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The role of aberrant hepatocyte growth factor receptor (c-MET, also known as tyrosine-protein kinase MET)/hepatocyte growth factor (HGF) signaling in cancer progression and invasion has been extensively studied. c-MET inhibitors have shown promising pre-clinical and early phase clinical trial anti-tumor activity in several tumor types, although results of most phase III trials with these agents have been negative. To date, two small molecule c-MET inhibitors, cabozantinib and crizotinib, have been approved by regulatory authorities for the treatment of selected cancer types, but several novel c-MET inhibitors (either monoclonal antibodies or small molecule c-MET tyrosine kinase inhibitors) and treatment combinations are currently under study in different settings. Here we provide an overview of the mechanism of action and rationale of c-MET inhibition in cancer, the efficacy of approved agents, and novel promising c-MET-inhibitors and novel targeted combination strategies under development in different cancer types, with a focus on the safety profile and tolerability of these compounds.

Background Reliability of mismatch repair proteins and microsatellite instability assessment is essential in order to define treatment strategy and identify candidates to immune checkpoint inhibitors in locally advanced gastroesophageal carcinoma. We evaluated the concordance of deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H) status between endoscopic biopsies and surgical specimens. Methods Consecutive patients with resectable gastric or gastroesophageal junction adenocarcinoma classified as MSI-H/dMMR by polymerase chain reaction (PCR) or immunohistochemistry (IHC) and operated at three referral Institutions were included. The primary endpoint was the rate of concordance between biopsy and surgical samples. If needed, central revision by IHC/PCR was performed by specialized pathologists from coordinating Institutions. Results Thirteen (19.7%) out of 66 patients showed discordant MSI-H/dMMR results in the original pathology reports. In most cases (11, 16.7%) this was due to the diagnosis of proficient mismatch repair status on biopsies. Among the ten cases available for central review, four were due to sample issues, four were reclassified as dMMR, one case showed dMMR status but was classified as microsatellite stable by PCR, one was linked to misdiagnosis of endoscopic biopsy by the local pathologist. Heterogeneity of mismatch repair proteins staining was observed in two cases. Conclusions Available methods can lead to conflicting results in MSI-H/dMMR evaluation between endoscopic biopsies and surgical samples of gastroesophageal adenocarcinoma. Strategies aiming to improve the reliability of assessment should be primarily focused on the optimization of tissue collection and management during endoscopy and adequate training of dedicated gastrointestinal pathologists within the multidisciplinary team.

Background Metabolic reprogramming towards aerobic glycolysis in cancer supports unrestricted cell proliferation, survival and chemoresistance. The molecular bases of these processes are still undefined. Recent reports suggest crucial roles for microRNAs. Here, we provide new evidence of the implication of miR-27a in modulating colorectal cancer (CRC) metabolism and chemoresistance. Methods A survey of miR-27a expression profile in TCGA-COAD dataset revealed that miR-27a-overexpressing CRCs are enriched in gene signatures of mitochondrial dysfunction, deregulated oxidative phosphorylation, mTOR activation and reduced chemosensitivity. The same pathways were analysed in cell lines in which we modified miR-27a levels. The response to chemotherapy was investigated in an independent cohort and cell lines. Results miR-27a upregulation in vitro associated with impaired oxidative phosphorylation, overall mitochondrial activities and slight influence on glycolysis. miR-27a hampered AMPK, enhanced mTOR signalling and acted in concert with oncogenes and tumour cell metabolic regulators to force an aerobic glycolytic metabolism supporting biomass production, unrestricted growth and chemoresistance. This latter association was confirmed in our cohort of patients and cell lines. Conclusions We disclose an unprecedented role for miR-27a as a master regulator of cancer metabolism reprogramming that impinges on CRC response to chemotherapy, underscoring its theragnostic properties.

Background Immune checkpoint inhibitors (ICIs) reported remarkable achievements in several solid tumours. However, in metastatic colorectal cancer (mCRC) promising results are limited to patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-high) tumours due to their immune-enriched microenvironment. Combining cytotoxic agents and bevacizumab in mCRC with proficient mismatch repair/microsatellite stability (pMMR/MSS) could make ICIs efficacious by increasing the exposure of neoantigens, especially with highly active chemotherapy regimens, inducing immunogenic cell death, increasing the tumoral infiltration of CD8+ T-cells and reducing tumour-associated myeloid-derived suppressor cells. VEGF-blockade also plays an immunomodulatory role by inhibiting the expansion of T regulatory lymphocytes. Consistently with this rationale, a phase Ib study combined the anti-PDL-1 atezolizumab with FOLFOX/bevacizumab as first-line treatment of mCRC, irrespective of microsatellite status, and reported interesting activity and efficacy results, without safety concerns. Phase III trials led to identify FOLFOXIRI plus bevacizumab as an upfront therapeutic option in selected mCRC patients. Drawing from these considerations, the combination of atezolizumab with an intensified upfront treatment (FOLFOXIRI) and bevacizumab could be worthy of investigation. Methods AtezoTRIBE is a prospective, open label, phase II, comparative trial in which initially unresectable and previously untreated mCRC patients, irrespective of microsatellite status, are randomized in a 1:2 ratio to receive up to 8 cycles of FOLFOXIRI/bevacizumab alone or in combination with atezolizumab, followed by maintenance with bevacizumab plus 5-fluoruracil/leucovorin with or without atezolizumab according to treatment arm until disease progression. The primary endpoint is PFS. Assuming a median PFS of 12 months for standard arm, 201 patients should be randomized in a 1:2 ratio to detect a hazard ratio of 0.66 in favour of the experimental arm. A safety run-in phase including the first 6 patients enrolled in the FOLFOXIRI/bevacizumab/atezolizumab arm was planned, and no unexpected adverse events or severe toxicities were highlighted by the Safety Monitoring Committee. Discussion The AtezoTRIBE study aims at assessing whether the addition of atezolizumab to an intensified chemotherapy plus bevacizumab might be an efficacious upfront strategy for the treatment of mCRC, irrespective of the microsatellite status. Trial registration AtezoTRIBE is registered at Clinicaltrials.gov ( NCT03721653 ), October 26th, 2018 and at EUDRACT (2017–000977-35), Februray 28th, 2017 .

BackgroundRectum-preservation for locally advanced rectal cancer has been proposed as an alternative to total mesorectal excision (TME) in patients with major (mCR) or complete clinical response (cCR) after neoadjuvant therapy. The purpose of this study was to report on the short-term outcomes of ReSARCh (Rectal Sparing Approach after preoperative Radio- and/or Chemotherapy) trial, which is a prospective, multicenter, observational trial that investigated the role of transanal local excision (LE) and watch-and-wait (WW) as integrated approaches after neoadjuvant therapy for rectal cancer.MethodsPatients with mid-low rectal cancer who achieved mCR or cCR after neoadjuvant therapy and were fit for major surgery were enrolled. Clinical response was evaluated at 8 and 12 weeks after completion of chemoradiotherapy. Treatment approach, incidence, and reasons for subsequent TME were recorded.ResultsFrom 2016 to 2019, 160 patients were enrolled; mCR or cCR at 12 weeks was achieved in 64 and 96 of patients, respectively. Overall, 98 patients were managed with LE and 62 with WW. In the LE group, Clavien–Dindo 3+ complications occurred in three patients. The rate of cCR increased from 8- to 12-week restaging. Thirty-three (94.3%) of 35 patients with cCR had ypT0–1 tumor. At a median 24 months follow-up, a tumor regrowth was found in 15 (24.2%) patients undergoing WW.ConclusionsLE for patients achieving cCR or mCR is safe. A 12-week interval from chemoradiotherapy completion to LE is correlated with an increased cCR rate. The risk of ypT > is reduced when LE is performed after cCR.

Background Pancreatic cancer oligometastatic to the liver represents a distinct subset of advanced disease, presenting a limited number of metastases in a single site. First-line chemotherapy is considered the standard of care, with a poor overall prognosis. However, the optimal strategy for oligometastatic patients presenting response or stability after treatment is unclear. In selected patients, surgical resection is associated with prolonged survival, according to retrospective series. The aim of this randomized clinical trial is to compare the efficacy and safety of surgery versus observation or continuation of chemotherapy in patients with resectable pancreatic cancer oligometastatic to the liver with stable disease or response after first-line chemotherapy. Methods The study is a phase-2 multicentric randomized controlled trial with 1:1 allocation ratio. Patients diagnosed with pancreatic cancer and a limited number (up to 3) of liver metastases, with no evidence of extrahepatic disease, who received systemic chemotherapy as the initial treatment and with disease response or stability after therapy will be considered eligible patients. Patients will be randomized to either Arm A (surgery) or Arm B (observation or continuation of chemotherapy). The primary outcome will be overall survival at two years, with secondary outcomes including progression-free survival, treatment-related adverse events, quality of life and translational analyses. Discussion This randomized controlled trial will evaluate the role of surgery in pancreatic cancer oligometastatic to the liver after response or stability to first-line chemotherapy. While systemic therapy remains the standard of care, selected patients may benefit from surgical resection. By comparing surgery to observation or continuation of chemotherapy, the SONAR trial aims to fill a critical gap in treatment strategies and potentially refine the management of this challenging disease. Trial registration The trial has been registered at ClinicalTrials.gov on 15/11/2024 before inclusion of the first patient (NCT06690528).

Non-ampullary small bowel adenocarcinoma is a rare neoplasm with an ominous prognosis, whose incidence is higher in some chronic immuno-inflammatory conditions, such as coeliac and Crohn’s disease. Recently, claudin 18.2, a transmembrane protein normally expressed in gastric mucosa, has been recognized as a novel pan-cancer therapeutic target, and several clinical trials with claudin-18-directed drugs have shown promising results on various gastrointestinal malignancies. This is the first study focusing on claudin-18 expression in small bowel adenocarcinomas. The immunohistochemical expression of claudin-18 (clone 43-14A) was assessed in 81 small bowel adenocarcinomas of diverse aetiologies and correlated with several clinico-pathologic features and patient survival. We found that 28% of adenocarcinomas were immunoreactive for claudin-18, with cutoff values of ≥1% at any intensity, while 6% of cancers showed immunoexpression of ≥75% with 2+/3+ score. Moreover, claudin-18 (≥1%) was positively associated with cytokeratin 7 (CK7) and MUC5AC expression, showing CK7+/MUC5AC+ carcinomas the highest rate of positive cases, whereas a negative correlation was found between claudin-18 and CDX2 expression. In addition, some cancer-adjacent dysplastic growths and foci of gastric-type metaplasia in Crohn’s disease-associated cases showed claudin-18 immunoreactivity. Survival analysis showed a non-significant trend towards a worse cancer-specific survival for claudin-18-positive cases. A fraction of small bowel adenocarcinomas, mainly sporadic or Crohn’s disease-associated, and often exhibiting a non-intestinal immunoprofile, expressed claudin-18, suggesting that claudin-18-directed targeted therapy is worth investigating in such cancers.

Background The standard treatment for localized/locally advanced gastroesophageal adenocarcinoma (GEA) is radical surgery and peri-operative FLOT treatment (5-fluorouracil plus leucovorin, oxaliplatin, and docetaxel), but around half patients still experience disease relapse. In gastrointestinal cancers, the presence of circulating tumor DNA (ctDNA) after surgery is associated with a high risk of relapse, and the lack of ctDNA clearance after post-operative treatment is strongly associated with early relapse. Therefore, liquid biopsy may guide the selection of patients with micrometastatic disease after preoperative chemotherapy and surgery for non-cross resistant regimens in the post-operative setting. Trastuzumab deruxtecan (T-DXd) is approved in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma after failure of at least one prior trastuzumab-based regimen. The DESTINY-Gastric01 and 02 trials showed remarkable activity and efficacy of T-DXd, thus supporting the investigation of this agent in early-stage disease to increase the chance of achieving disease eradication. Finally, the DESTINY-Gastric03 trial showed the safety profile and feasibility, with preliminary promising activity results of the combination of T-DXd with a fluoropyrimidine. Trial design TRINITY is an ongoing multicentre, randomized, open-label, interventional phase II study which will enroll approximately 46 patients with HER2-positive GEA, treated with pre-operative FLOT and radical surgery, and with the persistence of minimal residual disease detected by the Signatera™ assay in a liquid biopsy collected between 2 and 6 weeks after surgery. The trial is designed with an observational phase enrolling patients with HER2-positive GEA eligible for standard treatment with peri-operative FLOT and surgery. Eligible patients will be randomized on a 1:1 basis to the experimental treatment arm consisting of adjuvant T-DXd (6.4 mg/kg IV on day 1) plus either capecitabine (1000 mg/sqm BID orally on days 1–14) or 5-fluorouracil (600 mg/sqm continuous IV infusion on days 1–5) Q3 W for 6 cycles, or to the control arm with standard post-operative FLOT (at the same dose used during the last pre-operative cycle) for 4 cycles. Patients non-eligible for the interventional trial will continue the standard therapy and follow-up in the frame of the observational phase with collection of exploratory longitudinal liquid biopsies. The primary objective is ctDNA clearance at 1 year after randomization. Considering alpha- and beta-errors of 0.10 and 0.20 and hypothesizing a ctDNA clearance of 10% and 35% in the control and experimental arm, respectively, 23 patients per arm are required to prove the superiority of the experimental strategy. Secondary endpoints include disease-free survival, overall survival, metastases-free survival, patient-reported outcomes and safety. The trial also represents a translational platform, including extensive analysis of circulating, tissue, and immune biomarkers as exploratory endpoints. Enrollment is active and ongoing. Trial registration TRINITY is registered at ClinicalTrials.gov (NCT06253650).

BackgroundOnly a subset of polymerase epsilon (POLE) mutations is associated with hypermutant phenotype; we hypothesized that only loss-of-proofreading (LOP) POLE mutations are associated with favorable immunotherapy response.MethodsThis retrospective cohort study included a pan-cancer cohort of 69,223 patients from cBioPortal and a cohort of patients with 41 POLE mutant metastatic colorectal (CRC) treated with immunotherapy at the MD Anderson Cancer Center between January 2017 and May 2023. We evaluated prognosis according to POLE mutation functionality.ResultsIn the pan-cancer cBioPortal cohort (n=69,223) POLE was mutated in 2.8% (1,965) of tumors; of these, only 7.5% (n=148) had LOP POLE mutations (0.0% of entire cohort). Endometrial cancer (6.6%) and CRC (1.2%) were the only tumor types with greater than 1% incidence of LOP POLE mutation. Overall survival was similar between non-LOP POLE and POLE wildtype patients (HR=0.94, 95% CI 0.82 to 1.07, p=0.34); conversely, LOP POLE patients had significantly better outcomes (HR=0.23, 95% CI 0.16 to 0.32, p<0.0001). In the clinical cohort, all nine patients with LOP POLE mutations achieved durable clinical benefit (objective response rate (ORR) 88.9%, complete response rate (CR) 33.3%, disease control rate (DCR) 100%) and median progression-free survival (PFS) was not reached at the time of analysis, after median follow-up of 32 months. None of the nine patients with microsatellite stable (MSS), non-LOP POLE tumors achieved an ORR of 0%, with median PFS of 3.7 months (HR 0.05 LOP relative to non-LOP POLE, 95% CI 0.01 to 0.19, p<0.0001). Interestingly, median PFS on first-line cytotoxic agents was significantly shorter for patients with LOP POLE compared with patients with MSS non-LOP POLE mutant tumors (2.1 vs 9.7 months, HR 3.33, 95% CI 0.87 to 12.74, p=0.012).ConclusionsIdentifying the subset of POLE mutations that cause LOP is critical to distinguish patients likely to respond to immunotherapy. Patients with CRC with LOP POLE mutant tumors experienced deep, sustained response to immunotherapy but were resistant to standard cytotoxic chemotherapy, in stark contrast to those with non-LOP POLE mutations.

Background: Rectal cancer management involves surgery, chemotherapy (CT), radiotherapy (RT), and patient care strategies, all of which significantly affect health-related quality of life (HRQoL). Understanding these effects is critical for optimizing treatment protocols. This review aimed to systematically analyze the impact of rectal cancer treatment on HRQoL. Methods: Four databases, Scopus, EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials, were searched for randomized controlled trials (RCTs) published between January 2013 and December 2023. RCTs specifically focusing on rectal cancer treatments (surgical interventions, pre- and/or post-CT and/or RT, and patient care strategies) were included. An abstract review, data extraction, and a risk-of-bias assessment were independently conducted by two reviewers. Results: The 41 included studies comprised 9240 patients: 16 evaluated surgical interventions (3507 patients), 15 evaluated pre- and/or post-CT and/or RT protocols (5114 patients), and 10 focused on patient-care strategies (619 patients). Sphincter-sparing procedures were associated with better HRQoL than abdominoperineal resection, and rectal-sparing techniques were associated with better overall HRQoL than rectal resection. RT was associated with a poorer HRQoL. Continuity-of-care interventions improved HRQoL in ostomy patients, whereas transanal irrigation improved HRQoL after ostomy closure. Conclusions: This systematic review of RCTs underscores the importance of organ-sparing strategies, such as rectum-sparing approaches and continuity-of-care packages, in improving HRQoL in patients with rectal cancer. Although RT negatively affects HRQoL, treatment regimens should be individualized. Tailored organ-preservation approaches and structured follow-up care are essential for optimizing HRQoL in patients with rectal cancer.