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The multicentric prospective ColoBEAM study (NCT02751177) aimed to assess the feasibility of using liquid biopsy for the detection of KRAS, NRAS and BRAF gene mutations in patients with metastatic colorectal cancer (mCRC) in a real-world setting. The study involved eight medical centres. Tumour DNA from formalin-fixed paraffin embedded tissue was analysed using either PCR or next-generation sequencing as the gold standard, while circulating tumour DNA from plasma was evaluated using the beads emulsion and magnetics digital PCR technique. Blood sampling was conducted without strict timing constraints, allowing for a real-world reflection of clinical practice. Discrepancies between tissue and blood results were re-evaluated externally to ensure the reliability. A total of 202 patients had KRAS and NRAS (RAS) status available for analysis, and 198 patients had both RAS and BRAF statuses available. Overall, the study confirmed the feasibility of liquid biopsy, achieving a concordance rate of 83.2% for RAS mutations and 82.3% for RAS and BRAF mutations when compared with tissue biopsy. The sensitivity of liquid biopsy for detecting RAS mutations was 77.3%, with a specificity of 94.3%. For RAS and BRAF mutations combined, the sensitivity was 77.0% and the specificity was 93.7%. Further analysis based on patient characteristics at the time of blood sampling showed higher sensitivity in chemotherapy-naive patients (sensitivity, 86.1%; specificity, 91.3%) and in patients with liver metastases (sensitivity, 88.6%; specificity, 89.7%). Sensitivity was also higher when the primary tumour was present (sensitivity, 88.6%) and in cases of disease progression or recurrence (sensitivity, 82.8%). In conclusion, liquid biopsy was a feasible and valuable method for detecting RAS and BRAF mutations in patients with mCRC, offering a less invasive alternative to traditional tissue biopsy in real-world settings. The trial registration number is 2015-A01272-47/NCT02751177 (registered March 3, 2016). Key words: metastatic colorectal cancer, liquid biopsy, KRAS, NRAS, BRAF

Pancreatic cancer (PC) incidence rates are rapidly increasing in developed countries, with half the patients being metastatic at diagnosis. For decades, fluorouracil, then gemcitabine regimens were the preferred palliative first-line options for fit patients with metastatic PC. FOLFIRINOX (a combination of bolus and infusional fluorouracil, leucovorin, irinotecan and oxaliplatin) was introduced to clinical practice in 2010 due to the results of the phase II/III trial (PRODIGE 4/ACCORD 11) comparing FOLFIRINOX with single-agent gemcitabine as first-line treatment for patients with MPC. Median overall survival, progression-free survival, and objective response rate were superior with FOLFIRINOX over gemcitabine and there was prolonged time to definitive deterioration in quality of life. Although FOLFIRINOX was also associated with increased toxicity, mainly febrile neutropenia and diarrhea, there has been rapid uptake of this regimen. This review closely examines optimal management and prevention of toxicities, international recommendations for first-line treatment, and use of modified FOLFIRINOX protocols. In this review, we also look at the potential benefit of FOLFIRINOX in selected groups of patients: second-line therapy, adjuvant chemotherapy, induction therapy in patients with borderline resectable and locally advanced PC. Robust validation of the FOLFIRINOX regimen in these settings requires confirmation in further randomized trials.

Cell-free DNA detection is becoming a surrogate assay for tumor genotyping. Biological fluids often content a very low amount of cell-free tumor DNA and assays able to detect very low allele frequency mutant with a few quantities of DNA are required. We evaluated the ability of the fully-automated molecular diagnostics platform Idylla for the detection of KRAS, NRAS and BRAF hotspot mutations in plasma from patients with metastatic colorectal cancer (mCRC). First, we evaluated the limit of detection of the system using two set of laboratory made samples that mimic mCRC patient plasma, then plasma samples from patients with mCRC were assessed using Idylla system and BEAMing digital PCR technology. Limits of detection of 0.1%, 0.4% and 0.01% for KRAS, NRAS and BRAF respectively have been reached. With our laboratory made samples, sensitivity up to 0.008% has been reached. Among 15 patients' samples tested for KRAS mutation, 2 discrepant results were found between Idylla and BEAMing dPCR. A 100% concordance between the two assays has been found for the detection of NRAS and BRAF mutations in plasma samples. The Idylla system does not reach as high sensitivity as assays like ddPCR but has an equivalent sensitivity to modified NGS technics with a lower cost and a lower time to results. These data allowed to consider the Idylla system in a routine laboratory workflow for KRAS, NRAS and BRAF mutations detection in plasma.

In 2010, the FOLFIRINOX regimen (bolus and infusional 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) emerged as a new option in patients with metastatic pancreatic cancer and a good performance status. However, at that time, some doubts were raised regarding safety issues. Similarly, no data on FOLFIRINOX were published in patients with unresectable/locally advanced or borderline resectable pancreatic cancer. This article presents the available experience with FOLFIRINOX outside clinical trials in metastatic and locally advanced pancreatic cancer patients. The safety of the regimen in patients with biliary stents and in previously treated patients is also described. FOLFIRINOX usage in clinical practice, including modification of the regimen (omission of bolus 5-fluorouracil; FOLFOXIRI regimen), is also presented. These data suggest that a phase III randomized study is warranted to further explore the role of FOLFIRINOX in locally advanced pancreatic cancer.

The transition from traditional handwritten prescriptions to electronic prescribing systems represents a significant advancement, with the potential to enhance treatment efficacy, patient safety, and professional communication. This study aimed to examine the impact of this transition within a medical oncology service, assessing the compliance of electronic prescriptions with established good practice standards and exploring the associated risks. In this retrospective analysis, we compared handwritten prescriptions from the pre-electronic era (January to May 2018) with electronic prescriptions (January to May 2021) following the implementation of the electronic prescribing system PandaLab Pro (PandaLab SAS). The inclusion criteria focused on outpatient oncology treatments, with a clear set of exclusion parameters to ensure a focused study scope. We defined good compliance as the written mention of the evaluated terms. The compliance rates were then compared using a chi-square test. Our findings, based on a sample size of 260 prescriptions (randomized among 30,526 archived prescriptions), indicate a substantial improvement in electronic prescriptions' compliance with prescribers and patient details, treatment accuracy, and overall adherence to regulatory standards. Notably, electronic formats achieved a remarkable 80.8% accuracy rate in compliance with safety criteria compared with 8.5% for handwritten prescriptions (P<.001). The use of prefilled prescriptions significantly increased compliance from a safety perspective (56% vs 96.2%; P<.001) compared with electronic prescriptions from scratch. The analysis further underscores the advantages of prefilled electronic prescription templates, which significantly improved compliance rates compared with manually filled electronic and handwritten prescriptions. Furthermore, the study revealed a marked shift in prescribing behaviors, with electronic prescriptions tending to be more concise yet more numerous, suggesting an impact on medication management and patient adherence, which warrants further investigation. The study supports the transition to electronic prescribing systems in oncology, highlighting enhanced traceability, compliance with health authority standards, and patient safety. The implementation of prefilled templates supported by pharmacists has emerged as a pivotal factor in this improved process. While acknowledging certain limitations, such as the nonquantitative assessment of time savings and acceptability, this research advocates for the widespread adoption of electronic prescriptions and serves as a benchmark for future e-prescription initiatives in France.

Olaparib was approved in 2014 by the European Medicines Agency (EMA) as maintenance treatment for patients with breast cancer gene (BRCA)-mutated platinum-sensitive relapsed high-grade epithelial ovarian cancer (EOC) following the results of the Study 19. We present the results of a national real-world study on the effectiveness of olaparib in relapsed BRCA-mutated EOC patients. Patients with EOC, peritoneal, and/or fallopian-tube cancer treated with olaparib in a French Center between May 2014 and March 2017 were included. The primary end-point of the study was progression-free survival. Of the 128 patients analyzed, 89 were treated according to the EMA label. The median progression-free survival was 17.0 months. The most common treatment-related toxicity was fatigue. Treatment-related myelodysplastic syndrome (n=5) and a second cancer (n=1) were diagnosed. In this real-life setting, olaparib confirmed its efficacy and safety profile, as previously shown in clinical trials.

Despite great histological and molecular heterogeneity, the clinical management of high-grade ovarian carcinomas remains unspecialized. As a major subgroup, high-grade serous ovarian carcinomas (HGSOCs) require novel therapies. In addition to utilizing conventional histological prognostic markers and performing oncogenetic investigations, the molecular diagnostic method of next generation sequencing (NGS) was performed to identify 'druggable' targets that could provide access to innovative therapy. The present study was performed in 45 HGSOC patients (mean age, 59.1 years; range, 25-87 years) with histologically proven HGSOC. Breast cancer 1/2 (BRCA1/2) germline mutations were screened in 17 patients with a familial or personal history of cancer, which was justified by oncogenetic investigations. Tumor protein 53 (P53) and phosphatase and tensin homolog (PTEN) expression were assessed in formalin-fixed paraffin-embedded tissues using immunohistochemistry. Somatic mutations of Kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and MET proto-oncogene, receptor tyrosine kinase (MET) were screened using NGS on DNA extracts from frozen tumor specimens obtained at diagnosis. With a median follow-up of 38 months (range, 6-93 months), 20 patients are alive, 10 patients are disease-free and 14 patients progressed within 6 months following platinum-based therapy. P53 overexpression was detected in 67% of patients and PTEN loss was detected in 38% of the patients. The overexpression of mutant P53 was found to be associated with a longer progression-free and overall survival. In total, 2 NRAS (exon 3), 3 PIK3CA (exon 5 and 10) and 5 MET mutations (exons 14 and 18) were detected. In HGSOCs, in addition to P53 and PTEN alterations, somatic genetic abnormalities can be detected using NGS and provide molecular rationale for targeted therapies, potentially offering novel therapeutic opportunities to patients.

Introduction/BackgroundThe O’CaRE study assessed real-world burden of disease, treatment patterns, and outcomes in patients with OC in 5 European countries (UK, France, Germany, Spain, and Italy). The analysis presented provides real-world data on the cumulative impact of risk factors (RFs) on disease progression and survival following 1L treatment.MethodologyO’CaRE was a multicentre, noninterventional retrospective medical chart review study of patients aged ≥18 years diagnosed with epithelial ovarian, fallopian tube, or primary peritoneal cancer from 1 January 2014 to 31 December 2015. Patients were classified into moderate- or high-risk categories based on number of RFs for progression (Table). High-risk patients were further grouped by total number of RFs. Patients were followed from index date (date of diagnosis) until last activity or study end (maximum follow of 4 years). Kaplan-Meier methodology was used to estimate progression-free survival (PFS) and overall survival (OS).ResultsThe analysis included 412 patients: 7 (1.7%) had moderate risk of progression, whereas 405 (98%) had high risk of progression (table 1). For those with high risk, 84 (20.4%), 133 (32.3%), 139 (33.7%), and 49 (11.9%) had 1, 2, 3, and 4 RFs, respectively. Median PFS was 31.3 months for patients with 0 RFs and 12.6, 7.9, 5.9, and 3.5 months for patients with 1, 2, 3, or 4 RFs, respectively. Median OS was 41.9 months for patients with 0 RFs and not reached, 25.0, 18.0, and 7.4 months for patients with 1, 2, 3, or 4 RFs, respectively.Abstract 2022-RA-1505-ESGO Table 1Outcomes by risk factorsConclusionThis real-world analysis of patients with OC from 5 European countries demonstrated that higher numbers of RFs were associated with shorter median PFS and OS. This analysis provides real-world data relating to 1L treatment outcomes for patients with OC; if validated in clinical trials, the number of RFs could be a stratification factor for future 1L OC trials.

The COVID-19 pandemic has been associated with substantial reduction in screening, case identification, and hospital referrals among patients with cancer. However, no study has quantitatively examined the implications of this correlation for cancer patient management. To evaluate the association of the COVID-19 pandemic lockdown with the tumor burden of patients who were diagnosed with metastatic colorectal cancer (mCRC) before vs after lockdown. This cohort study analyzed participants in the screening procedure of the PANIRINOX (Phase II Randomized Study Comparing FOLFIRINOX + Panitumumab vs FOLFOX + Panitumumab in Metastatic Colorectal Cancer Patients Stratified by RAS Status from Circulating DNA Analysis) phase 2 randomized clinical trial. These newly diagnosed patients received care at 1 of 18 different clinical centers in France and were recruited before or after the lockdown was enacted in France in the spring of 2020. Patients underwent a blood-sampling screening procedure to identify their RAS and BRAF tumor status. mCRC. Circulating tumor DNA (ctDNA) analysis was used to identify RAS and BRAF status. Tumor burden was evaluated by the total plasma ctDNA concentration. The median ctDNA concentration was compared in patients who underwent screening before (November 11, 2019, to March 9, 2020) vs after (May 14 to September 3, 2020) lockdown and in patients who were included from the start of the PANIRINOX study. A total of 80 patients were included, of whom 40 underwent screening before and 40 others underwent screening after the first COVID-19 lockdown in France. These patients included 48 men (60.0%) and 32 women (40.0%) and had a median (range) age of 62 (37-77) years. The median ctDNA concentration was statistically higher in patients who were newly diagnosed after lockdown compared with those who were diagnosed before lockdown (119.2 ng/mL vs 17.3 ng/mL; P < .001). Patients with mCRC and high ctDNA concentration had lower median survival compared with those with lower concentration (14.7 [95% CI, 8.8-18.0] months vs 20.0 [95% CI, 14.1-32.0] months). This finding points to the potential adverse consequences of the COVID-19 pandemic and related lockdown. This cohort study found that tumor burden differed between patients who received an mCRC diagnosis before vs after the first COVID-19 lockdown in France. The findings of this study suggest that CRC is a major area for intervention to minimize pandemic-associated delays in screening, diagnosis, and treatment.

Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed. The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01771458. Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8–11·6) in the experimental group and 11·3 months (8·1–11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7–3·8) in the experimental group versus 2·0 months (1·8–2·1) in the control group (hazard ratio 0·88, 95% CI 0·65–1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3–4 adverse events (p=0·30). The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy. Institut Curie.