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BACKGROUND AND AIMS: Peritoneal metastasis (PM) in gastric cancer (GC) is associated with poor prognosis and significant morbidity. We sought to understand the genomic, transcriptomic, and tumor microenvironment (TME) features that contribute to peritoneal organotropism in GC. METHODS: We conducted a comprehensive multi-omic analysis of 548 samples from 326 patients, including primary tumors, matched normal tissues, peritoneal metastases, and adjacent-normal peritoneal tissues. We employed whole exome sequencing, whole transcriptome sequencing, and digital spatial profiling to investigate molecular alterations, gene expression patterns, and TME characteristics associated with PM. RESULTS: Our analysis identified specific genomic alterations in primary tumors, including mutations in ELF3, CDH1, and PIGR, and TME signatures, such as stromal infiltration and M2 macrophage enrichment, associated with increased risk of PM. We observed distinct transcriptional programs and immune compositions in GCPM compared to liver metastases, highlighting the importance of the TME in transcoelomic metastasis. We found differential expression of therapeutic targets between primary tumors and PM, with lower CLDN18.2 and FGFR2b expression in PM. We unravel the roles of the TME in niche reprogramming within the peritoneum, and provide evidence of pre-metastatic niche conditioning even in early GC without clinical PM. These findings were further validated using a humanized mouse model, which demonstrated niche remodeling in the peritoneum during transcoelomic metastasis. CONCLUSION: Our study provides a comprehensive molecular characterization of GCPM and unveils key biological principles underlying transcoelomic metastasis. The identified predictive markers, therapeutic targets, and TME alterations offer potential avenues for targeted interventions and improved patient outcomes.
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BACKGROUND: Trastuzumab deruxtecan has shown encouraging activity in patients with treatment-refractory HER2-positive, RAS wild-type and BRAF wild-type metastatic colorectal cancer. Dose optimisation and further antitumour assessments in patients with RAS mutations and those with previous anti-HER2 therapy are warranted. We aimed to evaluate two doses of trastuzumab deruxtecan (5·4 mg/kg and 6·4 mg/kg) to establish the recommended dose in patients with pretreated HER2-positive, RAS wild-type or mutant metastatic colorectal cancer. METHODS: DESTINY-CRC02 was a multicentre, randomised, two-stage, two-arm, phase 2 study done in 53 research hospitals and medical centres in Australia, Belgium, France, Italy, Japan, South Korea, Spain, Taiwan, the UK, and the USA. Eligible patients were aged 18 years and older or 20 years and older (depending on region) with pretreated pathologically documented, unresectable, recurrent, or metastatic HER2-positive, and RAS wild-type or mutant colorectal cancer. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and have received previous chemotherapy, and anti-EGFR, anti-VEGF, or anti-PD-L1 therapy, if clinically indicated. In stage 1, patients were randomly assigned (1:1), via a secure interactive response technology system, to receive 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan administered intravenously every 21 days. Stratification factors were ECOG performance status, HER2 status, and RAS status. In stage 2, patients were assigned into the 5·4 mg/kg treatment group only. The primary endpoint was confirmed objective response rate by blinded independent central review, assessed in all patients for whom treatment was assigned (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04744831, and is ongoing (not recruiting). FINDINGS: Between March 5, 2021, and March 29, 2022, 135 patients were centrally screened, 122 of whom were enrolled. In stage 1, 40 patients each were randomly assigned to receive trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg. In stage 2, an additional 42 patients were enrolled in the 5·4 mg/kg group. 64 (52%) participants were male and 58 (48%) were female. The median duration of follow-up was 8·9 months (IQR 6·7-10·5) in the 5·4 mg/kg group and 10·3 months (5·9-12·7) in the 6·4 mg/kg group. The confirmed objective response rate by blinded independent central review was 37·8% (31/82 [95% CI 27·3-49·2]) in the 5·4 mg/kg group and 27·5% (11/40 [14·6-43·9]) in the 6·4 mg/kg group. 34 (41%) of 83 patients in the 5·4 mg/kg group and 19 (49%) of 39 in the 6·4 mg/kg group had grade 3 or worse drug-related treatment-emergent adverse events. The most common grade 3 or worse drug-related treatment-emergent adverse events were neutrophil count decreased (13 [16%] of 83 patients), anaemia (six [7%]), nausea (six [7%]), and white blood cell count decreased (five [6%]) in the 5·4 mg/kg group; and were neutrophil count decreased (10 [26%] of 39 patients), anaemia (eight [21%]), platelet count decreased (four [10%]), and white blood cell count decreased (four [10%]) in the 6·4 mg/kg group. Drug-related serious adverse events occurred in 11 (13%) of 83 patients in the 5·4 mg/kg group and six (15%) of 39 patients in the 6·4 mg/kg group; the most common in the 5·4 mg/kg group was nausea (three [4%] patients) and the most common in the 6·4 mg/kg group were fatigue (two [5%] patients), neutropenia (two [5%]), and thrombocytopenia (two [5%]). A drug-related treatment-emergent adverse event related to death occurred in one (1%) patient in the 5·4 mg/kg group (due to hepatic failure). Adjudicated drug-related interstitial lung disease or pneumonitis events were observed in seven (8%) patients in the 5·4 mg/kg group (all grade 1 or 2) and in five (13%) patients in the 6·4 mg/kg group (four grade 1 or 2; one grade 5). INTERPRETATION: The promising antitumour activity and favourable safety profile support trastuzumab deruxtecan 5·4 mg/kg as the optimal single-agent dose for patients with pretreated HER2-positive metastatic colorectal cancer, including those with RAS mutations, previous anti-HER2 therapy, or both. FUNDING: Daiichi Sankyo and AstraZeneca.
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BACKGROUND: Metastatic Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors characterized by high morbidity and limited systemic treatment options, mainly based on radiometabolic treatments or chemotherapy. Based on the preclinical rationale that PGGLs carcinogenesis relies on angiogenesis, treatment with tyrosine kinase inhibitors (TKI) may represent another viable therapeutic option. METHODS: We conducted a prospective phase II study in patients with metastatic or unresectable PGGLs. Patients received sunitinib (50 mg daily for 4 weeks, followed by a 2-week rest period) until progressive disease (PD), unacceptable toxicity or consent withdrawal. The primary endpoint was 12-month progression-free survival (PFS) rate; secondary endpoints were safety overall response rate (ORR) according to RECIST 1.1 criteria and overall survival (OS). EudraCT Number: 2011-002632-99. RESULTS: Fifty patients were included. At a median follow-up of 71.7 months (IQR 35.4-100.1), the 1 year-PFS rate was 53.4 % (95 %CI 41.1-69.3) and median PFS was 14.1 months (95 % CI 8.9-25.7). ORR was 15.6 %, the median OS was 49.4 months (95 %CI 21.2-NA), and grade 3 or higher treatment-related adverse events were reported in 34 % patients. No significant correlation was found between specific genetic alterations or genomic clusters and sunitinib efficacy. CONCLUSION: Sunitinib is an active drug in patients with advanced PGGLs, capable of inducing prolonged disease control with a manageable toxicity profile.
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BACKGROUND: To date, only two studies have compared the outcomes of patients with liver-limited BRAF V600E-mutated colorectal liver metastases (CRLMs) managed with resection versus systemic therapy alone, and these have reported contradictory findings. METHODS: In this observational, international, multicentre study, patients with liver-limited BRAF V600E-mutated CRLMs treated with resection or systemic therapy alone were identified from institutional databases. Patterns of recurrence/progression and overall survival were compared using multivariable analyses of the entire cohort and a propensity score-matched cohort. RESULTS: Of 170 patients included, 119 underwent hepatectomy and 51 received systemic treatment. Surgically treated patients had a more favourable pattern of recurrence with most recurrences limited to a single site, whereas diffuse progression was more common among patients who received systemic treatment (19 versus 44%; P = 0.002). Surgically treated patients had longer median overall survival (35 versus 20 months; P < 0.001). Hepatectomy was independently associated with better OS than systemic treatment alone (HR 0.37, 95% c.i. 0.21 to 0.65). In the propensity score-matched cohort, surgically treated patients had longer median overall survival (28 versus 20 months; P < 0.001); hepatectomy was independently associated with better overall survival (HR 0.47, 0.25 to 0.88). CONCLUSION: BRAF V600E mutation should not be considered a contraindication to surgery for patients with resectable, liver-only CRLMs.
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Neoplasias Colorretais , Hepatectomia , Neoplasias Hepáticas , Proteínas Proto-Oncogênicas B-raf , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/mortalidade , Hepatectomia/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Mutação , Pontuação de Propensão , Recidiva Local de Neoplasia/genética , Adulto , Resultado do TratamentoRESUMO
BACKGROUND: CAVE is a single arm, Phase 2 trial, that demonstrated anti-tumor activity of cetuximab rechallenge plus avelumab in patients with RAS wild type (wt) metastatic colorectal cancer (mCRC). OBJECTIVE: We conducted a post hoc analysis to identify potential radiomic biomarkers for patients with CRC liver metastasis (LM). PATIENTS AND METHODS: Patients with LM that could be measured by enhanced contrast phase computed tomography (CT) imaging at baseline and at first response evaluation were included. Multiple texture parameters were extracted with the LifeX Software. Delta-texture (D-TA) variations were calculated by comparing data at baseline and after treatment. RESULTS: Overall, 55/77 patients (71%) had LM; 39 met the inclusion criteria for the current analysis. The D-TA parameters that significantly correlated at univariate analysis with median progression-free survival (mPFS) were EntropyHistogram (p = 0.021), HomogeneityGLCM (p < 0.001) and Dissimilarity GLCM (p = 0.002). At multivariate analysis, only HomogeneityGLCM resulted significant for PFS (p = 0.001). Patients (19/39, 48.7%) with reduction of HomogeneityGLCM experienced better mPFS (4.6 vs 2.9 months; HR 0.45; 95% CI 0.23-0.88; p = 0.021) and median overall survival (mOS) (17.3 vs 6.8 months; HR 0.40, 95% CI 0.21-0.80; p = 0.010). A trend to better mPFS, was also observed in patients with RAS/BRAF wt circulating tumor DNA and reduction of HomogeneityGLCM. Overall survival was significantly better in this subgroup of patients with low HomogeneityGLCM: mOS was 17.8 (95% CI 15.5-20.2) versus 6.8 months (95% CI 3.6-10.0) (HR 0.34, 95% CI 0.14-0.81; p = 0.016). CONCLUSION: Reduction in the D-TA parameter HomogeneityGLCM by radiomic analysis correlates with improved outcomes in patients with LM receiving cetuximab rechallenge plus avelumab therapy. Larger prospective studies are needed to validate and confirm these findings.
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Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/diagnóstico por imagem , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Tomografia Computadorizada por Raios X/métodos , Adulto , Cetuximab/administração & dosagem , Cetuximab/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Intervalo Livre de Progressão , Idoso de 80 Anos ou mais , RadiômicaRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 4-year results of the phase II randomized AtezoTRIBE study. Eligible patients with metastatic colorectal cancer (mCRC) received first-line fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/bevacizumab (control group, n = 73) or FOLFOXIRI/bevacizumab plus atezolizumab (experimental group, n = 145). We present overall survival (OS) and updated outcomes according to tumor immune-related biomarkers, both in the intention-to-treat (ITT) population and the cohort of patients with proficient mismatch repair (pMMR) tumors. Median follow-up was 45.2 months (IQR, 42.6-49.2). In the ITT population, median OS was 33.0 and 27.2 months for experimental and control groups, respectively (hazard ratio [HR], 0.78 [80% CI, 0.61 to 0.98]; P = .084). An interaction effect between Immunoscore Immune-Checkpoint (IC) and treatment arm was observed (Pint, .089), with higher benefit from atezolizumab in the Immunoscore IC-high group. In the pMMR cohort (N = 202), median OS was 30.8 and 29.2 months for experimental and control groups, respectively (HR, 0.80 [80% CI, 0.63 to 1.02]; P = .117). Interactions between treatment group and tumor mutational burden (TMB) and Immunoscore IC were reported (Pint, .043 and .092, respectively), with patients bearing TMB-high and Immunoscore IC-high tumors deriving higher benefit from the addition of atezolizumab. First-line FOLFOXIRI/bevacizumab plus atezolizumab improves OS in patients with mCRC. In the pMMR group, patients with Immunoscore IC-high and/or TMB-high tumors are identified as a subgroup of interest to further develop this treatment.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorretais , Fluoruracila , Irinotecano , Leucovorina , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Leucovorina/uso terapêutico , Leucovorina/administração & dosagem , Bevacizumab/administração & dosagem , Bevacizumab/uso terapêutico , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Irinotecano/uso terapêutico , Irinotecano/administração & dosagem , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Adulto , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/administração & dosagem , Camptotecina/análogos & derivadosRESUMO
BACKGROUND: Microsatellite instability high (MSI-H) and/or mismatch repair deficient (dMMR) status is the strongest predictive factor for immune checkpoint inhibitors (ICIs) benefit in patients with metastatic gastroesophageal cancer (mGC). Primary resistance to ICIs is a relevant issue, but prognostic and predictive factors are lacking. MATERIALS AND METHODS: In this multinational, retrospective cohort of patients with MSI-H/dMMR mGC treated with ICIs without chemotherapy we collected baseline laboratory values to establish the prognostic nutritional index (PNI). We evaluated the association between baseline PNI with the activity and efficacy of ICIs. RESULTS: At a median follow-up of 31.6 months, median progression-free survival (PFS) and 2-year PFS rate were not reached and 73.6 % in the PNI-high subgroup versus 6.3 months and 38.3 % in the PNI-low one (HR 0.32, 95 % CI: 0.16-0.61, p < .001). Median overall survival (OS) and 2-year OS rate were not reached and 81.9 % in the PNI-high subgroup versus 24.4 months and 50.5 % in the PNI-low one (HR 0.26, 95 % CI: 0.12-0.56, p < .001). In multivariable models, high PNI was associated with longer PFS and OS (HR 0.30, 95 % CI: 0.15-0.61, p <0.001 and 0.37, 95 % CI: 0.15-0.91, p = .031). CONCLUSIONS: High PNI is associated with longer PFS and OS, in patients with MSI-H mGC receiving ICIs. Patients with low baseline PNI may benefit from intensive therapeutic approaches.
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BACKGROUND: Biliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1-3). The only potential curative treatment is surgical resection. However, despite complex surgical procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20-40% and recurrence rates are up to ~ 75%(4-6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4-6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8). METHODS: PURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study. Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis. DISCUSSION: Considering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients' outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery. TRIAL REGISTRATION: PURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023-503295-25-00).
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Neoplasias do Sistema Biliar , Gencitabina , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/cirurgia , Cisplatino , Desoxicitidina , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/tratamento farmacológico , Qualidade de Vida , Estudos RetrospectivosRESUMO
Importance: The available evidence regarding anti-epidermal growth factor receptor (EGFR) inhibitor rechallenge in patients with refractory circulating tumor DNA (ctDNA) RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) is derived from small retrospective and prospective studies. Objective: To evaluate the efficacy of anti-EGFR rechallenge in patients with refractory ctDNA RAS/BRAF wt mCRC. Design, Setting, and Participants: This nonrandomized controlled trial used a pooled analysis of individual patient data from patients with RAS/BRAF wt ctDNA mCRC enrolled in 4 Italian trials (CAVE, VELO, CRICKET, and CHRONOS) and treated with anti-EGFR rechallenge between 2015 and 2022 (median [IQR] follow-up, 28.1 [25.8-35.0] months). Intervention: Patients received anti-EGFR rechallenge therapy, including cetuximab plus avelumab, trifluridine-tipiracil plus panitumumab, irinotecan plus cetuximab, or panitumumab monotherapy. Main Outcomes and Measures: Overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were calculated. Exploratory subgroup analysis evaluating several clinical variables was performed. Safety was reported. Results: Overall, 114 patients with RAS/BRAF wt ctDNA mCRC (median [IQR] age, 61 [29-88] years; 66 men [57.9%]) who received anti-EGFR rechallenge as experimental therapy (48 received cetuximab plus avelumab, 26 received trifluridine-tipiracil plus panitumumab, 13 received irinotecan plus cetuximab, and 27 received panitumumab monotherapy) were included in the current analysis. Eighty-three patients (72.8%) had received 2 previous lines of therapy, and 31 patients (27.2%) had received 3 or more previous lines of therapy. The ORR was 17.5% (20 patients), and the DCR was 72.3% (82 patients). The median PFS was 4.0 months (95% CI, 3.2-4.7 months), and the median OS was 13.1 months (95% CI, 9.5-16.7 months). The subgroup of patients without liver involvement had better clinical outcomes. The median PFS was 5.7 months (95% CI, 4.8-6.7 months) in patients without liver metastasis compared with 3.6 months (95% CI, 3.3-3.9 months) in patients with liver metastasis (hazard ratio, 0.56; 95% CI, 0.37-0.83; P = .004). The median OS was 17.7 months (95% CI, 13-22.4 months) in patients without liver metastasis compared with 11.5 months (95% CI, 9.3-13.9 months) in patients with liver metastasis (hazard ratio, 0.63; 95% CI, 0.41-0.97; P = .04). Treatments showed manageable toxic effects. Conclusions and Relevance: These findings suggest that anti-EGFR rechallenge therapy has promising antitumor activity in patients with refractory ctDNA RAS/BRAF wt mCRC. Within the limitation of a subgroup analysis, the absence of liver metastases was associated with significant improved survival. Trial Registration: ClinicalTrials.gov Identifiers: NCT02296203; NCT04561336; NCT03227926; NCT05468892.
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Neoplasias do Colo , Neoplasias Hepáticas , Neoplasias Retais , Humanos , Masculino , Pessoa de Meia-Idade , Cetuximab/uso terapêutico , Receptores ErbB , Irinotecano , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Panitumumabe , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Trifluridina , Feminino , Adulto , Idoso , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Surgery plus peri-operative/adjuvant chemotherapy is the standard of care for locally advanced GC/GEJC, though with unsatisfactory results. dMMR/MSI-high tumors have better prognosis and scant benefit from chemotherapy as compared to pMMR/MSS ones. The differential outcome of therapies in terms of safety and efficacy according to sex is still debated in GC/GEJC patients. METHODS: We previously performed an individual patient data pooled analysis of MAGIC, CLASSIC, ITACA-S, and ARTIST trials including GC/GEJC patients treated with surgery alone or surgery plus peri-operative/adjuvant chemotherapy to assess the value of MSI status. We performed a secondary analysis investigating the prognostic and predictive role of sex (female versus male) in the pooled analysis dataset in the overall population and patients stratified for MSI status (MSI-high versus MSS/MSI-low). Disease-free (DFS) and overall survival (OS) were calculated. RESULTS: Patients with MSI-high tumors had improved survival as compared to MSS/MSI-low ones irrespective of sex, whereas in those with MSS/MSI-low tumors, females had numerically longer OS and DFS (5-year OS was 63.2% versus 57.6%, HR 0.842; p = 0.058, and 5-year DFS was 55.8% versus 50.8%, HR 0.850; p = 0.0504 in female versus male patients). The numerical difference for the detrimental effect of chemotherapy in MSI-high GC was higher in females than males, while the significant benefit of chemotherapy over surgery alone was confirmed in MSS/MSI-low GC irrespective of sex. CONCLUSIONS: This pooled analysis including four randomized trials highlights a relevant impact of sex in the prognosis and treatment efficacy of MSI-high and MSS/MSI-low non-metastatic GC/GEJC.
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Junção Esofagogástrica , Instabilidade de Microssatélites , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas , Humanos , Masculino , Feminino , Junção Esofagogástrica/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Prognóstico , Fatores Sexuais , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , Quimioterapia AdjuvanteRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various cancers. ICI treatment is associated with the incidence of immune-related adverse events (irAEs) which can affect any organ. Data on irAEs occurrence in relation to sex- differentiation and their association with gender-specific factors are limited. AIMS: The primary objective of the G-DEFINER study is to compare the irAEs incidence in female and male patients who undergo ICI treatment. Secondary objectives are: to compare the irAEs incidence in pre- and postmenopausal female patients; to compare the irAEs incidence in female and male patients according to different clinical and gender-related factors (lifestyle, psychosocial, and behavioral factors). Exploratory objectives of the study are to compare and contrast hormonal, gene-expression, SNPs, cytokines, and gut microbiota profiles in relation to irAEs incidence in female and male patients. METHODS AND RESULTS: The patients are recruited from Fondazione IRCCS Istituto Nazionale dei Tumori, Italy, St Vincent's University Hospital, Ireland, Oslo University Hospital, Norway, and Karolinska Insitutet/Karolinska University Hospital, Sweden. The inclusion of patients was delayed due to the Covid pandemic, leading to a total of 250 patients recruited versus a planned number of 400 patients. Clinical and translational data will be analyzed. INTERPRETATION: The expected outcomes are to improve the management of cancer patients treated with ICIs, leading to more personalized clinical approaches that consider potential toxicity profiles. The real world nature of the trial makes it highly applicable for timely irAEs diagnosis.
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Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Feminino , Masculino , Neoplasias/tratamento farmacológico , Estudos Prospectivos , Inibidores de Checkpoint Imunológico/efeitos adversos , Fatores Sexuais , Incidência , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Estudos Observacionais como AssuntoRESUMO
Background: Perioperative chemotherapy (CT) is an established therapeutic approach for patients diagnosed with stage IB-III gastric cancer (GC). Objectives: This study aimed to investigate the efficacy of this approach in individuals with GC exhibiting high microsatellite instability (MSI-H). Design: A systematic review was conducted, including studies that provided data on (neo)adjuvant CT outcomes in patients with MSI-H GC. Methods: Systematic searches were conducted in PubMed, Cochrane Central of Controlled Trials, and Embase databases. Data were aggregated using hazard ratios (HRs) to compare overall survival between CT and surgery. Results: Data analysis from 23 studies, including 22,011 patients, revealed that the prevalence of MSI-H is 9.8%. Administration of adjuvant or perioperative CT did not significantly reduce the risk of death or relapse in patients with MSI-H GC (HR = 0.8, 95% CI 0.54-1.16; p = 0.24 and HR = 0.84, 95% CI 0.59-1.18; p = 0.31, respectively). Conclusion: Chemotherapy did not benefit patients diagnosed with MSI-H nonmetastatic GC but rather will be integrated with immune checkpoint inhibitors in the near future.
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PURPOSE: The multi-kinase inhibitor (mKi) regorafenib has demonstrated efficacy in chemorefractory patients with metastatic colorectal cancer (mCRC). However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice. EXPERIMENTAL DESIGN: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemorefractory patients with mCRC treated with regorafenib in a phase II clinical trial (PROSPECT-R n = 40; NCT03010722) and in a multicentric validation cohort (n = 241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish patient-derived organoids (PDO) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital-droplet PCR and/or ISH in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses. RESULTS: Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652-3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a "control" group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modeled regorafenib response observed in vivo and in patients, and showed that MIR652-3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option. CONCLUSIONS: Our results identify MIR652-3p as a potential biomarker and as a driver of cell and non-cell-autonomous mechanisms of resistance to regorafenib.
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Biomarcadores Tumorais , MicroRNA Circulante , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Compostos de Fenilureia , Piridinas , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/sangue , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Piridinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Animais , Feminino , Estudos Prospectivos , Masculino , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Idoso , Biópsia Líquida/métodos , Pessoa de Meia-Idade , Linhagem Celular Tumoral , MicroRNAs/genética , MicroRNAs/sangueRESUMO
BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, with a poor prognosis for patients with advanced disease. Since the oncogenic role of KRAS mutants has been poorly investigated in GC, this study aims to biochemically and biologically characterize different KRAS-mutated models and unravel differences among KRAS mutants in response to therapy. METHODS: Taking advantage of a proprietary, molecularly annotated platform of more than 200 GC PDXs (patient-derived xenografts), we identified KRAS-mutated PDXs, from which primary cell lines were established. The different mutants were challenged with KRAS downstream inhibitors in in vitro and in vivo experiments. RESULTS: Cells expressing the rare KRAS A146T mutant showed lower RAS-GTP levels compared to those bearing the canonical G12/13D mutations. Nevertheless, all the KRAS-mutated cells displayed KRAS addiction. Surprisingly, even if the GEF SOS1 is considered critical for the activation of KRAS A146T mutants, its abrogation did not significantly affect cell viability. From the pharmacologic point of view, Trametinib monotherapy was more effective in A146T than in G12D-mutated models, suggesting a vulnerability to MEK inhibition. However, in the presence of mutations in the PI3K pathway, more frequently co-occurrent in A146T models, the association of Trametinib and the AKT inhibitor MK-2206 was required to optimize the response. CONCLUSION: A deeper genomic and biological characterization of KRAS mutants might sustain the development of more efficient and long-lasting therapeutic options for patients harbouring KRAS-driven GC.
Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fosfatidilinositol 3-Quinases/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular TumoralRESUMO
Claudin-18.2 (CLDN18.2) is a member of the tight junction protein family and is a highly selective biomarker with frequent abnormal expression during the occurrence and development of various primary malignant tumors, including gastric cancer (GC) and esophago-gastric junction adenocarcinomas (EGJA). For these reasons, CLDN18.2 has been investigated as a therapeutic target for GC/EGJA malignancies. Recently, zolbetuximab has been proposed as a new standard of care for patients with CLDN18.2-positive, HER2-negative, locally advanced and metastatic GC/EGJA. The use of CLDN18 IHC assays to select patients who might benefit from anti-CLDN18.2 therapy is currently entering clinical practice. In this setting, pathologists play a central role in therapeutic decision-making. Accurate biomarker assessment is essential to ensure the best therapeutic option for patients. In the present review, we provide a comprehensive overview of available evidence on CLDN18.2 testing and its impact on the therapeutic management of patients with GC/EGJA, as well as some practical suggestions for CLDN18.2 staining interpretation and potential pitfalls in the real-world setting.
Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Prova Pericial , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Moléculas de Adesão Celular , Adenocarcinoma/patologia , Claudinas/metabolismo , BiomarcadoresRESUMO
Importance: The NAPOLI 3 trial showed the superiority of fluorouracil, leucovorin, liposomal irinotecan, and oxaliplatin (NALIRIFOX) over the combination of gemcitabine and nab-paclitaxel (GEM-NABP) as first-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). Analyses comparing NALIRIFOX and GEM-NABP with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) have not yet been reported. Objective: To derive survival, response, and toxic effects data from phase 3 clinical trials and compare NALIRIFOX, FOLFIRINOX, and GEM-NABP. Data Sources: After a systematic search of PubMed, Scopus, Embase, and American Society of Clinical Oncology and European Society for Medical Oncology meetings' libraries, Kaplan-Meier curves were extracted from phase 3 clinical trials conducted from January 1, 2011, until September 12, 2023. Study Selection: Phase 3 clinical trials that tested NALIRIFOX, FOLFIRINOX, or GEM-NABP as first-line treatment of metastatic PDAC and reported overall survival (OS) and progression-free survival (PFS) curves were selected. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses of Individual Participant Data reporting guidelines. Data Extraction And Synthesis: Individual patient OS and PFS data were extracted from Kaplan-Meier plots of original trials via a graphic reconstructive algorithm. Overall response rates (ORRs) and grade 3 or higher toxic effects rates were also collected. A pooled analysis was conducted, and results were validated via a network meta-analysis. Main Outcomes and Measures: The primary end point was OS. Secondary outcomes included PFS, ORR, and toxic effects rates. Results: A total of 7 trials with data on 2581 patients were analyzed, including 383 patients treated with NALIRIFOX, 433 patients treated with FOLFIRINOX, and 1756 patients treated with GEM-NABP. Median PFS was longer in patients treated with NALIRIFOX (7.4 [95% CI, 6.1-7.7] months) or FOLFIRINOX (7.3 [95% CI, 6.5-7.9] months; [HR], 1.21 [95% CI, 0.86-1.70]; P = .28) compared with patients treated with GEM-NABP (5.7 [95% CI, 5.6-6.1] months; HR vs NALIRIFOX, 1.45 [95% CI, 1.22-1.73]; P < .001). Similarly, GEM-NABP was associated with poorer OS (10.4 [95% CI, 9.8-10.8]; months) compared with NALIRIFOX (HR, 1.18 [95% CI, 1.00-1.39]; P = .05], while no difference was observed between FOLFIRINOX (11.7 [95% CI, 10.4-13.0] months) and NALIRIFOX (11.1 [95% CI, 10.1-12.3] months; HR, 1.06 [95% CI, 0.81-1.39]; P = .65). There were no statistically significant differences in ORR among NALIRIFOX (41.8%), FOLFIRINOX (31.6%), and GEM-NABP (35.0%). NALIRIFOX was associated with lower incidence of grade 3 or higher hematological toxic effects (eg, platelet count decreased 1.6% vs 11.8% with FOLFIRINOX and 10.8% with GEM-NABP), but higher rates of severe diarrhea compared with GEM-NABP (20.3% vs 15.7%). Conclusions and Relevance: In this systematic review and meta-analysis, NALIRIFOX and FOLFIRINOX were associated with similar PFS and OS as first-line treatment of advanced PDAC, although NALIRIFOX was associated with a different toxicity profile. Careful patient selection, financial toxic effects consideration, and direct comparison between FOLFIRINOX and NALIRIFOX are warranted.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Irinotecano/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucovorina/uso terapêutico , Oxaliplatina/uso terapêutico , Gencitabina , Fluoruracila/uso terapêuticoRESUMO
In retrospective studies, metformin use has been associated with better clinical outcomes in diabetic patients with advanced, well-differentiated neuroendocrine tumors (WDNETs). However, prospective evidence of metformin safety and activity is lacking. Here, we conducted the first-in-human phase Ib MetNET2 trial to investigate the safety and antitumor activity of metformin in combination with the somatostatin analog lanreotide autogel (ATG) in both diabetic and non-diabetic patients with advanced WDNETs of the gastrointestinal (GI) or thoracic tract. Enrolled patients received lanreotide ATG 120 mg plus oral metformin, up to a maximum dosage of 2550 mg/day. We enrolled 20 patients, of whom 18 (90%) and 2 (10%) had WDNETs of the GI and thoracic tract, respectively. Fourteen patients (70%) were non-diabetic. With a 5% incidence of SAEs, the study met its primary objective of demonstrating treatment safety. With a median follow-up of 39 months (95% CI 28-NE), median PFS was 24 months (95% CI 16-NE), with 12-month and 24-month PFS probability of 75% (95% CI 58-97) and 49% (95% CI 31-77), respectively. We found no statistically significant PFS differences between diabetic and non-diabetic patients. Among exploratory analyses, the presence of tumor genomic alterations in DNA damage pathways was associated with trend towards worse PFS, whereas a precocious reduction of HOMA-IR index and plasma cholesterol concentration showed a trend towards an association with better PFS. In conclusion, metformin plus lanreotide ATG is a safe and well tolerated combination treatment that is associated with promising antitumor activity in both non-diabetic and diabetic patients with WDNETs, and that warrants further investigation in larger clinical trials.
Assuntos
Diabetes Mellitus , Metformina , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/induzido quimicamente , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Estudos Prospectivos , Somatostatina/efeitos adversos , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/tratamento farmacológico , Pulmão/patologiaRESUMO
Background: Retreatment with anti-EGFR monoclonal antibodies is a promising strategy in patients with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) who achieved benefit from previous anti-EGFR exposure upon exclusion of mutations in RAS/BRAF genes according to circulating tumor DNA (ctDNA) analysis by means of liquid biopsy (LB). This treatment approach is now being investigated in the randomized phase II trial PARERE (NCT04787341). We here present preliminary findings of molecular screening. Methods: Patients with RAS/BRAFV600E wt mCRC according to tissue genotyping who benefited from previous anti-EGFR-based treatment (fluoropyrimidines, oxaliplatin, irinotecan, and antiangiogenics) and then experienced disease progression to EGFR targeting were eligible for screening in the PARERE trial. The next-generation sequencing (NGS) panel Oncomine™ was employed for ctDNA testing. Results: A total of 218 patients underwent LB, and ctDNA sequencing was successful in 201 of them (92%). RAS/BRAFV600E mutations were found in 68 (34%) patients and were mainly subclonal (median variant allele fraction [VAF] for KRAS, NRAS, and BRAF mutant clones: 0.52%, 0.62%, and 0.12%, respectively; p = 0.01), with KRASQ61H being the most frequently detected (31%). Anti-EGFR-free intervals did not predict ctDNA molecular status (p = 0.12). Among the 133 patients with RAS/BRAFV600E wt tumors according to LB, 40 (30%) harbored a mutation in at least another gene potentially implied in anti-EGFR resistance, mainly with subclonal expression (median VAF, 0.56%). In detail, alterations in PIK3CA, FBXW7, GNAS, MAP2K, ERBB2, BRAF (class I and II non-BRAFV600E), SMAD, EGFR, AKT1, and CTNNB1 occurred in 13%, 8%, 7%, 3%, 2%, 2%, 1%, 1%, 1%, and 1% cases, respectively. Co-mutations were detected in 13 (33%) out of 40 patients. Conclusions: This is the largest prospective cohort of mCRC patients screened with LB for anti-EGFR retreatment in a randomized study. ctDNA genotyping reveals that at least one out of three patients candidate for retreatment should be excluded from this therapy, and other potential drivers of anti-EGFR resistance are found in approximately one out of three patients with RAS/BRAFV600E wt ctDNA.