Abstract
Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite ...accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its N
6
,2’-O-dimethyladenosine (m
6
A
m
) demethylase activity. While m
6
A
m
is strategically located next to the m
7
G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m
6
A
m
level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m
6
A
m
methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m
6
A
m
modification in stem-like properties acquisition. FTO-mediated regulation of m
6
A
m
marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m
6
A
m
modification and its potential adverse consequences for colorectal cancer management.
Background
The correlation between immune cells and the Lauren classification subtypes and their prognostic impact in advanced gastric cancer (AGC) are unknown.
Methods
Circulating natural killer ...(NK) cells, CD4
+
and CD8
+
T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were quantified in peripheral blood mononuclear cells (PBMCs) from 67 patients with untreated AGC enrolled in the PRODIGE 17-ACCORD 20 trial. CD56
+
cells (NK), CD8
+
, and FoxP3
+
(Treg) tumor-infiltrating lymphocytes (TILs) were assessed in tumor samples.
Results
Circulating NK and Treg proportions were significantly lower in patients with diffuse/mixed-type AGC (
n
= 27) than those with intestinal type (
n
= 40; median 6.3% vs 11.5%;
p
= 0.02 and median 3.3% vs 5.2%;
p
= 0.03, respectively). Proportions of circulating MDSC, CD4
+
and CD8
+
T cells were not associated with one pathological type. Among tumor-infiltrating cells, CD8
+
T cells, but not NK or FoxP3
+
cells, were significantly lower in diffuse/mixed-type AGC (median 21 vs 59 cells/field;
p
= 0.009). Patients with high circulating NK cell counts (> 17%) had a better overall survival than those with < 17% (HR 0.40; 95% CI 0.15–1.06;
p
= 0.04). Patients with high CD8
+
TIL counts (> 31 cells/field) had significantly longer overall survival (HR 0.44; 95% CI 0.21–0.92;
p
= 0.02). The prognostic value of CD8
+
TILs was maintained after adjustment for confounding factors, including the Lauren classification (HR = 0.42; 95% CI 0.18–0.96;
p
= 0.039).
Conclusion
Diffuse/mixed-type AGC has lower rates of CD8
+
TILs and circulating NK cells and Tregs than the intestinal type. This “cold tumor” phenotype may be associated with a worse outcome.
Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients ...enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA.
According to the protocol, serum samples were collected before chemotherapy and on completion of chemotherapy. HPV16 ctDNA was quantified by droplet digital PCR (ddPCR) and correlated with prospectively registered patient characteristics and outcomes. A landmark was set at the time of chemotherapy completion for postchemotherapy progression-free survival (PFS) analyses.
Among 57 patients with HPV16-related advanced SCCA, HPV ctDNA was detected in 91.1% (95% confidence interval, 81.1-96.2) of baseline samples. Baseline HPV ctDNA levels were not associated with any patient characteristics; baseline ctDNA level below the cutoff obtained by AUC (area under the curve) was associated with a longer PFS (HR = 2.1;
= 0.04). Among the 36 patients who completed 5 months of chemotherapy, residual HPV ctDNA was detected after chemotherapy in 38.9% of patients. Residual HPV ctDNA detected at chemotherapy completion was associated with shorter postchemotherapy PFS (median PFS 3.4 months vs. not reached; HR = 5.5;
< 0.001) and a reduction of 1-year overall survival rate (OR = 7.0;
= 0.02).
This prospective study in advanced SCCA demonstrated a significant prognostic impact of HPV ctDNA level before first-line chemotherapy and HPV ctDNA negativity after chemotherapy completion. With a limited cost and short turnaround, this assay is a promising tool to optimize the therapeutic management of SCCA.
.
What is known and Objective
Sunitinib pharmacokinetics can be influenced by the physio‐pathological conditions of individual patients. Therapeutic drug monitoring (TDM) helps to optimize efficacy and ...reduce the risk of adverse effects. We report on the use of Bayesian analysis to optimize sunitinib blood levels.
Case Summary
We describe two patients with risk of sunitinib pharmacokinetic variability due to gastrectomy and ongoing haemodialysis, respectively. TDM and Bayesian estimation allowed maintaining their sunitinib pharmacokinetic profiles within the usual limits.
What is new and conclusion
Our analysis showed that Bayesian analysis can be successfully applied for real‐time TDM to optimize sunitinib blood levels in patients with major comorbidities.
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.
Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the ...anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients.
Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy.
Although the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA.
NCT03519295.
Background
BRAFV600E mutations occurring in about 10% of metastatic colorectal cancers (mCRCs) are usually associated with a poor outcome. However, their prognostic factors are unknown.
Materials and ...Methods
We built a multicenter clinico‐biological database gathering data from patients with BRAFV600E‐mutant mCRC treated in one of the 16 French centers from 2006 to 2017. The primary endpoint was to identify prognostic factors using a Cox model.
Results
We included 287 patients (median age, 67 years 28–95; female, 57%). Their median overall survival was 20.8 months (95% confidence interval CI, 17.97–27.04), and median progression‐free survival in the first‐line setting was 4.34 months (95% CI, 3.81–5.03). Chemotherapy regimen and biological agents (antiangiogenic or anti‐epidermal growth factor receptor) were not associated with overall and progression‐free survival. Stage IV disease (synchronous metastases) and absence of curative‐intent surgery were statistically associated with poor overall survival. Among the 194 patients with mismatch repair (MMR) status available, overall survival was significantly longer in patients with deficient MMR tumors compared with those with proficient MMR tumors (adjusted hazard ratio = 0.56; p = .009).
Conclusion
Despite that BRAFV600E‐mutant mCRCs are associated with poor overall and progression‐free‐survival, patients with deficient MMR tumors and/or resectable disease experienced a longer survival. These results highlight the importance of MMR testing and resectability discussion in patients with BRAFV600E mCRC in day‐to‐day practice.
Implications for Practice
Mismatch repair (MMR) testing and resectability discussion in patients with BRAFV600E metastatic colorectal cancer (mCRC) should be performed in day‐to‐day practice to steer treatment decision making in patients with BRAFV600E‐mutant mCRC.
摘要
背景。在转移性结直肠癌 (mCRC) 病例中，约发生10% 的BRAFV600E 突变，通常与不良预后有关。然而，影响预后的因素尚未可知。
材料和方法。我们建立了一个多中心临床生物学数据库，旨在收集 2006 年至 2017 年在法国 16 家中心中任意一家治疗的 BRAFV600E 突变型mCRC患者的数据。主要目的是利用 Cox 模型确定影响预后的因素。
结果。我们纳入了 287 名患者 平均年龄 67 岁 (28–95)；女性占 57%。他们的中位总生存期为 20.8 个月 95% 置信区间 (CI)，17.97–27.04，在一线治疗中，中位无进展生存期为 4.34 个月(95% CI，3.81–5.03)。化疗方案和生物制剂(抗血管生成或抗表皮生长因子受体)与总生存期和无进展生存期无关。在统计学上，癌症四期(同步转移)和无根治性手术与较短的总生存期有关。在 194 名存在错配修复 (MMR) 状态的患者中，相较于MMR完整的肿瘤患者，MMR缺陷肿瘤患者的总生存期明显较长(校正风险比 = 0.56；p = .009)。
结论。尽管 BRAFV600E 突变型mCRC可导致较短的总生存期和无进展生存期，但MMR缺陷肿瘤患者和/或可切除病灶的患者生存期更长。这些结果表明，在日常临床实践中，MMR检测和可切除性讨论对于 BRAFV600E 突变型mCRC患者至关重要。
实践意义:在日常实践中，应针对 BRAFV600E 突变型转移性结直肠癌患者 (mCRC) 进行错配修复 (MMR) 检测和开展可切除性讨论，以指导 BRAFV600E 突变型mCRC患者的治疗决策。
This article describes the real‐life management of BRAFV600E‐mutant metastatic colorectal cancer in a large cohort of patients treated in 16 French centers from 2006 to 2017. Potential prognostic factors to steer treatment decisions are identified.
Introduction: Stereotactic MR-guided Adaptive RadioTherapy (SMART) is a novel process to treat pancreatic tumors. We present an update of the data from our prospective registry of SMART for ...pancreatic tumors. Materials and methods: After the establishment of the SMART indication in a multidisciplinary board, we included all patients treated for pancreatic tumors. Primary endpoints were acute and late toxicities. Secondary endpoints were survival outcomes (local control, overall survival, distant metastasis free survival) and dosimetric advantages of adaptive process on targets volumes and OAR. Results: We included seventy consecutive patients in our cohort between October 2019 and April 2022. The prescribed dose was 50 Gy in 5 consecutive fractions. No severe acute SMART related toxicity was noted. Acute and late Grade ≤ 2 gastro intestinal were low. Daily adaptation significantly improved PTV and GTV coverage as well as OAR sparing. With a median follow-up of 10.8 months since SMART completion, the median OS, 6-months OS, and 1-year OS were 20.9 months, 86.7% (95% CI: (75−93%), and 68.6% (95% CI: (53−80%), respectively, from SMART completion. Local control at 6 months, 1 year, and 2 years were, respectively, 96.8 % (95% CI: 88−99%), 86.5 (95% CI: 68−95%), and 80.7% (95% CI: 59−92%). There was no grade > 2 late toxicities. Locally Advanced Pancreatic Cancers (LAPC) and Borderline Resectable Pancreatic Cancers (BRPC) patients (52 patients) had a median OS, 6-months OS, and 1-year OS from SMART completion of 15.2 months, 84.4% (95% CI: (70−92%)), and 60.5% (95% CI: (42−75%)), respectively. The median OS, 1-year OS, and 2-year OS from initiation of induction chemotherapy were 22.3 months, 91% (95% CI: (78−97%)), and 45.8% (95% CI: (27−63%)), respectively. Twenty patients underwent surgical resection (38.7 % of patients with initially LAPC) with negative margins (R0). Conclusion: To our knowledge, this is the largest series of SMART for pancreatic tumors. The treatment was well tolerated with only low-grade toxicities. Long-term OS and LC rates were achieved. SMART achieved high secondary resection rates in LAPC patients.
ObjectiveThe BEACON CRC randomised controlled trial (NCT02928224) in BRAF-mutant metastatic colorectal cancer (mCRC) patients showed improved overall survival for the combination treatment of ...encorafenib (BRAF inhibitor) with cetuximab (EGFR inhibitor) compared with cetuximab with chemotherapy (FOLFIRI (folinic acid, fluorouracil and irinotecan) or irinotecan). We aimed to evaluate the cost-effectiveness of encorafenib with cetuximab in adult patients with BRAF-mutant mCRC after prior systemic therapy, from the perspective of the French healthcare system.DesignA partitioned survival analysis model was developed to assess the cost-effectiveness of encorafenib with cetuximab using data from BEACON CRC (encorafenib with cetuximab and cetuximab with FOLFIRI or irinotecan). For two further comparator treatments (FOLFIRI alone and bevacizumab with FOLFIRI), a systemic literature review identified appropriate clinical trial data for indirect comparison. Piecewise modelling extrapolation was used to fulfil a lifetime horizon in the model. A discount rate of 2.5% was used. Treatment-emergent adverse events ≥grade 3 with an incidence of ≥2% were included, as well as relative dose intensity and utility values.Outcome measuresThe effectiveness outcomes of the model were expressed in terms of incremental life years gained and incremental quality-adjusted life years (QALY) gained. The cost-effectiveness of encorafenib with cetuximab was assessed using the incremental cost-effectiveness ratio (ICER). Results were presented probabilistically to account for parametric uncertainty. Deterministic and scenario analyses were conducted.ResultsThe ICER for encorafenib with cetuximab versus cetuximab with FOLFIRI or irinotecan, FOLFIRI alone and bevacizumab with FOLFIRI was €69 823/QALY, €70 421/QALY and €72 336/QALY, respectively. Encorafenib with cetuximab was considered cost-effective compared with the three comparators at a willingness to pay threshold of €90 000/QALY, with probabilities of being cost-effective of 89.8%, 98.2% and 86.4%, respectively.ConclusionsThis analysis showed encorafenib with cetuximab to be a cost-effective treatment in mCRC patients with a BRAF V600E mutation.
Background
The AcSé-crizotinib program provides extensive screening of crizotinib-targeted genomic alteration in several malignancies. We here report the results in patients with esogastric
MET
...-amplified adenocarcinomas.
Objective
The objective of the study was to evaluate the efficacy and tolerability of crizotinib in patients with pretreated esogastric
MET
-amplified adenocarcinoma who have no alternative treatment options.
Patients and Methods
MET
expression was evaluated by fluorescence in situ hybridization in tumor samples with immunohistochemistry scores ≥ 2+. Patients with chemo-refractory tumors showing ≥ 6
MET
copies were eligible for crizotinib 250 mg twice daily. The primary efficacy outcome was the objective response rate after two cycles of crizotinib.
Results
MET
was prospectively analyzed in 570 esogastric adenocarcinomas. Amplifications were found in 35/570 adenocarcinomas (29/523 gastric and 6/47 esophageal). Nine patients were treated with crizotinib. The objective response rate after two cycles was 33.3% (95% CI 7.5–70), the best overall response rate was 55.6% (95% CI 21.2–86.3), with median progression-free survival of 3.2 months (95% CI 1.0–5.4), and overall survival of 8.1 months (95% CI 1.7–24.6). Safety was consistent with that previously reported for crizotinib.
Conclusions
Large-scale screening for
MET
-amplified esogastric adenocarcinomas is feasible.
MET
amplification was observed in 5.5% of gastric and 12.8% of esophageal adenocarcinomas. Crizotinib shows encouraging results in selected patients. Thus, c-MET inhibition for
MET
-amplified tumors deserves further evaluation.
Trial Registration Number
NCT02034981.
Date of Registration
14 January 2014.
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