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1.
Tumour metabolism and its unique properties in prostate adenocarcinoma.
Bader, DA, McGuire, SE
Nature reviews. Urology. 2020;(4):214-231
Abstract
Anabolic metabolism mediated by aberrant growth factor signalling fuels tumour growth and progression. The first biochemical descriptions of the altered metabolic nature of solid tumours were reported by Otto Warburg almost a century ago. Now, the study of tumour metabolism is being redefined by the development of new molecular tools, tumour modelling systems and precise instrumentation together with important advances in genetics, cell biology and spectroscopy. In contrast to Warburg's original hypothesis, accumulating evidence demonstrates a critical role for mitochondrial metabolism and substantial variation in the way in which different tumours metabolize nutrients to generate biomass. Furthermore, computational and experimental approaches suggest a dominant influence of the tissue-of-origin in shaping the metabolic reprogramming that enables tumour growth. For example, the unique metabolic properties of prostate adenocarcinoma are likely to stem from the distinct metabolism of the prostatic epithelium from which it emerges. Normal prostatic epithelium employs comparatively glycolytic metabolism to sustain physiological citrate secretion, whereas prostate adenocarcinoma consumes citrate to power oxidative phosphorylation and fuel lipogenesis, enabling tumour progression through metabolic reprogramming. Current data suggest that the distinct metabolic aberrations in prostate adenocarcinoma are driven by the androgen receptor, providing opportunities for functional metabolic imaging and novel therapeutic interventions that will be complementary to existing diagnostic and treatment options.
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2.
FOLFIRINOX for the Treatment of Advanced Gastroesophageal Cancers: A Phase 2 Nonrandomized Clinical Trial.
Park, H, Jin, RU, Wang-Gillam, A, Suresh, R, Rigden, C, Amin, M, Tan, BR, Pedersen, KS, Lim, KH, Trikalinos, NA, et al
JAMA oncology. 2020;(8):1231-1240
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Abstract
IMPORTANCE Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). The combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been efficacious as first-line therapy for other gastrointestinal cancers, such as pancreatic and colon cancers. OBJECTIVE To evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTS This is an open-label, single-arm phase 2 study of first-line FOLFIRINOX in patients with advanced gastroesophageal adenocarcinoma. Estimated sample size included 41 patients with ERBB2-negative disease with 90% power to detect an ORR of 60% or greater with α of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX. INTERVENTIONS Starting doses were fluorouracil, 400 mg/m2 bolus, followed by 2400 mg/m2 over 46 hours; leucovorin, 400 mg/m2; irinotecan, 180 mg/m2; and oxaliplatin, 85 mg/m2. Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease. MAIN OUTCOMES AND MEASURES The primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS), and duration of response. RESULTS From November 2013 to May 2018, 67 patients were enrolled (median [range] age, 59.0 [34-78] years; including 56 [84%] men), and 26 of 67 (39%) had ERBB2-positive disease. Median follow-up was 17.4 months. The ORR was 61%(95% CI, 44.5%-75.8%) (25 of 41) in the ERBB2-negative group and 85% (95% CI, 65.1%-95.6%) (22 of 26) in the ERBB2-positive group, including 1 patient with complete response. For ERBB2-negative patients, median PFS was 8.4 months and median OS was 15.5 months; for ERBB2-positive patients, median PFS was 13.8 months and median OS was 19.6 months. Fifty-six patients (84%) had dose modifications or treatment delays. The most common toxic effects were neutropenia (91%, n = 61), diarrhea (63%, n = 42), peripheral sensory neuropathy (61%, n = 41), and nausea (48%, n = 32), with no unexpected toxic effects. CONCLUSIONS AND RELEVANCE The FOLFIRINOX regimen with or without trastuzumab was associated with improved ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01928290.
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Alcohol, Alcoholic Beverages and Risk of Esophageal Cancer by Histological Type: A Dose-Response Meta-Analysis of Observational Studies.
Yu, X, Chen, J, Jiang, W, Zhang, D
Alcohol and alcoholism (Oxford, Oxfordshire). 2020;(5):457-467
Abstract
AIMS: We conducted a dose-response meta-analysis to explore the association between alcohol and particular alcoholic beverages with risk of esophageal cancer (EC) by histological type [esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC)] and whether the association differs according to gender. METHODS PubMed and Web of Science databases were searched for relevant articles published between January 1960 and December 2019. The pooled relative ratios (RRs) and 95% confidence interval (CI) were calculated with the fixed or random effect model. The dose-response relationship was assessed by restricted cubic spline. RESULTS A total of 74 published articles involving 31,105 cases among 3,369,024 participants were included in this meta-analysis. The pooled RRs of the highest versus lowest alcohol intake were 3.67 (95% CI, 2.89,4.67) for EC, 5.11 (95% CI, 3.60,7.25) for ESCC and 0.96 (95% CI, 0.79,1.16) for EAC. The above-mentioned associations were observed in cohort design, for different alcoholic beverages (beer, wine and liquor/spirits) and gender. Evidence of a nonlinear dose-response relationship for EC risk with alcohol intake was found (Pnon-linearity < 0.001), and a linear relationship (Pnon-linearity = 0.216) suggested that the risk of ESCC increased by 33% for every 12.5 g/day increment of alcohol intake. CONCLUSIONS This meta-analysis suggests that alcohol intake might significantly increase the incidence of EC, especially for ESCC.
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Genetic Predisposition to Colon and Rectal Adenocarcinoma Is Mediated by a Super-enhancer Polymorphism Coactivating CD9 and PLEKHG6.
Ke, J, Tian, J, Mei, S, Ying, P, Yang, N, Wang, X, Zou, D, Peng, X, Yang, Y, Zhu, Y, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2020;(4):850-859
Abstract
BACKGROUND Genome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the underlying biological mechanisms. METHODS Through a comprehensive bioinformatics analysis on multi-omics data, we screen potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs, and then subject them to a two-stage case-control study containing 4,929 cases and 7,083 controls from the Chinese population. A series of functional assays, including reporter gene assays, electrophoretic mobility shift assays (EMSA), CRISPR-Cas9 genome editing, chromosome conformation capture (3C) assays, and cell proliferation experiments, are performed to characterize the variant's molecular consequence and target genes. RESULTS The SNP rs11064124 in 12p13.31 is found significantly associated with the risk of colon and rectal adenocarcinoma with an odds ratio (OR) of 0.87 [95% confidence interval (CI), 0.82-0.92, P = 8.67E-06]. The protective rs11064124-G weakens the binding affinity with vitamin D receptor (VDR) and increases the enhancer's activity and interactions with two target genes' promoters, thus coactivating the transcription of CD9 and PLEKHG6, which are both putative tumor suppressor genes for colon and rectal adenocarcinoma. CONCLUSIONS Our integrative study highlights an SE polymorphism rs11064124 and two susceptibility genes CD9 and PLEKHG6 in 12p13.31 for colon and rectal adenocarcinoma. IMPACT These findings suggest a novel insight for genetic pathogenesis of colon and rectal adenocarcinoma, involving transcriptional coactivation of diverse susceptibility genes via the SE element as a gene regulation hub.
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Standardization of acquisition protocols using PET/CT with 18F-Choline in prostate cancer.
Garcia, JR, Cozar, M, Soler, M, Bassa, P, Riera, E, Buxeda, M, Valls, E, Ferrer, J
Revista espanola de medicina nuclear e imagen molecular. 2020;(4):204-211
Abstract
AIM: To standardize acquisition protocols for 18F-Choline PET/CT to prevent from urine interference, to determine the best time point for the whole-body study, and to assess whether "dual point" acquisition allows for differentiating malignant vs. benign lesions. METHODS One hundred consecutive patients with prostate cancer were prospectively studied. Immediately after 18F-Choline injection, a pelvis study was acquired, and a whole-body was subsequently obtained 1 and 2 hours p.i. Mean SUVmax was obtained in regions and for every sequential imaging. Mean analysis (χ2) and SUV percentage change (2/1 hours; 1 hours/0 min) were obtained. Metabolic pattern dynamics were assessed: accumulative vs. clearance. Patient follow-up after therapy and directed classification whenever ethically possible were performed. RESULTS Fifty-three prostate foci, without disturbing urinary activity was ever found on early images. Accumulative pattern in 42, with percentage increase was: 0 min/1 hour: +16.7% (χ20.94); 1/2 hours: +10,0% (χ2 0.83). Clearance pattern in 11, with percentage decrease: 0 min/1 hour: -21.4% (χ20.91): -7.7% (χ20.85), corresponding in 7 to initial staging and in 4 post-radiotherapy biochemical recurrence. Every infradiaphragmatic uptake (n: 24) showed accumulative pattern, with percentage increase of +9.1% (χ20.97), all of them depicted on early imaging. As for 12 supradiaphragmantic uptake, 8 of them showed clearance pattern with percentage decrease: -13.0% (χ20.95). Accumulative pattern showed in 4 of them with percentage increase +13.0% (χ2 0.96), thus being assessed as invasive/malignant. Every bone uptake (n: 18) showed accumulative pattern, with percentage increase: +17.1% (χ20.95), all of them depicted on 1 hour imaging. CONCLUSIONS As for prostate assessment is concerned, dual point at 0 min/1 hour proved to be the best procedure. As for supradiaphragmatic lymph-nodes detection, dual point with 1/2 hours performed best. As for infradiaphragmatic and bone involvement, as well as for inconclusive findings, the 2 hour imaging increased our diagnostic confidence.
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Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI-1 study.
Bang, YJ, Li, CP, Lee, KH, Chiu, CF, Park, JO, Shan, YS, Kim, JS, Chen, JS, Shim, HJ, Rau, KM, et al
Cancer science. 2020;(2):513-527
Abstract
The global, randomized NAPOLI-1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine-based therapy. Median overall survival (OS) with nal-IRI+5-FU/LV was 6.1 vs 4.2 months with 5-FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post-hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal-IRI+5-FU/LV (n = 34) had significantly longer median OS versus 5-FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal-IRI+5-FU/LV versus 5-FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal-IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5-FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal-IRI+5-FU/LV versus 5-FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal-IRI+5-FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine-based therapy, with a safety profile agreeing with previous findings. The nal-IRI+5-FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506).
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S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin as first-line therapy in patients with advanced gastric cancer (SOLAR): a randomised, open-label, phase 3 trial.
Kang, YK, Chin, K, Chung, HC, Kadowaki, S, Oh, SC, Nakayama, N, Lee, KW, Hara, H, Chung, IJ, Tsuda, M, et al
The Lancet. Oncology. 2020;(8):1045-1056
Abstract
BACKGROUND S-1 plus leucovorin and oxaliplatin showed promising efficacy for treatment of advanced gastric cancer in a randomised phase 2 study. We aimed to evaluate the efficacy and safety of oral TAS-118 (S-1 plus leucovorin) and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer. METHODS We did a randomised, open-label, phase 3 trial in 62 centres across Japan and South Korea. Patients aged 20 years or older, with a histologically confirmed advanced gastric cancer with negative or unknown HER2 status, with Eastern Cooperative Oncology Group performance status of 0 or 1, measurable or evaluable metastatic lesions, and no previous treatment were randomly assigned (1:1) via an interactive web response system using the minimisation method, stratified by performance status, presence of a measurable lesion, and country, to receive TAS-118 (S-1 40-60 mg and leucovorin 25 mg orally twice daily for 7 days) plus oxaliplatin (85 mg/m2 intravenously on day 1) every 2 weeks, or S-1 (40-60 mg orally twice daily) for 21 days plus cisplatin (60 mg/m2 intravenously on day 1 or 8) every 5 weeks. The primary endpoint was overall survival in patients who had advanced gastric cancer with measurable or evaluable metastatic lesions and who received the study drug. Safety was assessed in all patients who received the study drug. This study was registered at ClinicalTrials.gov, NCT02322593. FINDINGS Between Jan 28, 2015, and Dec 5, 2016, 711 patients were randomised to TAS-118 plus oxaliplatin (n=356) or S-1 plus cisplatin (n=355). 11 untreated patients and 19 ineligible patients were excluded from the primary analysis (TAS-118 plus oxaliplatin group n=347, S-1 plus cisplatin group n=334) following recommendation from the independent data monitoring committee. After median follow-up of 26·0 months (IQR 22·0-32·8), median overall survival was 16·0 months (95% CI 13·8-18·3) in the TAS-118 plus oxaliplatin group and 15·1 months (95% CI 13·6-16·4) in the S-1 plus cisplatin group (hazard ratio 0·83, 95% CI 0·69-0·99; p=0·039). The most common grade 3 or higher adverse events in the 352 patients in the TAS-118 plus oxaliplatin group and the 348 patients in the S-1 plus cisplatin group were anaemia (56 [16%] vs 64 [18%]), neutropenia (54 [15%] vs 88 [25%]), decreased appetite (53 [15%] vs 46 [13%]), diarrhoea (33 [9%] vs 15 [4%]), and peripheral sensory neuropathy (30 [9%] vs one [<1%]). Serious adverse events were observed in 155 (44%) of 352 patients in the TAS-118 plus oxaliplatin group and 159 (46%) of 348 patients in the S-1 plus cisplatin group. Two treatment-related deaths occurred in the TAS-118 plus oxaliplatin group (pulmonary tuberculosis and viral pneumonia). INTERPRETATION TAS-118 plus oxaliplatin showed a clinically meaningful improvement in efficacy compared with S-1 plus cisplatin, and could be considered a new first-line treatment option for advanced gastric cancer in Asian patients. FUNDING Taiho Pharmaceutical and Yakult Honsha.
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Treatment of Patients with Advanced Gastroesophageal Adenocarcinoma: Does Age Matter?
Lorenzen, S, Hofheinz, RD
Drugs & aging. 2019;(5):403-409
Abstract
Gastroesophageal cancer is the fourth most frequent malignant disease and, despite significant advances in chemotherapy, the prognosis of unresectable or recurrent gastroesophageal cancer is poor. The majority of patients, nearly two-thirds, are over the age of 65 years at diagnosis. Elderly patients are a heterogeneous population and aging occurs at different rates in different individuals. The chronological age of a patient does not necessarily reflect the physiological age. However, elderly patients are more likely to have a number of concomitant diseases and impaired organ function, which should be considered when making treatment decisions. Therefore, treatment in older adults requires particular caution, and physiologic age rather than chronologic age should be considered when deciding for or against systemic therapy. Older patients are generally underrepresented in clinical trials and many elderly patients do not receive effective combination therapies due to concerns with tolerability. Age itself is not a negative predictive factor and treatment should not be omitted just on the basis of chronological age. Older patients who fulfill the standard inclusion criteria of clinical trials seem to have a similar advantage from palliative chemotherapy for gastroesophageal adenocarcinoma as younger patients; however, large prospective trials in the elderly population are needed to guide clinicians in making evidence-based decisions.
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Advances in the diagnosis and surveillance of Barrett's esophagus (with videos).
, , Trindade, AJ, Navaneethan, U, Aslanian, HR, Bhutani, MS, Krishnan, K, Lichtenstein, DR, Melson, J, Pannala, R, Parsi, MA, et al
Gastrointestinal endoscopy. 2019;(3):325-334
Abstract
BACKGROUND AND AIMS Most patients diagnosed with esophageal adenocarcinoma do not carry a known diagnosis of Barrett's esophagus (BE), suggesting that an improved approach to screening may potentially be of benefit. The use of dysplasia as a biomarker and random biopsy protocols for its detection has limitations. In addition, detecting and appropriately classifying dysplasia in patients with known BE can be difficult. METHODS This document reviews several technologies with a recently established or potential role in the diagnosis and/or surveillance of BE as well as risk stratification for progression to esophageal adenocarcinoma. RESULTS Two technologies were reviewed for imaging or tissue sampling: (1) wide-area transepithelial sampling and (2) volumetric laser endomicroscopy. Four technologies were reviewed for molecular and biomarker technologies for diagnosis and risk stratification: (1) Cytosponge, (2) mutational load, (3) fluorescence in situ hybridization, and (4) immunohistochemistry. CONCLUSION Several technologies discussed in this document may improve dysplasia detection in BE in a wide-field manner. Moreover, the addition of different biomarkers may aid in enhanced risk stratification to optimize approaches to surveillance or treatment for patients with BE.
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The Rationale and Efficacy of Primary and Secondary Prevention in Adenocarcinomas of the Upper Gastrointestinal Tract.
Bornschein, J, Bird-Lieberman, EL, Malfertheiner, P
Digestive diseases (Basel, Switzerland). 2019;(5):381-393
Abstract
While the primary risk factor for oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO) is gastro-oesophageal reflux, the infection with Helicobacter pylori (H. pylori) is the dominant risk factor for gastric cancer. Reduction of reflux by dietary measures and proton pump inhibitors has some merits in OAC prevention, and the chemopreventive effect of Aspirin and statins is being widely investigated; however, improved outcome in OAC occurs primarily as the result of secondary prevention. Early detection of neoplastic lesions in Barrett's metaplasia can be achieved by surveillance endoscopies. Novel endoscopic imaging modalities carry similar importance as the endoscopic treatment techniques as without detection of early lesions, therapy cannot be applied. Minimally invasive approaches are currently being investigated to identify patients with BO who are at particular risk of neoplastic progression. While dietary factors also play an important role in the prevention of gastric cancer and chemoprevention seems to be promising, the most beneficial effect has been shown for the eradication of H. pylori infection, which results in at least a one third reduction of gastric cancer risk. This effect can be further improved if the eradication takes place prior to the development of pre-neoplastic gastric conditions such as mucosal atrophy or intestinal metaplasia (IM). The definition of the "point of no return", after which eradication is less effective, is of high importance, although H. pylori eradication can still be beneficial even at more advance stages of mucosal changes. For this reason, patients with advanced atrophy and IM should undergo endoscopic surveillance in the same way as patients with BO. There is also need for development of non-invasive tests to identify patients at high risk of progression to gastric cancer to improve outcome of these surveillance approaches.