Olaparib with or without bevacizumab versus bevacizumab plus a fluoropyrimidine as maintenance therapy in advanced colorectal cancer: The randomized phase 3 LYNK-003 study.

BACKGROUND: The randomized, open-label, phase III LYNK-003 study assessed the efficacy of first-line maintenance olaparib, alone or in combination with bevacizumab, versus bevacizumab plus a fluoropyrimidine in participants with unresectable or metastatic colorectal cancer (mCRC). We present results of the prespecified interim futility analysis. METHODS: Eligible participants were ≥18 years of age with unresectable or mCRC that had not progressed after induction with first-line bevacizumab plus 5-fluorouracil plus oxaliplatin plus leucovorin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX). Participants were randomly assigned 1:1:1 to olaparib plus bevacizumab, olaparib alone, or bevacizumab plus a fluoropyrimidine (5-fluorouracil or capecitabine). The primary end point was progression-free survival (PFS) per RECIST v1.1 by central review. RESULTS: Between August 2020 and May 2022, 309 participants were assigned to olaparib plus bevacizumab (n = 104), olaparib (n = 107), or bevacizumab plus fluoropyrimidine (n = 98). At interim analysis, with a median follow-up of 7.6 months (range 0.1-19.7 months), the median PFS was 3.7 months (95% CI 2.8-5.3) with olaparib plus bevacizumab (HR 1.52; 95% CI 1.02-2.27; P = 0.982) and 3.5 months (95% CI 2.0-3.7) with olaparib (HR 2.11; 95% CI 1.39-3.18; P = 0.999) versus 5.6 months (95% CI 3.8-5.9) with bevacizumab plus fluoropyrimidine. Treatment-related adverse events occurred in 64 (62%), 52 (50%), and 57 (59%) participants, respectively. There were no treatment-related deaths. CONCLUSION: The LYNK-003 study was stopped prematurely as criteria for futility were met. Maintenance olaparib with or without bevacizumab did not demonstrate clinical efficacy compared with bevacizumab plus a fluoropyrimidine. GOV REGISTRATION: NCT04456699.

Targeting DNA Damage Repair Mechanisms in Pancreas Cancer.

Impaired DNA damage repair (DDR) is increasingly recognised as a hallmark in pancreatic ductal adenocarcinoma (PDAC). It is estimated that around 14% of human PDACs harbour mutations in genes involved in DDR, including, amongst others, BRCA1/2, PALB2, ATM, MSH2, MSH6 and MLH1. Recently, DDR intervention by PARP inhibitor therapy has demonstrated effectiveness in germline BRCA1/2-mutated PDAC. Extending this outcome to the significant proportion of human PDACs with somatic or germline mutations in DDR genes beyond BRCA1/2 might be beneficial, but there is a lack of data, and consequently, no clear recommendations are provided in the field. Therefore, an expert panel was invited by the European Society of Digestive Oncology (ESDO) to assess the current knowledge and significance of DDR as a target in PDAC treatment. The aim of this virtual, international expert meeting was to elaborate a set of consensus recommendations on testing, diagnosis and treatment of PDAC patients with alterations in DDR pathways. Ahead of the meeting, experts completed a 27-question survey evaluating the key issues. The final recommendations herein should aid in facilitating clinical practice decisions on the management of DDR-deficient PDAC.

68Ga-DOTATATE PET/CT Distinguishes Neuroendocrine Tumor Mesenteric Lymph Node Metastasis From an Extensive IgG4-Positive Fibrosis Surrounding It.

ABSTRACT: A 56-year-old woman presented with right iliac fossa pain. Abdominal CT showed a mesenteric mass in the right iliac fossa, adjacent to the vena cava inferior and right ureter. Biopsy of the mass revealed a well-differentiated neuroendocrine tumor. 68Ga-DOTATATE PET/CT showed strong somatostatin receptor expression only within in a small, central area of this mesenteric mass, with faint 68Ga-DOTATATE uptake in the majority of this mesenteric mass. Pathology revealed an IgG4-positive storiform fibrosis surrounding a mesenteric adenopathy. 68Ga-DOTATATE PET/CT discriminates between neuroendocrine tumor lymph node metastases and fibrosis, hereby avoiding potential sampling error of tumor biopsies and guiding surgical approach.

Molecular detection of Helicobacter pylori and clarithromycin resistance in gastric biopsies: a prospective evaluation of RIDA®GENE Helicobacter pylori assay.

Background: Empirical treatment of Helicobacter pylori (HP) depends on the local prevalence of clarithromycin resistance but data are lacking and culturing of HP is time-consuming. We evaluated RIDA®GENE Helicobacter pylori assay (r-biopharm), a quantitative PCR assay for detecting HP and clarithromycin resistance mutations in gastric biopsies.Material/methods: Gastric biopsies were obtained from each of 436 consecutive patients referred for gastroscopic investigation and results of qPCR were compared to culture and immunohistochemical staining (IHCS).Results: Of 436 samples, 47 were positive for HP by PCR (11%), 42 by culture (9.7%) and 44 by IHCS (10%). Compared to culture, sensitivity and specificity of the qPCR were 100% and 99%, respectively, and 96% and 99% compared to IHCS. The sensitivity and specificity for clarithromycin resistance detection were 92% and 97%, respectively.Conclusions: RIDA®GENE Helicobacter pylori assay reliably and rapidly detects HP and its resistance to clarithromycin in human gastric biopsies.

Molecular Targeting of a BRAF Mutation in Pancreatic Ductal Adenocarcinoma: Case Report and Literature Review.

Current standard-of-care treatment for advanced pancreatic ductal adenocarcinoma is mainly based on conventional cytotoxic chemotherapy. Until recently, no randomized clinical trials had shown any clinically meaningful outcome benefit from targeted therapy in this indication. This is in contrast to many other tumor types. The majority of pancreatic tumors are driven by KRAS mutations, which are generally not amenable to targeted therapy. Driving mutations in the BRAF oncogene have proven to be an interesting molecular target in the management of advanced melanoma and colorectal adenocarcinoma and can be found in 3% of patients with advanced pancreatic ductal adenocarcinoma. Here, we report objective tumor response to treatment with the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib in a patient with poorly differentiated, V600E mutant, advanced pancreatic ductal adenocarcinoma.

Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study.

PURPOSE: To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600E-mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial ( ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35). PATIENTS AND METHODS: Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E-mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival. RESULTS: Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with BRAF V600E-mutant tumors (one patient had a non-BRAF V600E-mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free survival was 8.0 months (95% CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95% CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months). CONCLUSION: In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated BRAF V600E-mutant mCRC.

Impact of endoscopy system, high definition, and virtual chromoendoscopy in daily routine colonoscopy: a randomized trial.

BACKGROUND: To improve detection of mucosal lesions during colonoscopy a number of imaging modalities have been suggested, including high definition and virtual chromoendoscopy. Given the theoretical advantage of these new imaging techniques, we aimed to investigate their use for the detection of polyps in patients referred for colonoscopy in a large tertiary hospital. METHODS: Demographic, endoscopic, and histological data from 1855 consecutive patients undergoing colonoscopy were collected prospectively. Patients were randomly assigned to three endoscopy systems (Fujinon, Olympus, or Pentax) in combination with four modalities: conventional white-light colonoscopy (n = 505), high definition white-light colonoscopy (n = 582), virtual chromoendoscopy (n = 285) and high definition virtual chromoendoscopy (n = 483). RESULTS: The mean adenoma detection rate (ADR) was 34.9 %, and the adenoma per colonoscopy rate (APCR) was 2.1. No significant differences were noted between the three endoscopy systems. Moreover, no differences in ADR or APCR were observed between the four imaging modalities. High definition white-light colonoscopy resulted in a significantly higher detection of sessile serrated adenomas (8.2 % vs. 3.8 %; P < 0.01) and adenocarcinomas (2.6 % vs. 0.5 %; P < 0.05) compared with the conventional procedure. CONCLUSIONS: No significant differences in ADR or APCR between different endoscopy systems, high definition, and/or virtual chromoendoscopy could be observed in routine colonoscopies in the general population. High definition endoscopy was associated with a significantly higher detection rate of serrated adenomas and adenocarcinomas.

Lanreotide in the prevention and management of high-output ileostomy after colorectal cancer surgery.

Objective: Patients with stage III and high-risk stage II colorectal cancer (CRC) are advised to initiate adjuvant treatment as soon as feasible and certainly before 8 to 12 weeks after resection of the tumor. A protective ileostomy is often constructed during surgery to protect a primary anastomosis "at risk", especially in rectal cancer surgery. However, up to 17% of patients with a stoma suffer from high output, a major complication that can prevent adjuvant treatment implementation or completion. To avoid delay or cancellation of adjuvant therapy after CRC resection, effective strategies must be implemented to successfully treat and/or prevent high-output stoma (HOS). Methods: We report two clinical case reports clearly demonstrating the impact and management of HOS in this setting. A review of the available literature and ongoing clinical studies is provided. Results: The clinical cases describe patients with advanced stage CRC and focus on the different strategies for HOS management, presenting their outcome and how each strategy affects the implementation of adjuvant treatment. The patient population with the highest risk of developing HOS is described, along with the rationale for using somatostatin analogs, such as lanreotide, to treat and prevent high output. Conclusion: In patients with CRC and protective ileostomies after primary resection, HOS could be treated with somatostatin analogs in combination with dietary recommendations and Saint Mark's solution. The role of this therapeutic approach as a preventive strategy in patients at high risk of developing HOS, deserves further exploration in a prospective randomized clinical trial.

Practical management of toxicities associated with targeted therapies for advanced gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine tumors are heterogeneous, rare malignancies that arise most frequently in the gastroenteropancreatic tract (GEPNET). The therapeutic armamentarium for the treatment of GEPNETs has expanded significantly over the last two decades, however the ideal sequencing strategy remains controversial. As this disease may be relatively slow-growing, patients are expected to be treated for longer periods, so that even mild toxicities can influence quality of life, compliance and outcome in the long run. Prospective data on optimal adverse event management are lacking and recommendations are largely based on expert opinion and drug prescribing information. This review summarizes practical recommendations for toxicity management associated with the most commonly used GEPNET treatment options and stresses important focus points for future clinical trials.

Current and future biomarkers in the treatment of colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. CRC develops as a consequence of genomic instability, characterized by various genetic and epigenetic alterations. Its molecular heterogeneity explains the large variability in patient prognosis and treatment response, emphasizing the need for development of accurate prognostic and predictive biomarkers. This article delineates the different pathways of colorectal carcinogenesis and its molecular subtype classification. With this review, we aim to provide a comprehensive overview of the current and future biomarkers guiding clinical decision-making and CRC treatment.

DPYD Genotyping to Predict Adverse Events Following Treatment With Fluorouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon Cancer: A Secondary Analysis of the PETACC-8 Randomized Clinical Trial.

IMPORTANCE: Previous pharmacogenetic studies have shown the prognostic impact of several rare dihydropyrimidine dehydrogenase gene (DPYD) variants on fluorouracil-related adverse events (fluorouracil AEs). However, conflicting results highlight the need for prospective validation in large, homogeneous patient populations uniformly treated with current standard combination therapies used in colon cancer (CC). OBJECTIVE: To determine the impact of DPYD variants on fluorouracil AEs in patients with stage III CC treated with a fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) regimen. DESIGN, SETTING, AND PARTICIPANTS: Pharmacogenetic substudy of 1545 patients who participated from December 2005 to November 2009 in the European Pan-European Trials in Alimentary Tract Cancer (PETACC)-8 randomized phase 3 clinical trial. INTERVENTIONS: Patients with resected stage III CC were randomized to receive standard adjuvant FOLFOX4 alone or FOLFOX4 combined with cetuximab for 6 months. MAIN OUTCOMES AND MEASURES: Patients were genotyped on 25 DPYD variants. We tested the individual associations between each DPYD variant and grade 3 or greater fluorouracil AEs. RESULTS: A total of 1545 patients (57.6% male; median [range] age, 60 [19-75] years) were included in the analysis. The incidence of grade 3 or greater fluorouracil AEs in D949V and V732I (DPYD*6) carriers was 18 in 21 (85.7%) and 121 in 199 (60.8%), respectively. After adjusting for multiple variables, statistically significant associations were identified between grade 3 or greater fluorouracil AEs and both D949V (odds ratio [OR], 6.3 [95% CI, 2.0-27.0]; P < .001) and V732I variants (OR, 1.7 [95% CI, 1.3-2.4]; P < .001). Grade 3 or greater overall hematologic adverse events were associated with V732I (OR, 1.9 [95% CI, 1.4-2.6]) and D949V (OR, 5.2 [95% CI, 2.0-16.0]), and V732I was associated with grade 3 or greater neutropenia (OR, 1.8 [95% CI, 1.3-2.4]). The association of V732I with the occurrence of grade 3 or greater fluorouracil AEs and overall hematologic adverse events was validated in an independent cohort of 339 patients with metastatic colorectal cancer receiving FOLFOX4 in the Fédération Francophone de Cancérologie Digestive 2000-05 phase 3 trial. CONCLUSIONS AND RELEVANCE: In this large phase 3 study, statistically significant associations were found between DPYD variants (D949V and V732I) and increased incidence of grade 3 or greater fluorouracil AEs in patients treated with adjuvant fluorouracil-based combination chemotherapy. Further studies are warranted to confirm and quantitate these associations. TRIAL REGISTRATION: eudract Identifier 2005-003463-23.

Urea-splitting urinary tract infection contributing to hyperammonemic encephalopathy.

BACKGROUND: We present a case of severe neurological symptoms caused by hyperammonemia, secondary to a urinary tract infection with urea-splitting bacteria. INVESTIGATIONS: Blood analysis, urinalysis, urine culture, abdominal ultrasonography, cystography, CT. DIAGNOSIS: Hyperammonemia as a result of urinary tract infection with urea-spliting bacteria. MANAGEMENT: Desobstruction of the urinary tract and bladder or pouch rinsing, antibiotics, reduction of the dietary and endogenous nitrogen load, and endogenous nitrogen breakdown. Identification, prevention and treatment of underlying causes.