EUS-FNA Biopsies to Guide Precision Medicine in Pancreatic Cancer: Results of a Pilot Study to Identify KRAS Wild-Type Tumours for Targeted Therapy

Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death and lacks effective treatment options. Diagnostic endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsies represent an appealing source of material for molecular analysis to inform targeted therapy, as they are often the only available tissue for patients presenting with PDAC irrespective of disease stage. However, EUS-FNA biopsies are typically not used to screen for precision medicine studies due to concerns about low tissue yield and quality. Epidermal growth factor receptor (EGFR) inhibition has shown promise in clinical trials of unselected patients with advanced pancreatic cancer, but has not been prospectively tested in KRAS wild-type patients. Here, we examine the clinical utility of EUS-FNA biopsies for molecular screening of KRAS wild-type PDAC patients for targeted anti-EGFR therapy to assess the feasibility of this approach. Patients and Methods: Fresh frozen EUS-FNA or surgical biopsies from PDAC patient tumours were used to screen for KRAS mutations. Eligible patients with recurrent, locally advanced, or metastatic KRAS wild-type status who had received at least one prior line of chemotherapy were enrolled in a pilot study (ACTRN12617000540314) and treated with panitumumab at 6mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was 4-month progression-free survival (PFS). Results: 275 patient biopsies were screened for KRAS mutations, which were detected in 88.3% of patient samples. 8 eligible KRAS wild-type patients were enrolled onto the interventional study between November 2017 and December 2020 and treated with panitumumab. 4-month PFS was 14.3% with no objective tumour responses observed. The only grade 3/4 treatment related toxicity observed was hypomagnesaemia. Conclusions: This study demonstrates proof-of-principle feasibility to molecularly screen patients with pancreatic cancer for targeted therapies, and confirms diagnostic EUS-FNA biopsies as a reliable source of tumour material for molecular analysis. Single agent panitumumab was safe and tolerable but led to no objective tumour responses in this population

Irinotecan or FOLFIRI for 2nd line colorectal

Background Second-line treatment with irinotecan for advanced or metastatic colorectal cancer prolongs survival. It is uncertain whether irinotecan is better administered with 5- fluorouracil or alone in patients previously treated with a fluoropyrimidine. We compared toxicity (particularly diarrhoea), quality of life, and efficacy of combination chemotherapy and irinotecan in these patients. Methods In DaVINCI, a randomised phase II trial, patients with advanced colorectal cancer were randomly allocated to: combination therapy (FOLFIRI), irinotecan (180 mg/m2 IV over 90 min, day 1), 5-fluorouracil (400 mg/m2 IV bolus and 2400 mg/m2 by 46-hour infusion from day 1) and folinic acid (20 mg/m2 IV bolus, day 1), 2-weekly; or single-agent, irinotecan (350 mg/m2 IV over 90 min), 3-weekly. Toxicity was evaluated every treatment cycle; QOL and response 6 weekly. Analysis was by intention to treat. Results were also combined with those of other trials. Findings We randomised 44 patients to combination and 45 to single-agent. The most common toxicity was complete alopecia (single-agent 37%, combination 14%, P<0.02). Eight patients in the irinotecan arm and 4 in the combination arm had grade 3–4 diarrhoea (P=0.24). The treatment groups did not differ significantly in overall QOL changes, response rate, or progression free or overall survival. In a systematic review of 29 trials of second-line irinotecan-based treatment, single-agent irinotecan was associated with more diarrhoea and alopecia than the combination, but efficacy was similar. Interpretation Combination treatment compared with single-agent irinotecan appears to reduce the rateof complete alopecia and diarrhoea without compromising efficacy on clinical outcomes.Australasian Gastro-Intestinal Trials Grou

Opposite associations between alanine aminotransferase and γ-glutamyl transferase levels and all-cause mortality in type 2 diabetes: analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Aims Reported associations between liver enzymes and mortality may not hold true in type 2 diabetes, owing to a high prevalence of non-alcoholic fatty liver disease, which has been linked to cardiovascular disease and mortality in its own right. Our study aimed to determine whether alanine aminotransferase (ALT) or γ-glutamyl transferase (GGT) levels predict mortality in type 2 diabetes, and to examine possible mechanisms. Methods Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analysed to examine the relationship between liver enzymes and all-cause and cause-specific mortality over 5 years. Results Over 5 years, 679 (6.9%) individuals died. After adjustment, for every standard deviation increase in ALT (13.2U/L), the HR for death on study was 0.85 (95% CI 0.78-0.93), p70 U/L, compared with GGT ≤70 U/L, had HR 1.82 (1.48−2.24), p70 U/L was associated with higher risks of death due to cardiovascular disease, cancer and non-cancer/non-cardiovascular causes. The relationship for ALT persisted after adjustment for indirect measures of frailty but was attenuated by elevated hsCRP. Conclusions As in the general population, ALT has a negative, and GGT a positive, correlation with mortality in type 2 diabetes when ALT is less than two times the upper limit of normal. The relationship 4 for ALT appears specific for death due to cardiovascular disease. Links of low ALT with frailty, as a potential mechanism for relationships seen, were neither supported nor conclusively refuted by our analysis and other factors are also likely to be important in those with type 2 diabetes

Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial

© Cuzick et al. Open Access article distributed under the terms of CC BY.http://dx.doi.org/10.1016/S1470-2045(14)71171-

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

Abstract Aims/hypothesis Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate’s renal effects in a FIELD washout sub-study. Methods Type 2 diabetic patients (n=9795) aged 50 to 75 years were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin:creatinine ratio) measured at baseline, year 2 and close-out) and estimated GFR, measured 4 to 6 monthly according to the Modification of Diet in Renal Disease study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n=661). Analysis was by intention-to-treat. Results During fenofibrate run-in, plasma creatinine increased by 10.0 µmol/l (p<0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 µmol/l vs 1.89 µmol/l annually, p=0.01), with less estimated GFR loss (1.19 vs 2.03 ml min−1 1.73 m−2 annually, p<0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min−1 1.73 m−2, p=0.065) than on placebo (6.9 ml min−1 1.73 m−2, p<0.001), sparing 5.0 ml min−1 1.73 m−2 (95% CI 2.3-7.7, p<0.001). Greater preservation of estimated GFR with fenofibrate was observed during greater reduction over the active run-in period (pre-randomisation) of triacylglycerol (n=186 vs 170) and baseline hypertriacylglycerolaemia (n=89 vs 80) alone, or combined with low HDL-cholesterol (n=71 vs 60). Fenofibrate reduced urine albumin concentrations and hence albumin:creatinine ratio by 24% vs 12% (p<0.001; mean difference 14% [95% CI 9-18]; p<0.001), with 14% less progression and 18% more albuminuria regression (p<0.001) than in participants on placebo. End-stage renal event frequency was similar (n=21 vs 26, p=0.48). Conclusions/interpretation Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals) and the NHMRC of Australia.Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals

Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

Abstract Aims/hypothesis Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate’s renal effects in a FIELD washout sub-study. Methods Type 2 diabetic patients (n=9795) aged 50 to 75 years were randomly assigned to fenofibrate (n=4895) or placebo (n=4900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin:creatinine ratio) measured at baseline, year 2 and close-out) and estimated GFR, measured 4 to 6 monthly according to the Modification of Diet in Renal Disease study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n=661). Analysis was by intention-to-treat. Results During fenofibrate run-in, plasma creatinine increased by 10.0 µmol/l (p<0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 µmol/l vs 1.89 µmol/l annually, p=0.01), with less estimated GFR loss (1.19 vs 2.03 ml min−1 1.73 m−2 annually, p<0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min−1 1.73 m−2, p=0.065) than on placebo (6.9 ml min−1 1.73 m−2, p<0.001), sparing 5.0 ml min−1 1.73 m−2 (95% CI 2.3-7.7, p<0.001). Greater preservation of estimated GFR with fenofibrate was observed during greater reduction over the active run-in period (pre-randomisation) of triacylglycerol (n=186 vs 170) and baseline hypertriacylglycerolaemia (n=89 vs 80) alone, or combined with low HDL-cholesterol (n=71 vs 60). Fenofibrate reduced urine albumin concentrations and hence albumin:creatinine ratio by 24% vs 12% (p<0.001; mean difference 14% [95% CI 9-18]; p<0.001), with 14% less progression and 18% more albuminuria regression (p<0.001) than in participants on placebo. End-stage renal event frequency was similar (n=21 vs 26, p=0.48). Conclusions/interpretation Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals) and the NHMRC of Australia.Laboratoires Fournier, Dijon, France (now part of Solvay and Abbott Pharmaceuticals

Prognostic nomogram for progression-free survival in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer on maintenance olaparib therapy following response to chemotherapy

Background: The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients. / Methods: The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib. / Results: The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3–11.3), 5.4 (4.8–5.8) and 2.9 (2.8–4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1–22.4) and 8.3 (7.1–10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot). / Conclusions: This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies

Concordance between CA-125 and RECIST progression in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer treated in the SOLO2 trial with olaparib as maintenance therapy after response to chemotherapy

BACKGROUND: Limited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo. METHODS: We extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV). RESULTS: Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90-99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45-59%). Within treatment arms, PPV was similar (olaparib: 95% [84-99%], placebo: 97% [87-100%]) but NPV was lower in patients on placebo (olaparib: 60% [52-68%], placebo: 30% [20-44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST. CONCLUSIONS: Almost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone

Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial

Oxaliplatin and 5-fluorouracil have a significant activity in locally advanced oesophageal squamous cell cancer (OSCC). However, their optimal dosage and efficacy when combined with concurrent radiotherapy as neoadjuvant treatment are unknown. This non-randomised, phase I/II study aimed to define the maximum tolerated dose (MTD) and assessed the histopathological tumour response rate to neoadjuvant oxaliplatin in weekly escalating doses (40, 45, 50 mg m−2) and continuous infusional 5-fluorouracil (CI-5FU; 225 mg m−2) plus concurrent radiotherapy. Patients had resectable OSCC. Resection was scheduled for 4–6 weeks after chemoradiotherapy. During phase I (dose escalation; n=19), weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 was established as the MTD and was the recommended dosage for phase II. Oesophageal mucositis was the dose-limiting toxicity at higher doses. During phase II, histopathological responses (<10% residual tumour cells within the specimen) were observed in 10 of 16 patients (63%; 95% confidence interval: 39–82%). Overall, 16 of the 25 patients (64%) who underwent resection had a histopathological response; tumour-free resection (R0) was achieved in 80%. Neoadjuvant weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 with concurrent radiotherapy provides promising histological response rates and R0 resection rates in locally advanced OSCC