only been a significant improvement in survival for colorectal cancer (HR 0.82 (95% CI 0.68–0.99; p < 0.04)), but not the other subsites. A lower overall survival was noted for males in both age cohorts (18–50 years—HR 1.24 (95% CI 1.09–1.13; p < 0.01) and >50 years—HR 1.13 (95% CI 1.10–1.16; p < 0.001), respectively) compared to females. Conclusions: This study from South Australia demonstrates a significant increase in young-onset gastrointestinal adenocarcinomas over the last 28 years, with a greater increase in the male sex. The only significant improvement in survival in this cohort has been noted in colorectal cancer patients.Dominique Schell, Shahid Ullah, Mark E. Brooke-Smith, Paul Hollington, Marina Yeow, Christos S. Karapetis ... et al

MicroRNA profiling in oesophageal adenocarcinoma cell lines and patient serum samples reveals a role for mir-451a in radiation resistance

Many patients with Oesophageal Adenocarcinoma (OAC) do not benefit from chemoradiotherapy treatment due to therapy resistance. To better understand the mechanisms involved in resistance and to find potential biomarkers, we investigated the association of microRNAs, which regulate gene expression, with the response to individual treatments, foc

Outcome for esophageal cancer following treatment with chemotherapy and radiotherapy but not esophagectomy: nonsurgical treatment of esophageal cancer

Urs Zingg1,2, Dennis DiValentino1, Alexander McQuinn1, Ahmad Mardzuki1, Sarah K Thompson2,  Christos S Karapetis1,3, David I Watson11Flinders University Department of Surgery, Flinders Medical Centre, Bedford Park, South Australia, Australia; 2Discipline of Surgery, University of Adelaide, Adelaide, South Australia, Australia; 3Department of Medical Oncology, Flinders Medical Centre, Bedford Park, South Australia, AustraliaBackground: More than 50% of patients with esophageal cancer are not suitable for surgery. The aim of this study was to analyze the outcome of patients undergoing standard nonsurgical treatment.Methods: Data of all patients undergoing nonsurgical treatment for esophageal cancer were identified from a prospective database.Results: Seventy-five patients were treated for localized disease, and 52 for metastatic disease at diagnosis. Except for age, which was higher in patients without metastases, there were no significant differences between the patients with vs. without metastatic disease. Kaplan–Meier analysis showed a median survival of 10.8 months for all patients. There was a significant difference in survival (p < 0.001) between the groups with versus without metastases, with median survival in the patients without metastases 13.6 months versus 6.5 months in patients with metastases. Patients undergoing nonsurgical treatment for localized disease had a five-year survival of 12%. No significant difference between adenocarcinoma and squamous cell carcinoma was identified. Subanalysis of patients who received chemoradiotherapy revealed similar results to the overall group of patients.Conclusion: In patients with localized disease at diagnosis, long-term survival can be achieved in some patients, whereas five-year survival is rare in patients who present with metastatic disease.Keywords: nonsurgical treatment, esophageal cancer, chemoradiotherapy, metastases, surviva

Current opinion on optimal systemic treatment for metastatic colorectal cancer: outcome of the ACTG/AGITG expert meeting ECCO 2013

The treatment of metastatic colorectal cancer has evolved greatly in the last 15 years, involving combined chemotherapy protocols and, in more recent times, new biologic agents. Clinical benefit from the use of targeted therapy with bevacizumab, aflibercept, cetuximab, panitumumab and regorafenib in the treatment of metastatic colorectal cancer is now well established with median overall survival accepted as over 24 months, and with super selection for extended RAS patients higher again. The optimal timing of treatment options requires careful consideration of predictive biomarkers, and importantly the potential for interactions, to derive the maximal benefit. A group of colorectal subspecialty medical oncologists from Australia, the USA, the Netherlands and Germany met during ECCO 2013 to discuss current practice. Subsequent new data from the American Society of Clinical Oncology were also reviewed. This article reviews the evidence discussed in support of modern treatments for colorectal cancer and the decision-making behind the treatment choices, with their benefits and risks.Timothy J Price, Eva Segelov, Matthew Burge, Daniel G Haller, Niall C Tebbutt, Christos S Karapetis, Cornelis JA Punt, Nick Pavlakis, Dirk Arnold, Peter Gibbs and Jeremy D Shapir

The outcome of patients (pts) with metastatic colorectal cancer (mCRC) based on site of metastases (mets) and the impact of molecular markers and site of primary cancer on metastatic pattern

Abstract No.: 356

Hepatic functional imaging and genomics to predict irinotecan pharmacokinetics and pharmacodynamics: The PREDICT IR study

Issue Section: Developmental therapeutics - Abstract #405PM. Michael, W. Liauw, S-A. McLachlan, E. Link, A. Matera, M. Thompson, M. Jefford, R.J. Hicks, C. Cullinane, I. Campbell, P.J. Beale, C.S. Karapetis, T.J. Price, M.E. Burg

Pharmacogenomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: the predict IR study

Purpose Irinotecan (IR) displays signifcant PK/PD variability. This study evaluated functional hepatic imaging (HNI) and extensive pharmacogenomics (PGs) to explore associations with IR PK and PD (toxicity and response). Methods Eligible patients (pts) suitable for Irinotecan-based therapy. At baseline: (i) PGs: blood analyzed by the Afymetrix DMET™-Plus-Array (1936 variants: 1931 single nucleotide polymorphisms [SNPs] and 5 copy number variants in 225 genes, including 47 phase I, 80 phase II enzymes, and membrane transporters) and Sanger sequencing (variants in HNF1A, Topo-1, XRCC1, PARP1, TDP, CDC45L, NKFB1, and MTHFR), (ii) HNI: pts given IV 250 MBq-99mTc-IDA, data derived for hepatic extraction/excretion parameters (CLHNI, T1/2-HNI, 1hRET, HEF, Td1/2). In cycle 1, blood was taken for IR analysis and PK parameters were derived by non-compartmental methods. Associations were evaluated between HNI and PGs, with IR PK, toxicity, objective response rate (ORR) and progression-free survival (PFS). Results N=31 pts. The two most signifcant associations between PK and PD with gene variants or HNI parameters (P<0.05) included: (1) PK: SN38-Metabolic Ratio with CLHNI, 1hRET, (2) Grade 3+diarrhea with SLC22A2 (rs 316019), GSTM5 (rs 1296954), (3) Grade 3+neutropenia with CLHNI, 1hRET, SLC22A2 (rs 316019), CYP4F2 (rs2074900) (4) ORR with ALDH2 (rs 886205), MTHFR (rs 1801133). (5) PFS with T1/2-HNI, XDH (rs 207440), and ABCB11 (rs 4148777). Conclusions Exploratory associations were observed between Irinotecan PK/PD with hepatic functional imaging and extenssive pharmacogenomics. Further work is required to confrm and validate these fndings in a larger cohort of patients. Australian New Zealand Clinical Trials Registry (ANZCTR) Number ACTRN12610000897066, Date registered: 21/10/2010.Michael Michael, Winston Liauw, Sue, Anne McLachlan, Emma Link, Annetta Matera, Michael Thompso

The survival outcome of patients with metastatic colorectal cancer based on the site of metastases and the impact of molecular markers and site of primary cancer on metastatic pattern

Background: Pattern of spread in patients with metastatic colorectal cancer (mCRC) is variable and may reflect different biology in subsets of patients. This is a retrospective study to explore the outcome of patients with mCRC based on their site of metastasis at diagnosis and to explore the association between tumor characteristics [KRAS/RAS, BRAF, mismatch repair (MMR) status, site of primary] and the site of metastasis. Methods: Patients from two Australian databases were divided into six groups based on site of metastasis at time of diagnosis of metastatic disease; lung-only, liver-only, lymph node-only or any patients with brain, bone or peritoneal metastases. Primary endpoint was overall survival (OS) of each cohort compared with the rest of the population. A Mantel–Haenszel chi-squared test used to explore the association between site of metastasis and selected tumor characteristics. Results: Five thousand nine hundred and sixty-seven patients were included. In a univariate analysis, median OS was significantly higher when metastases were limited to lung or liver and shorter for those with brain, bone or peritoneal metastases (p < .001) in both datasets. BRAF mutation was strongly associated with peritoneal metastases (relative risk = 1.8, p < .001) with lower incidence of lung (RR = 0.3, p = .004) and liver (RR = 0.7, p = .005) limited metastases. Lung-only metastases were more frequent with KRAS/RAS mutation (RR = 1.4, p = .007). Left colon tumors were associated with bone (RR = 1.6, p < .001) and lung-only metastases (RR = 2.3, p = .001) while peritoneal spread was less frequent compared with right colon tumors (RR = 0.6, p < .001). Rectal cancer was associated with brain, bone and lung metastases (RR = 1.7; p = .002, 1.7; p < .001, 2.0; p < .001). Liver-only metastases were less frequent in deficient MMR tumors (RR = 0.7, p = .01). Conclusion: Survival duration with mCRC is related to the site of metastases with lung limited disease showing a more favorable survival outcome compared to other single metastatic site disease. The BRAF mutation and primary rectal cancer were associated with poor prognostic metastatic site

Evaluation of pharmacogenomics and hepatic nuclear imaging–related covariates by population pharmacokinetic models of irinotecan and its metabolites

Published online: 4 September 2021Background Body surface area (BSA)–based dosing of irinotecan (IR) does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variabilities. Functional hepatic nuclear imaging (HNI) and excretory/metabolic/PD pharmacogenomics have shown correlations with IR disposition and toxicity/efficacy. This study reports the development of a nonlinear mixed-effect population model to identify pharmacogenomic and HNI-related covariates that impact on IR disposition to support dosage optimization. Methods Patients had advanced colorectal cancer treated with IR combination therapy. Baseline blood was analysed by Affymetrix DMET™ Plus Array and, for PD, single nucleotide polymorphisms (SNPs) by Sanger sequencing. For HNI, patients underwent 99mTc-IDA hepatic imaging, and data was analysed for hepatic extraction/excretion parameters. Blood was taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1. Population modelling utilised NONMEM version 7.2.0, with structural PK models developed for each moiety. Covariates include patient demographics, HNI parameters and pharmacogenomic variants. Results Analysis included (i) PK data: 32 patients; (ii) pharmacogenomic data: 31 patients: 750 DMET and 22 PD variants; and (iii) HNI data: 32 patients. On initial analysis, overall five SNPs were identified as significant covariates for CLSN38. Only UGT1A3_c.31 T > C and ABCB1_c.3435C > T were included in the final model, whereby CLSN38 reduced from 76.8 to 55.1%. Conclusion The identified UGT1A3_c.31 T > C and ABCB1_c.3435C > T variants, from wild type to homozygous, were included in the final model for SN38 clearance.Zheng Liu ... Timothy Price ... et al