Circulating tumour DNA at baseline for individualised prognostication in patients with chemotherapy-naïve metastatic colorectal cancer. An AGEO prospective study.

PURPOSE: Baseline circulating tumour DNA (ctDNA) is a potential prognostic marker in metastatic colorectal cancer (mCRC) patients. However, few studies have compared ctDNA with the usual prognostic factors, and no ctDNA cut-off has been proposed for daily use in clinical practice. PATIENTS AND METHODS: Chemotherapy-naive patients with mCRC were prospectively included. Plasma samples were collected at diagnosis and analysed centrally by both NGS and methylation digital PCR. Baseline patient and disease characteristics, treatment regimens, and secondary surgeries were collected. The restricted cubic spline method was used to define the optimal cut-off of ctDNA mutated allelic frequency (MAF). Prognostic values were assessed on overall survival (OS) using Cox models. RESULTS: From July 2015 to December 2016, 412 patients were included. ctDNA was undetectable in 83 patients (20%). ctDNA was an independent prognostic marker for OS considering the whole study population. The optimal cut-off for ctDNA MAF was 20% with median OS of 16.0 and 35.8 months for patients with MAF ≥20% and<20%, respectively (hazard ratio = 0.40; 95% confidence intervals: 0.31-0.51; P < 0.0001). The independent prognostic value of ctDNA MAF at 20% was confirmed in subgroups defined by RAS/BRAF status or resectability of metastases. Combining ctDNA MAF and carcinoembryonic antigen levels allowed us to define three different prognostic groups with median OS of 14.2, 21.1, and 46.4 months (P < 0.0001). CONCLUSION: ctDNA with a MAF cut-off of 20% improves prognostication of chemotherapy-naïve mCRC patients and may be useful in the future for individualised therapeutic decisions and as a stratification factor in clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02502656.

Cholangiocarcinomes avancés et gènes de fusion.

Advanced cholangiocarcinoma and gene fusions Cholangiocarcinomas (CCAs) are rare digestive tumors classified as intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCAs. These tumors are most often diagnosed at an advanced stage, unresectable or metastatic, and associated with a poor prognosis. The identification in recent years of multiple molecular alterations of interest, particularly in iCCA, has nevertheless allowed the development of new targeted therapeutic options for a significant proportion of patients. Gene fusions are among the most frequent alterations, involving FGFR2 in 10-15% of iCCAs in particular, and NTRK genes at a lower frequency (<1%). A dedicated analysis, most often based on RNA sequencing, is required to identify such alterations. Three FGFR inhibitors, pemigatinib, infigratinib and futinatinib, have recently received FDA approval for use in pre-treated patients. These compounds are currently being evaluated as first-line therapy in several phase III trials. Promising results have also been reported with new-generation inhibitors such as RLY-4008, which may soon constitute new therapeutic options. In the case of NTRK fusion, larotrectinib and entrectinib have also demonstrated their efficacy. The objectives of this review are to clarify the specific diagnostic modalities for gene fusions and to summarize the results of the main trials and developments underway for the management of advanced CCA with gene fusions.

[Advanced GIST: Which treatments in 2022?] / GIST avancées : quels traitements en 2022 ?

Gastrointestinal stromal tumors (GIST) are rare digestive tumors. Activating KIT mutations are the most common molecular alteration in these patients, identified in approximately 70 % of cases, followed by PDGFRA mutations (10-15 %), of which the D842V mutation accounts for most cases. Succinate dehydrogenase (SDH) deficiency and alterations involving NF1, BRAFV600E, RAS or NTRK genes are rare molecular subgroups. In advanced GIST, treatment is based on tyrosine kinase inhibitors, including imatinib, which has been the standard first-line treatment since the early 2000s, with sunitinib and regorafenib as second- and third-line standards, respectively. Two new compounds have recently been evaluated in patients with advanced GIST. Ripretinib has become the validated fourth-line therapy for patients with KIT or PDGFRA non-D842V mutations, and avapritinib has been shown to be effective in patients with D842V mutations who were previously resistant to validated treatments. Avapritinib is now the recommended first-line treatment in this subgroup and may represent an additional option, whose place remains to be clarified, in pre-treated patients without D842V mutations. Specific treatments are available or under evaluation for some rare subgroups, and new therapeutic strategies are likely to further improve the management of advanced GIST in the coming years. This overview summarizes the results of recent trials and the place of these new molecules, as well as the main strategies under development for advanced GIST.

Treatments after Immune Checkpoint Inhibitors in Patients with dMMR/MSI Metastatic Colorectal Cancer.

BACKGROUND: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. METHODS: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. RESULTS: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1-21.3 months) was observed in 4 pts (13%). CONCLUSIONS: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

Intraductal Papillary Mucinous Carcinoma Versus Conventional Pancreatic Ductal Adenocarcinoma: A Comprehensive Review of Clinical-Pathological Features, Outcomes, and Molecular Insights.

Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. However, IPMNs and IPMCs include distinct subtypes of precursor (gastric, pancreato-biliary, intestinal) and invasive (tubular, colloid) lesions, also associated to specific characteristics. Notably, consistent data have shown intestinal IPMNs and associated colloid carcinomas, defining the "intestinal pathway", to be associated with less aggressive features. Genomic specificities have also been uncovered, such as mutations of the GNAS gene, and recent data provide more insights into the mechanisms involved in IPMCs carcinogenesis. This review synthetizes available data on clinical-pathological features and outcomes associated with IPMCs and their subtypes. We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed.

[Neoadjuvant treatment for rectal cancer]. / Traitement néoadjuvant des cancers du rectum.

The management of patients with locally advanced rectal cancer has improved significantly in the past few years with preoperative radiotherapy (RT) and total mesorectal excision. The rate of local recurrence is now around 5 % while the risk of metastatic recurrence has not been reduced which is about 30 %. The benefit of adjuvant chemotherapy remains questionable apart from patients with ypN+tumor after preoperative chemoradiotherapy (CRT) for whom FOLFOX is an option. In recent years, several therapeutic trials have evaluated the benefit of extending the time between the end of RT and surgery and/or the benefit of neoadjuvant chemotherapy, administered as induction (before RT) or in consolidation (after RT and before surgery). The first results of two positive phase 3 trials, PRODIGE 23 and RAPIDO, have been reported in 2020. The two regimens evaluated in these trials are markedly different but have shown that neoadjuvant chemotherapy significantly reduces the risk of distant metastasis. Current developments largely related to a de-escalation of therapy: organ conservation according to a "Watch and Wait" strategy or local resection of the scar, administration of neoadjuvant chemotherapy without RT. These therapeutic strategies have not yet been validated but should be in the news tomorrow. The purpose of this review is to present recent data reported in patients with locally advanced rectal cancer.

Chemotherapy of metastatic colon cancer in France: A population-based study.

AIMS: to describe, using data from a cancer registry in a well-defined French population, the therapeutic strategies and survival of patients with metastatic colon cancer (mCC). METHODS: all patients with synchronous mCC diagnosed within the 2005-2014 period recorded in the digestive cancers registry of Burgundy were included. RESULTS: 1286 mCC patients were included (57% male), of which 34.5% did not receive any antitumor treatment. Both, advanced age (≥75 years) and the Charlson comorbidity score ≥2 were significantly associated with the absence of antitumor treatment. Among the patients treated with chemotherapy, 59 and 33% received at least two and three lines, respectively. Most patients treated with chemotherapy (68%) did not receive first-line targeted therapy. Of patients aged ≥75 years, 57% received no chemotherapy and 56% of treated patients had first-line treatment only. CONCLUSION: this population-based study shows that more than one-third of patients with mCC receive no chemotherapy and that only 59% of treated patients receive treatment beyond the first line. This study also highlights the fact that more than half of patients ≥75 years do not get any antitumor treatment. In patients <75 years, the proportion of patients receiving chemotherapy and/or undergoing curative intent surgery tended to increase over time.

Role of FOLFIRINOX and chemoradiotherapy in locally advanced and borderline resectable pancreatic adenocarcinoma: update of the AGEO cohort.

BACKGROUND: FOLFIRINOX has shown promising results in locally advanced (LAPA) or borderline resectable (BRPA) pancreatic adenocarcinoma. We report here a cohort of patients treated with this regimen from the AGEO group. METHODS: This is a retrospective multicentre study. We included all consecutive patients with non-pre-treated LAPA or BRPA treated with FOLFIRINOX. RESULTS: We included 330 patients (57.9% male, 65.4% <65 years, 96.4% PS <2). Disease was classified as BRPA in 31.1% or LAPA in 68.9%. Objective response rate with FOLFIRINOX was 29.5% and stable disease 51%. Subsequent CRT was performed in 46.4% of patients and 23.9% had curative intent surgery. Resection rates were 42.1% for BRPA and 15.5% for LAPA. Main G3/4 toxicities were fatigue (15%), neutropenia (12%) and neuropathy (G2/3 35%). After a median follow-up of 26.7 months, median OS (mOS) and PFS were 21.4 and 12.4 months, respectively. For patients treated by FOLFIRINOX alone, or FOLFIRINOX followed by CRT, or FOLFIRINOX + /- CRT + surgery, mOS was 16.8 months, 21.8 months and not reached, respectively (p < 0.0001). CONCLUSIONS: FOLFIRINOX for LAPA and BRPA seems to be effective with a manageable toxicity profile. These promising results in "real-life" patients now have to be confirmed in a Phase 3 randomised trial.

Plasma circulating tumor DNA in pancreatic adenocarcinoma for screening, diagnosis, prognosis, treatment and follow-up: A systematic review.

While no biomarker is currently recommended for the management of pancreatic adenocarcinoma (PA), circulating tumor DNA (ctDNA) seems promising but little is known on how it may help to manage our patients in the near future. This systematic review of literature was designed to explore the current knowledge on ctDNA as a screening, diagnostic, prognostic, predictive and theranostic biomarker in the management of PA. We retrieved 62 full-text articles, 3 meta-analyses, 2 clinical trials, 1 abstract and 13 ongoing trials. Results were categorized into sections about screening, diagnosis, prognosis and follow-up of localized and advanced PA together with possible theranostics applications. Although its specificity is excellent, the current sensitivity of ctDNA remains a limitation especially in patients without metastatic disease. Therefore, this biomarker cannot be currently used as a screening or diagnostic tool. Increasing evidence suggests that ctDNA is a relevant candidate biomarker to assess minimal residual disease after radical surgery, but also a strong independent biomarker linked to a poor prognosis in advanced PA. Some recent data also indicates that ctDNA is an attractive biomarker for longitudinal follow-up and possibly early treatment adaptation. Its role in tumor profiling in advanced disease to decide targeted treatments remains to be explored. Altogether, ctDNA appears to be a reliable prognostic tool. Though promising results have been reported, further studies are still needed to define exactly how ctDNA can help physicians in the screening, diagnosis and treatment, as PA is expected to become a major cause of cancer-related deaths in the forthcoming decade.

Adjuvant chemotherapy in pancreatic cancer: state of the art and future perspectives.

PURPOSE OF REVIEW: The modalities of management of resectable pancreatic ductal adenocarcinoma (PDAC) have evolved in recent years with new practice guidelines on adjuvant chemotherapy and results of randomized phase III trials. The aim of this review is to describe the state of the art in this setting and to highlight future possible perspectives. RECENT FINDINGS: Resectable PDAC is the tumor without vascular contact or a limited venous contact without vein irregularity. Several pathologic and biologic robust prognostic factors such as an R0 resection defined by a margin at least 1 mm have been validated. In phase III trials, the doublet gemcitabine-capecitabine provided a statistically significant, albeit modest overall survival benefit, but failed to show an improvement in relapse-free survival. Similarly, gemcitabine plus nab-paclitaxel did not increase disease-free survival. Modified FOLFIRINOX led to improved disease-free survival, overall survival, and metastasis-free survival, with acceptable toxicity. In the future, prognostic and/or predictive biomarkers could lead the optimization of therapeutic strategies and neoadjuvant treatment could become a standard of care in PDAC. SUMMARY: After curative intent resection, modified FOLFIRINOX is the standard of care in adjuvant in fit patients with PDAC. Others regimens (monotherapy or gemcitabine-based) are an option in unfit patients.

BRAF Mutation Status in Circulating Tumor DNA from Patients with Metastatic Colorectal Cancer: Extended Mutation Analysis from the AGEO RASANC Study.

In patients with metastatic colorectal cancer (mCRC), RAS and BRAF mutations are currently determined by tumor sample analysis. Here, we report BRAF mutation status analysis in paired tumor tissue and plasma samples of mCRC patients included in the AGEO RASANC prospective cohort study. Four hundred and twenty-five patients were enrolled. Plasma samples were analyzed by next-generation sequencing (NGS). When no mutation was identified, we used two methylated specific biomarkers (digital droplet PCR) to determine the presence or absence of circulating tumor DNA (ctDNA). Patients with conclusive ctDNA results were defined as those with at least one mutation or one methylated biomarker. The kappa coefficient and accuracy were 0.79 (95% CI: 0.67-0.91) and 97.3% (95% CI: 95.2-98.6%) between the BRAF status in plasma and tissue for patients with available paired samples (n = 405), and 0.89 (95% CI: 0.80-0.99) and 98.5% (95% CI: 96.4-99.5%) for those with conclusive ctDNA (n = 323). The absence of liver metastasis was the main factor associated to inconclusive ctDNA results. In patients with liver metastasis, the kappa coefficient was 0.91 (95% CI, 0.81-1.00) and accuracy was 98.6% (95% CI, 96.5-99.6%). We demonstrate satisfying concordance between tissue and plasma BRAF mutation detection, especially in patients with liver metastasis, arguing for plasma ctDNA testing for routine BRAF mutation analysis in these patients.