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The BRAF V600E mutation is a well-accepted poor prognostic factor in patients with metastatic colorectal cancer (mCRC), as it confers Ras-independent stimulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway involved in proliferation, migration, angiogenesis and the suppression of apoptosis. Analysis of the potential predictive value of BRAF for treatment efficacy is inherently confounded by this known prognostic impact. Currently, approved therapeutic strategies for patients with BRAF -mutant ( BRAF -mt) mCRC are suboptimal, and uncertainty exists regarding how to best treat these patients. Based on the available evidence, it is currently not possible to confirm the superiority of any available treatment options cited in European Society for Medical Oncology and National Comprehensive Cancer Network guidelines (that is, doublet or triplet chemotherapy regimens plus anti-vascular endothelial growth factor or anti-epidermal growth factor receptors), even if triplet chemotherapy plus bevacizumab is the most accepted standard regimen. In this review, we highlight still-emerging strategies that could be deployed to combat BRAF -mt mCRC, including triplet chemotherapy plus available biologic agents, rationally derived combinations of targeted agents and immunotherapy. While it is clear that the needs of patients with BRAF -mt mCRC are currently unmet, we are cautiously optimistic that the recently renewed research interest in these patients will yield clinically relevant insights and therapeutic strategies.

Background Pretherapeutic screening for dihydropyrimidine dehydrogenase (DPD) deficiency is recommended or required prior to the administration of fluoropyrimidine-based chemotherapy. However, the best strategy to identify DPD-deficient patients remains elusive. Methods Among a nationwide cohort of 5886 phenotyped patients with cancer who were screened for DPD deficiency over a 3 years period, we assessed the characteristics of both DPD phenotypes and DPYD genotypes in a subgroup of 3680 patients who had completed the two tests. The extent to which defective allelic variants of DPYD predict DPD activity as estimated by the plasma concentrations of uracil [U] and its product dihydrouracil [UH 2 ] was evaluated. Results When [U] was used to monitor DPD activity, 6.8% of the patients were classified as having DPD deficiency ([U] > 16 ng/ml), while the [UH 2 ]:[U] ratio identified 11.5% of the patients as having DPD deficiency (UH 2 ]:[U] < 10). [U] classified two patients (0.05%) with complete DPD deficiency (> 150 ng/ml), and [UH 2 ]:[U] < 1 identified three patients (0.08%) with a complete DPD deficiency. A defective DPYD variant was present in 4.5% of the patients, and two patients (0.05%) carrying 2 defective variants of DPYD were predicted to have low metabolism. The mutation status of DPYD displayed a very low positive predictive value in identifying individuals with DPD deficiency, although a higher predictive value was observed when [UH 2 ]:[U] was used to measure DPD activity. Whole exon sequencing of the DPYD gene in 111 patients with DPD deficiency and a “wild-type” genotype (based on the four most common variants) identified seven heterozygous carriers of a defective allelic variant. Conclusions Frequent genetic DPYD variants have low performances in predicting partial DPD deficiency when evaluated by [U] alone, and [UH 2 ]:[U] might better reflect the impact of genetic variants on DPD activity. A clinical trial comparing toxicity rates after dose adjustment according to the results of genotyping or phenotyping testing to detect DPD deficiency will provide critical information on the best strategy to identify DPD deficiency.

AbstractObjectiveTo evaluate sintilimab versus placebo in combination with chemotherapy (cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil) as first line treatment of unresectable locally advanced, recurrent, or metastatic oesophageal squamous cell carcinoma.DesignMulticentre, randomised, double blind, phase 3 trial.Setting66 sites in China and 13 sites outside of China between 14 December 2018 and 9 April 2021.Participants659 adults (aged ≥18 years) with advanced or metastatic oesophageal squamous cell carcinoma who had not received systemic treatment.InterventionParticipants were randomised 1:1 to receive sintilimab or placebo (3 mg/kg in patients weighing <60 kg or 200 mg in patients weighing ≥60 kg) in combination with cisplatin 75 mg/m2 plus paclitaxel 175 mg/m2 every three weeks. The trial was amended to allow investigators to choose the chemotherapy regimen: cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil (800 mg/m2 continuous infusion on days 1-5).Main outcome measuresOverall survival in all patients and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1.Results659 patients were randomly assigned to sintilimab (n=327) or placebo (n=332) with chemotherapy. 616 of 659 patients (93%) received sintilimab or placebo in combination with cisplatin plus paclitaxel and 43 of 659 patients (7%) received sintilimab or placebo in combination with cisplatin plus 5-fluorouracil. At the interim analysis, sintilimab with chemotherapy showed better overall survival compared with placebo and chemotherapy in all patients (median 16.7 v 12.5 months, hazard ratio 0.63, 95% confidence interval 0.51 to 0.78, P<0.001) and in patients with combined positive scores of ≥10 (17.2 v 13.6 months, 0.64, 0.48 to 0.85, P=0.002). Sintilimab and chemotherapy significantly improved progression free survival compared with placebo and chemotherapy in all patients (7.2 v 5.7 months, 0.56, 0.46 to 0.68, P<0.001) and in patients with combined positive scores of ≥10 (8.3 v 6.4 months, 0.58, 0.45 to 0.75, P<0.001). Adverse events related to treatment occurred in 321 of 327 patients (98%) in the sintilimab-chemotherapy group versus 326 of 332 (98%) patients in the placebo-chemotherapy group. Rates of adverse events related to treatment, grade ≥3, were 60% (196/327) and 55% (181/332) in the sintilimab-chemotherapy and placebo-chemotherapy groups, respectively.ConclusionsCompared with placebo, sintilimab in combination with cisplatin plus paclitaxel showed significant benefits in overall survival and progression free survival as first line treatment in patients with advanced or metastatic oesophageal squamous cell carcinoma. Similar benefits of sintilimab with cisplatin plus 5-fluorouracil seem promising.Trial registrationClinicalTrials.gov NCT03748134.

Small bowel cancers are rare diseases whose prognosis is poorer than that of colon cancers. Due to disease rarity, there is little data on small bowel adenocarcinoma (SBA) treatment, and most recommendations come from expert agreements or analogies to the management of colon cancer. Although relatively high rates of local recurrence are observed for duodenal malignancies, distant metastatic relapse remains common and requires adjuvant systemic therapy. Given the similarities between SBA and colorectal cancer, radiotherapy and chemotherapy strategies used for the latter disease are frequently pursued for the former disease, specifically for tumors located in the duodenum. However, no previous randomized study has evaluated the benefit of adjuvant chemotherapy on the overall survival of SBA patients. Most previous studies on treatment outcomes and prognostic factors in this context were based on large international databases, such as the Surveillance, Epidemiology, and End Results or the National Cancer Database. Studies are required to establish and validate prognostic and predictive markers relevant in this context to inform the use of (neo) adjuvant treatment. Among those, deficient mismatch repair tumors represent 20% of SBAs, but their impact on chemosensitivity remains unknown. Herein, we summarize the current evidence on the management of localized SBA, including future perspectives.

Small bowel adenocarcinoma (SBA) is diagnosed at an advanced (unresectable or metastatic) tumor stage in approximately one-third of cases. This is partly due to the non-specific symptomatology and limitations in endoscopic and radiologic detection methods. In this context, the prognosis remains poor and systemic chemotherapy appears to benefit patients when compared to best supportive care alone, despite the absence of randomized controlled trials. The results of a recent large prospective cohort (ARCAD-NADEGE) reported that the absence of chemotherapy was a predictive factor for a lower overall survival (OS) even though poor differentiation and SBA associated with Crohn’s disease correlate with poor prognosis. In retrospective series, the median OS ranges from approximately 9 to 18 months with current treatment approaches. A combination of a fluoropyrimidine and oxaliplatin (FOLFOX or CAPOX) appears to be the most utilized and effective first-line chemotherapy regimen. Other front-line alternatives are the combination of 5-FU and cisplatin or fluoropyrimidine and irinotecan (FOLFIRI). In second-line, FOLFIRI is an effective option after progression on platinum-based therapy. Taxane-based therapy appears to be an alternative option, but further evaluation in larger series is needed. To a limited extent, the role of surgical resection for metastatic disease appears to be a valid option, though this approach has not been evaluated in prospective clinical studies. Due to the rareness of the disease, inclusion in clinical trials should be prioritized, and there is hope that targeted therapies and immunotherapy may enter the therapeutic arsenal for these patients.

Perioperative FLOT (fluorouracil, oxaliplatin, and docetaxel) triplet chemotherapy is the standard of care for localised and resectable gastric and gastro-oesophageal junction adenocarcinoma. We aimed to compare a modified FLOT regimen (also known as TFOX) with FOLFOX as first-line treatment for patients with HER2-negative advanced gastric and gastro-oesophageal junction adenocarcinoma. PRODIGE 51-FFCD-GASTFOX is an open-label, multicentre, randomised, phase 3 trial conducted at 96 medical centres in France. Eligible individuals were aged 18 years or older, had histologically confirmed, HER2-negative adenocarcinoma of the stomach or gastro-oesophageal junction that was locally advanced unresectable or metastatic and previously untreated, measurable disease per Response Evaluation Criteria in Solid Tumours, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were randomly assigned (1:1), using the minimisation method, to receive FOLFOX (folinic acid 400 mg/m2, oxaliplatin 85 mg/m2, and 5-fluorouracil bolus 400 mg/m2 then 5-fluorouracil 2400 mg/m2 as a continuous 46 h infusion every 2 weeks) or TFOX (docetaxel 50 mg/m2, folinic acid 400 mg/m2, and oxaliplatin 85 mg/m2 then 5-fluorouracil 2400 mg/m2 as a continuous 46 h infusion every 2 weeks). Randomisation was stratified by centre, ECOG performance status, (neo)adjuvant chemotherapy or chemoradiotherapy, tumour stage, tumour location, and pathological histological subtype. The primary endpoint was progression-free survival (assessed in the intention-to-treat population), defined as time from randomisation to the first radiological or clinical progression (or both), or death due to any cause, whichever occurred first. Secondary endpoints included overall survival (defined as time from randomisation to death due to any cause) and objective response rate (defined as the proportion of patients with a best overall complete or partial response). Hazard ratio and 95% CIs were estimated using an unstratified Cox proportional hazards model. When the proportional hazards assumption was violated, the restricted mean survival time was used to estimate the treatment effect size. This study is registered with ClinicalTrials.gov, NCT03006432, and EudraCT, 2016–002331–16. Between Dec 19, 2016, and Dec 26, 2022, 507 patients were randomly assigned (254 to the TFOX group and 253 to the FOLFOX group [intention-to-treat population]). The median age was 64·2 years (IQR 56·7–70·8), and 399 (79%) participants were male and 108 (21%) were female. At median follow-up of 42·8 months (25·8–49·9), the median progression-free survival was 7·59 months (95% CI 7·06–7·95) in the TFOX group versus 5·98 months (5·65–6·97) in the FOLFOX group. The assumption of proportional hazards was violated (p=0·013); therefore, the 12-month restricted mean progression-free survival was calculated: 7·52 months (7·06–7·97) in the TFOX group versus 6·62 months (6·16–7·09) in the FOLFOX group (p=0·0072). The median overall survival was 15·08 months (13·70–16·72) in the TFOX group versus 12·65 months (10·94–14·00) in the FOLFOX group (proportional hazards assumption was confirmed; HR 0·82 [0·68–0·99]; p=0·048) and the objective response rate was 62·3% (56·0–68·3) versus 53·4% (47·0–59·8; p=0·045). The most common grade 3 and 4 treatment-emergent adverse events were diarrhoea (37 [15%] in the TFOX group vs 18 [7%] in the FOLFOX group), peripheral neuropathy (80 [32%] vs 49 [20%]), neutropenia (67 [27%] vs 44 [18%]), and fatigue (40 [16%] vs 20 [8%]). Serious treatment-related adverse events occurred in 66 (27%) participants in the TFOX group and 33 (13%) in the FOLFOX group. There were two (<1%) treatment-related deaths in the TFOX group (one due to septic shock and one due to gastrointestinal perforation) and one (<1%) in the FOLFOX group (due to septic shock). The modified FLOT/TFOX regimen significantly improved progression-free survival, overall survival, and objective response rate compared with FOLFOX in previously untreated patients with advanced HER2-negative gastric and gastro-oesophageal junction adenocarcinoma. The modified FLOT/TFOX regimen might represent a new first-line treatment option for patients eligible for this docetaxel triplet chemotherapy. Fédération Francophone de Cancérologie Digestive.

Patients with locally advanced resectable (LAR) gastric/gastroesophageal junction (G/GEJ) adenocarcinomas have a high recurrence risk despite pre- and post-operative treatment. In the PLAGAST prospective study (NCT02674373), we investigated the ability of circulating tumor DNA (ctDNA) to predict treatment response and improve risk stratification. Plasma samples were prospectively collected before neoadjuvant therapy (NAT), during-NAT, post-NAT, and post-surgery. The primary endpoint was recurrence-free survival (RFS), and the secondary endpoints were overall survival (OS), tumor regression grade (TRG), and pathological tumor stage. ctDNA positivity decreased over these four therapeutic timelines (69.6%, 51.2%, 26.8%, and 20%, respectively). ctDNA-positivity was associated with significantly worse outcomes during-NAT (RFS: HR = 6.17, P  = 0.002; OS: HR = 4.71, P  = 0.022), post-NAT (RFS: HR = 5.26, P  = 0.001; OS: HR = 7.35, P  = 0.001) and after surgery (RFS: HR = 12.94, P  < 0.0001; OS: HR = 14.54, P  < 0.0001). Patients with early ctDNA clearance during NAT had better outcomes compared to those who cleared ctDNA post-NAT, while patients who remained ctDNA-positive pre-, during-, and post-NAT had worse outcomes (RFS: HR = 18.57, P  = 0.01; OS: HR = 16.06, P  = 0.007). Our data suggests that longitudinal ctDNA monitoring is prognostic of patient outcomes and may guide therapeutic decision-making in patients with LAR G/GEJ adenocarcinoma. Despite pre- and post-operative treatment, patients with locally advanced resectable gastric/gastroesophageal junction adenocarcinomas have a high recurrence risk. Here, the authors analyse a prospective cohort of patients and find ctDNA status is correlated with survival outcomes.

Circulating tumor DNA (ctDNA) has emerged as a good candidate for tracking tumor dynamics in different cancer types, potentially avoiding repeated tumor biopsies. Many different genes can be mutated within a tumor, complicating procedures for tumor monitoring, even with highly sensitive next-generation sequencing (NGS) strategies. Droplet-based digital PCR (dPCR) is a highly sensitive and quantitative procedure, allowing detection of very low amounts of circulating tumor genetic material, but can be limited in the total number of target loci monitored. We analyzed hypermethylation of 3 genes, by use of droplet-based dPCR in different stages of colorectal cancer (CRC), to identify universal markers for tumor follow-up. Hypermethylation of WIF1 (WNT inhibitory factor 1) and NPY (neuropeptide Y) genes was significantly higher in tumor tissue compared to normal tissue, independently of tumor stage. All tumor tissues appeared positive for one of the 2 markers. Methylated ctDNA (MetctDNA) was detected in 80% of metastatic CRC and 45% of localized CRC. For samples with detectable mutations in ctDNA, MetctDNA and mutant ctDNA (MutctDNA) fractions were correlated. During follow-up of different stage CRC patients, MetctDNA changes allowed monitoring of tumor evolution. These results indicate that MetctDNA could be used as a universal surrogate marker for tumor follow-up in CRC patients, and monitoring MetctDNA by droplet-based dPCR could avoid the need for monitoring mutations.

Background:Hepatocholangiocarcinoma (cHCC-ICC) is a rare liver tumour for which no data on chemosensitivity exist. The aims of this multicentre study were to evaluate overall survival (OS), progression-free survival (PFS), and prognostic factors in cHCC-ICC treated by gemcitabine plus platinum as first-line.Methods:Unresectable cHCC-ICC treated by gemcitabine plus platinum-based chemotherapy between 2008 and 2017 were retrospectively analysed. Diagnosis was based on histology or, in case of ICC or HCC histology, on discordant computerised tomography scan enhancement patterns associated with discordant serum tumour marker elevation suggesting the alternative tumour. OS and PFS were evaluated by Kaplan-Meier method and prognostic factors by Log-rank test and Cox model.Results:Among 30 patients included, cHCC-ICC was histologically proven in 22 (73.3%). 18 (60%) received gemcitabine plus oxaliplatin (GEMOX), 9 (30%) GEMOX plus bevacizumab, and 3 (10%) gemcitabine plus cisplatin. RECIST criteria were reported in 28 patients: 8 (28.6%) showed partial response, 14 (50%) stable disease, and 6 (21.4%) tumour progression at first evaluation. Median PFS and OS were 9.0 and 16.2 months, respectively. Serum bilirubin [egs]30 μmol l-1 (P=0.001) and positive serology for HBV and/or HCV (P=0.014) were independent poor prognostic factors for OS.Conclusions:Gemcitabine plus platinum-based chemotherapy is effective as first-line for advanced cHCC-ICC.