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BACKGROUND: Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, inhibits angiogenesis and reduces tumor growth. Serum VEGF-C, lactate dehydrogenase, and inflammatory markers have been reported as predictive markers related to bevacizumab treatment. Programmed cell death ligand 1 (PD-L1) could act upon VEGF receptor 2 to induce cancer cell angiogenesis and metastasis. AIM: To investigate the efficacy of bevacizumab-containing chemotherapy in patients with metastatic colorectal cancer (CRC) according to the expression of PD-L1. METHODS: This analysis included CRC patients who received bevacizumab plus FOLFOX or FOLFIRI as first-line therapy between June 24, 2014 and February 28, 2022, at Samsung Medical Center (Seoul, South Korea). Analysis of patient data included evaluation of PD-L1 expression by the combined positive score (CPS). We analyzed the efficacy of bevacizumab according to PD-L1 expression status in patients with CRC. RESULTS: A total of 124 patients was included in this analysis. Almost all patients were treated with bevacizumab plus FOLFIRI or FOLFOX as the first-line chemotherapy. While 77% of patients received FOLFOX, 23% received FOLFIRI as backbone first-line chemotherapy. The numbers of patients with a PD-L1 CPS of 1 or more, 5 or more, or 10 or more were 105 (85%), 64 (52%), and 32 (26%), respectively. The results showed no significant difference in progression-free survival (PFS) and overall survival (OS) with bevacizumab treatment between patients with PD-L1 CPS less than 1 and those with PD-L1 CPS of 1 or more (PD-L1 < 1% vs PD-L1 ≥ 1%; PFS: P = 0.93, OS: P = 0.33), between patients with PD-L1 CPS less than 5 and of 5 or more (PD-L1 < 5% vs PD-L1 ≥ 5%; PFS: P = 0.409, OS: P = 0.746), and between patients with PD-L1 CPS less than 10 and of 10 or more (PD-L1 < 10% vs PD-L1 ≥ 10%; PFS: P = 0.529, OS: P = 0.568). CONCLUSION: Chemotherapy containing bevacizumab can be considered as first-line therapy in metastatic CRC irrespective of PD-L1 expression.
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BACKGROUND: The Kirsten rat sarcoma virus (KRAS) is a prominent proto-oncogene. Several treatments for KRAS mutations have been developed. However, KRAS amplification, a KRAS alteration, is poorly understood, and there is currently no appropriate treatment other than conventional chemotherapy. This study aimed to elucidate the role of KRAS amplification in different types of cancers. METHODS: From October 2019 to June 2023, we performed next-generation sequencing using Trusight Oncology 500 on 3895 patients with 37 different cancer types at the Samsung Medical Center. We analyzed the distribution of KRAS amplification according to cancer type and its correlation with tumor mutation burden (TMB). Concomitant KRAS mutations were also identified. RESULTS: Of the total 3895 patients, 99 (2.5â¯%) had KRAS amplification. The highest frequency of KRAS amplification was detected in 2â¯% (27/1350) of patients with colorectal cancer, followed by 3.48â¯% (32/920) of patients with gastric cancer and 3.88â¯% (9/232) patients with of pancreatic cancer. MSI-High was not detected in patients with KRAS amplification. There was no correlation between KRAS copy number variation and TMB status. Among patients with KRAS amplification, 27.3â¯% (27/99) had a concomitant KRAS mutation. More than 50â¯% of patients had G12D or G12V mutations. In gastric cancer, patients with both KRAS amplification and mutation were extremely rare at 3.1â¯% (1/32); however, in colorectal cancer, more than half of the patients had KRAS amplification and mutation (51.9â¯%, 14/27). KRAS amplification and mutations are associated with mutations in tumor suppressor genes TP53, BRCA2, ARID1B, and PTCH1. CONCLUSIONS: Of the 3895 patients with metastatic solid tumors, 99 (2.5â¯%) had KRAS amplification, and next-generation sequencing analysis provided a deeper understanding of KRAS amplification.
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Amplificación de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Proteínas Proto-Oncogénicas p21(ras)/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Neoplasias/genética , Neoplasias/patología , Adulto , Prevalencia , Biomarcadores de Tumor/genética , Metástasis de la Neoplasia/genéticaRESUMEN
Background: In v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant colorectal cancer (CRC), encorafenib-cetuximab has been established as standard second-line therapy, but not all patients respond and the duration of response is relatively short. Overcoming intrinsic or acquired resistance to BRAF/EGFR inhibitors is crucial for enhancing treatment outcomes in metastatic BRAF-mutated CRC. The aim of the study is to investigate the resistance mechanisms in BRAF-mutant CRC patient refractory to BRAF/EGFR targeted therapy. Methods: We established patient-derived cells (PDCs) from a patient with BRAF/PTEN-mutant metastatic colon cancer who progressed rapidly on encorafenib plus cetuximab. To explore potential treatment options for inherent resistance caused by simultaneous PTEN mutation in BRAF-mutated CRC, we conducted cell viability assays using PDCs treated with encorafenib-cetuximab in combination with a cyclin-dependent kinase-4 and 6 (CDK4/6) inhibitor. Results: The patient's tumor had concurrent PTEN loss-of-function alteration at diagnosis and PDCs were generated from ascites after resistance to the BRAF/EGFR inhibitor. The PDCs were resistant to the encorafenib-cetuximab combination even at a high concentration of cetuximab (up to 500 µg/mL). Adding the CDK4/6 inhibitor, ribociclib, to encorafenib-cetuximab showed a synergistic effect in a proliferation assay. Ribociclib plus encorafenib-cetuximab represented a significantly lower expression of Ki-67 compared to the dual combination alone. An MTS assay showed that triplet therapy with ribociclib, encorafenib, and cetuximab suppressed cell viability more efficiently than the two-drug combinations. Investigating the combined effect of triplet therapy using the calculated combination index (CI) showed that ribociclib had a synergistic effect with encorafenib-cetuximab when applied to PDCs with a concurrent BRAF/PTEN mutation. Conclusions: Our results suggest that combining the CDK4/6 inhibitor with the BRAF/EGFR inhibitor might be a novel treatment strategy for concomitant BRAF and PTEN-mutant CRC.
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INTRODUCTION: We conducted an open-label, single-arm, multi-center phase II trial to evaluate the efficacy and safety of imatinib chemotherapy-refractory or metastatic solid tumor patients with c-KIT mutations and/or amplification. METHODS: c-KIT mutations and amplification were detected using NGS. Imatinib (400 mg daily) was administered continuously in 28-day cycles until disease progression, unacceptable adverse events, or death by any cause. The primary endpoint was the objective response rate (ORR). RESULT: In total, 18 patients were enrolled on this trial. The most common tumor type was melanoma (n = 15, 83.3%), followed by ovarian cancer, breast cancer, and metastasis of unknown origin (MUO) (each n = 1, 5.5%). The total number of evaluable patients was 17, of which one patient had a complete response, six patients had partial response, and two patients had stable disease. The overall response rate (ORR) of 41.2% (95% CI 17.80-64.60) and a disease control rate of 52.9% (95% CI 29.17-76.63). The median progression-free survival was 2.2 months (95% CI 1.29-3.20), and median overall survival was 9.1 months (95% CI 2.10-16.11). The most common adverse events were edema (31.3%), anorexia (25.0%), nausea (18.8%), and skin rash (18.8%). CONCLUSION: Imatinib demonstrated modest anti-tumor activity and a manageable safety profile in chemotherapy-refractory solid tumors with c-KIT mutation, especially in melanoma patients.
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Mesilato de Imatinib , Mutación , Neoplasias , Proteínas Proto-Oncogénicas c-kit , Humanos , Proteínas Proto-Oncogénicas c-kit/genética , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/administración & dosificación , Femenino , Persona de Mediana Edad , Masculino , Adulto , Anciano , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Neoplasias/mortalidad , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , República de Corea , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Resultado del TratamientoRESUMEN
PURPOSE: For the treatment of locally advanced rectal cancer (LARC), research on primary lesions with mesorectal fascia (MRF) involvement is lacking. This study analyzed the clinical outcomes and efficacy of dose-escalated neoadjuvant concurrent chemoradiotherapy (NCRT) to patients with LARC involving MRF. MATERIALS AND METHODS: We retrospectively reviewed 301 patients who were diagnosed with LARC involving MRF and underwent NCRT followed by total mesorectal excision (TME). Patients who received radiotherapy (RT) doses of ≤50.4 Gy were defined as the non-boost group, while ≥54.0 Gy as the boost group. Pathological tumor response and survival outcomes, including intrapelvic recurrence-free survival (IPRFS), distant metastases-free survival (DMFS) and overall survival (OS), were analyzed. RESULTS: A total of 269 patients (89.4%) achieved a negative pathological circumferential resection margin and 104 (34.6%) had good pathological tumor regression grades. With a median follow-up of 32.4 months, IPRFS, DMFS, and OS rates at 5-years were 88.6%, 78.0%, and 91.2%, respectively. In the subgroup analysis by RT dose, the boost group included more advanced clinical stages of patients. For the non-boost group and boost group, 5-year IPRFS rates were 90.3% and 87.0% (p = 0.242), 5-year DMFS rates were 82.0% and 71.3% (p = 0.105), and 5-year OS rates were 93.0% and 80.6% (p = 0.439), respectively. Treatment related toxicity was comparable between the two groups (p = 0.211). CONCLUSION: Although this retrospective study failed to confirm the efficacy of dose-escalated NCRT, favorable IPRFS and pathological complete response was achieved with NCRT followed by TME. Further studies combining patient customized RT dose with systemic therapies are needed.
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Minnelide is a water-soluble disodium salt variant of triptolide, an HSP70 inhibitor that can prevent tumor progression and induce apoptosis. Maximum tolerated dose (MTD), safety, and antitumor activity of Minnelide alone and its combination with paclitaxel were evaluated in this open-label, single-center, dose-escalation phase I study (NCT05566834) in patients who were previously treated for advanced gastric cancer (AGC). Minnelide was administered orally using a 3 + 3 dose-escalation design as monotherapy (Regimen A), and in combination with paclitaxel (Regimen B & C). Our results show that no patients experienced dose limiting toxicity (DLT) in the combination group (Regimen B& C) while 2 patients experienced DLT from the Regimen A group (n = 11) (Minnelide 1.5 mg). The MTD was Minnelide 1.25 mg once daily for 21days Q4 weeks as monotherapy. The most common Grade ≥3 AEs were neutropenia (19.4 %) and abdominal pain (11.1 %). In Regimen C, 71.5 % achieved either a partial response or a stable disease with the median PFS of 4.5 months, and the median OS of 10.7 months. The combination of Minnelide plus paclitaxel as salvage treatment in AGC patients showed meaningful clinical activity with a manageable safety profile. Based on these encouraging results, a phase II study is being initiated to test the effectiveness of the combination regimen in patients with advanced gastric cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica , Diterpenos , Compuestos Epoxi , Dosis Máxima Tolerada , Paclitaxel , Fenantrenos , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Masculino , Persona de Mediana Edad , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Fenantrenos/administración & dosificación , Fenantrenos/efectos adversos , Fenantrenos/uso terapéutico , Diterpenos/administración & dosificación , Diterpenos/efectos adversos , Adulto , Compuestos Epoxi/administración & dosificación , Compuestos Epoxi/efectos adversos , Resultado del Tratamiento , OrganofosfatosRESUMEN
BACKGROUND/AIM: The DNA checkpoint (DNACHK) pathway is engaged in signaling the need for cell cycle arrest. This pathway is being actively researched to assess its role in cancer immunotherapy. PATIENTS AND METHODS: A total of 62 patients participated in this study. These patients were treated with immune checkpoint inhibitors (ICIs) for advanced biliary tract cancers (BTCs) from March 2020 to August 2022 at Samsung Medical Center. DNACHK mutated were defined as genomic alterations, such as single nucleotide variants, multi-nucleotide variants, and short insertion and deletions in seven genes; checkpoint kinase 1 (CHEK1), checkpoint kinase 2 (CHEK2), BRCA1, DNA repair-associated (BRCA1), the serine/threonine kinase ATM, the serine/threonine kinase ATR, mediator of DNA damage checkpoint 1 (MDC1) and tumor protein p53 binding protein 1 (TP53BP1). We analyzed the effect of DNACHK mutations on the efficacy of ICIs in advanced BTCs. RESULTS: Patient median age at diagnosis was 68.0 years. 10 patients (16.1%) had GB cancer; the remaining patients (n=52, 83.9%) were diagnosed with cholangiocarcinoma. Thirty-seven (59.7%) patients were categorized into the DNACHK wild-type (WT) group and 25 (40.3%) into the DNACHK mutated (MT) group. The most observed DNA checkpoint mutations were ATM mutations (n=14). Patients in the DNACHK MT group had better disease control rate (DCR) than patients in the DNACHK WT (60.0% vs. 48.6%, p=0.53). Median overall survival (OS) was 8.1 months (95% CI 5.1-22.8) in the MT group and 5.6 months (95%CI 3.1-11.0) in the WT group (p=0.33). CONCLUSION: The DNACHK pathway is expected to serve as a potential biomarker for ICI treatment.
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Neoplasias del Sistema Biliar , Biomarcadores de Tumor , Inhibidores de Puntos de Control Inmunológico , Mutación , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Anciano , Masculino , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Anciano de 80 o más Años , AdultoRESUMEN
This study addresses the demand for research models that can support patient-treatment decisions and clarify the complexities of a tumor microenvironment by developing an advanced non-animal preclinical cancer model. Based on patient-derived tumor spheroids (PDTS), the proposed model reconstructs the tumor microenvironment with emphasis on tumor spheroid-driven angiogenesis. The resulting microfluidic chip system mirrors angiogenic responses elicited by PDTS, recapitulating patient-specific tumor conditions and providing robust, easily quantifiable outcomes. Vascularized PDTS exhibited marked angiogenesis and tumor proliferation on the microfluidic chip. Furthermore, a drug that targets the vascular endothelial growth factor receptor 2 (VEGFR2, ramucirumab) was deployed, which effectively inhibited angiogenesis and impeded tumor invasion. This innovative preclinical model was used for investigating distinct responses for various drug combinations, encompassing HER2 inhibitors and angiogenesis inhibitors, within the context of PDTS. This integrated platform could potentially advance precision medicine by harmonizing diverse data points within the tumor microenvironment with a focus on the interplay between cancer and the vascular system.
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Neoplasias , Factor A de Crecimiento Endotelial Vascular , Humanos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Angiogénesis , Neovascularización Patológica/metabolismo , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Línea Celular Tumoral , Neoplasias/tratamiento farmacológicoRESUMEN
Adding anti-programmed cell death protein 1 (anti-PD-1) to 5-fluorouracil (5-FU)/platinum improves survival in some advanced gastroesophageal adenocarcinomas (GEA). To understand the effects of chemotherapy and immunotherapy, we conducted a phase II first-line trial (n = 47) sequentially adding pembrolizumab to 5-FU/platinum in advanced GEA. Using serial biopsy of the primary tumor at baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab, we transcriptionally profiled 358,067 single cells to identify evolving multicellular tumor microenvironment (TME) networks. Chemotherapy induced early on-treatment multicellular hubs with tumor-reactive T-cell and M1-like macrophage interactions in slow progressors. Faster progression featured increased MUC5A and MSLN containing treatment resistance programs in tumor cells and M2-like macrophages with immunosuppressive stromal interactions. After pembrolizumab, we observed increased CD8 T-cell infiltration and development of an immunity hub involving tumor-reactive CXCL13 T-cell program and epithelial interferon-stimulated gene programs. Strategies to drive increases in antitumor immune hub formation could expand the portion of patients benefiting from anti-PD-1 approaches. SIGNIFICANCE: The benefit of 5-FU/platinum with anti-PD-1 in first-line advanced gastric cancer is limited to patient subgroups. Using a trial with sequential anti-PD-1, we show coordinated induction of multicellular TME hubs informs the ability of anti-PD-1 to potentiate T cell-driven responses. Differential TME hub development highlights features that underlie clinical outcomes. This article is featured in Selected Articles from This Issue, p. 695.
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Neoplasias Gástricas , Microambiente Tumoral , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Masculino , Inmunoterapia/métodos , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Persona de Mediana Edad , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacologíaRESUMEN
BACKGROUND: c-mesenchymal epithelial transition factor receptor (c-MET) and fibroblast growth factor receptor 2 (FGFR2) amplification have been identified as factors associated with advanced stage and poor prognosis in gastric cancer (GC). While they are typically considered mutually exclusive, concurrent amplifications have been reported in a small subset of GC patients. METHODS: in this retrospective study, we analyzed the clinical outcomes of GC patients with MET and FGFR2 amplification using the next-generation sequencing (NGS) database cohort at Samsung Medical Center, which included a total of 2119 patients between October 2019 and April 2021. RESULTS: Of 2119 cancer patients surveyed, the number of GC patients was 614 (29.0%). Out of 614 GC patients, 39 (6.4%) had FGFR2 amplification alone, 22 (3.6%) had MET amplification, and 2 GC patients (0.3%) had concurrent FGFR2 and MET amplification. Two patients with concurrent FGFR2 and MET amplification did not respond to first-line chemotherapy. These two patients had significantly shorter overall survival (3.6 months) compared to patients with FGFR2 or MET amplification alone (13.6 months and 8.4 months, respectively) (p = 0.004). Lastly, we tested the existence of FGFR2 and MET in tumor specimens from different organ sites. Initially, the NGS was tested in a primary tumor specimen from stomach cancer, where the MET copy number was 14.1 and the FGFR2 copy number was 5.3. We confirmed that both MET and FGFR2 were highly amplified in the primary tumor using FISH (MET-CEP7 ratio = 5 and FGFR2-CEP7 ratio = 3). However, although the MET copy number was normal in peritoneal seeding using FISH, FGFR2 remained amplified using FISH (FGFR2-CEP7 ratio = 7) with high FGFR2 protein overexpression. Hence, there was intra-patient molecular heterogeneity. CONCLUSIONS: our findings suggest that concurrent amplification of FGFR2 and MET in GC patients is associated with clinical aggressiveness and may contribute to non-responsiveness to chemotherapy or targeted therapy.
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PURPOSE: Therapeutic targeting of RAF1 is a promising cancer treatment, but the relationship between clinical features and RAF1 aberrations in terms of the MAPK signaling pathway is poorly understood in various solid tumors. METHODS: Between October 2019 and June 2023 at Samsung Medical Center, 3895 patients with metastatic solid cancers underwent next-generation sequencing (NGS) using TruSight Oncology 500 (TSO500) assays as routine clinical practice. We surveyed the incidence of RAF1 aberrations including mutations (single-nucleotide variants [SNVs]), amplifications (copy number variation), and fusions. RESULTS: Among the 3895 metastatic cancer patients, 77 (2.0%) exhibited RAF1 aberrations. Of these 77 patients, 44 (1.1%) had RAF1 mutations (SNV), 25 (0.6%) had RAF1 amplifications, and 10 (0.3%) had RAF1 fusions. Among the 10 patients with RAF1 fusions, concurrent RAF1 amplifications and RAF1 mutations were detected in one patient each. The most common tumor types were bladder cancer (11.5%), followed by ampulla of Vater (AoV) cancer (5.3%), melanoma (3.0%), gallbladder (GB) cancer (2.6%), and gastric (2.3%) cancer. Microsatellite instability high (MSI-H) tumors were observed in five of 76 patients (6.6%) with RAF1 aberrations, while MSI-H tumors were found in only 2.1% of patients with wild-type RAF1 cancers (p < 0.0001). CONCLUSION: We demonstrated that approximately 2.0% of patients with metastatic solid cancers have RAF1 aberrations according to NGS of tumor specimens.
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With the advances in chemotherapy and immunotherapy, a small subset of patients may be eligible for conversion surgery after achieving tumor regression with chemotherapy. This is a retrospective cohort study of 118 patients with stage IV gastric cancer who received palliative chemotherapy and conversion surgery with a negative resection margin at Samsung Medical Center. Baseline features included comorbidities, body mass index (BMI), carcinoembryonic antigen (CEA) level, primary tumor size, biopsy histology, distant metastatic sites, and molecular markers-HER2, MSI/MMR, PD-L1, and EBV. Post-chemotherapy features included BMI, CEA level, chemotherapy regimen, objective response to chemotherapy, and number of preoperative chemotherapy cycles. Post-operational features included tumor size, histologic differentiation and Lauren's classification, pathologic tumor and nodal stages, invasion of lymphatics/vessels/nerves, peritoneal cytology, and the receipt of postoperative chemotherapy. Of 118 patients, 60 patients received total gastrectomy and 58 patients received subtotal gastrectomy. In all, 21 patients achieved a pathologic complete response, and 97 patients achieved downstaging to yp stage I, II, or III. Before conversion surgery, patients received first-line capecitabine/oxaliplatin (62%), HER2 inhibitors combined with chemotherapy (18%), immune checkpoint inhibitors (15%), and inhibitors of MET or VEGFR2 (5%). In the multivariable analysis, BMI at the time of diagnosis, either HER2 positive, high MSI, or deficient MMR, and the use of targeted agents were significant prognostic factors. Conversion surgery could be considered in patients with stage IV gastric cancer regardless of the initial disease burden. BMI and molecular markers are important prognostic factors that can be used to select candidates.
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Gastric cancer (GC) with peritoneal metastases and malignant ascites continues to have poor prognosis. Exosomes mediate intercellular communication during cancer progression and promote therapeutic resistance. Here, we report the significance of exosomes derived from malignant ascites (EXOAscites) in cancer progression and use modified exosomes as resources for cancer therapy. EXOAscites from patients with GC stimulated invasiveness and angiogenesis in an ex vivo three-dimensional autologous tumor spheroid microfluidic system. EXOAscites concentration increased invasiveness, and blockade of their secretion suppressed tumor progression. In MET-amplified GC, EXOAscites contain abundant MET; their selective delivery to tumor cells enhanced angiogenesis and invasiveness. Exosomal MET depletion substantially reduced invasiveness; an additive therapeutic effect was induced when combined with MET and/or VEGFR2 inhibition in a patient-derived MET-amplified GC model. Allogeneic MET-harboring exosome delivery induced invasion and angiogenesis in a MET non-amplified GC model. MET-amplified patient tissues showed higher exosome concentration than their adjacent normal tissues. Manipulating exosome content and production may be a promising complementary strategy against GC.
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Exosomas , MicroARNs , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Ascitis/patología , Línea Celular TumoralRESUMEN
Background: In metastatic colorectal cancer (mCRC), the prognostic relevance of the human epidermal growth factor receptor-2 (HER2) remains controversial. We evaluated the impact of HER2 overexpression on outcomes of standard chemotherapy in patients with mCRC. Methods: This retrospective study included patients with mCRC who received standard chemotherapy for mCRC and were tested for HER2 expression at Samsung Medical Center, Seoul, Korea, between January 15, 2017, and February 05, 2022. The HER2 test was performed using immunohistochemistry. We assessed the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) according to HER2 status. All statistical analyses were performed using SPSS® version 25 (IBM, Armonk, NY, USA). Results: In total, 108 patients were included; 10 (9.3%) had HER2-positive tumors. The ORR for patients with mCRC receiving standard chemotherapy did not differ for HER2-positive and HER2-negative tumors. The median PFS for patients with mCRC with HER2-positive or HER2-tumors after receiving first-line chemotherapy was 18.52 months [95% confidence interval (CI): 4.355-32.695] or 10.95 months (95% CI: 9.317-12.585; P=0.417), respectively, and that after second-line chemotherapy was 7.08 months (95% CI: 6.801-7.363) or 5.34 months (95% CI: 4.433-6.255; P=0.837), respectively. Likewise, OS did not differ according to HER2 expression (median OS: HER2-positive tumors, 49.1 months (95% CI: 0.000-98.365); HER2-negative tumors, 37.7 months (95% CI: 27.111-48.366; P=0.410). Conclusions: The tumor response and survival of patients with mCRC after standard chemotherapy did not differ by HER2 expression. These findings suggest that the status of HER2 expression need not be considered when choosing regimens as the current first- and second-line treatments.
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Background: As rare tumors, there are limited treatment options for neuroendocrine neoplasms (NENs). Recently, microsatellite instability (MSI) and tumor mutation burden (TMB) have been emerging as potential biomarkers in various tumors. However, there is a lack of research on the use of these biomarkers in gastro-entero-pancreatic (GEP)-NENs. Methods: We analyzed 31 patients diagnosed with GEP-NEN between 2013 to 2022. The TMB and MSI analyses using next-generation sequencing (NGS) were performed for all patients. The TruSightTM Oncology 500 assay from Illumina was used as the NGS panel. Results: Out of the 31 patients analyzed, the most frequent primary origin was the pancreas (12 patients, 38.7%), followed by the stomach (4 patients, 12.9%), gallbladder (4 patients, 12.9%), rectum (7 patients, 22.6%), small bowel (2 patients, 6.5%), and bile duct (1 patient, 3.2%). Among these patients, 19 (61.3%) were diagnosed with well-differentiated neuroendocrine tumors, with grade 2 being the most common (15 patients, 48.4%), followed by grade 3 (3 patients, 9.7%) and grade 1 (1 patient, 3.2%). Neuroendocrine carcinoma was confirmed in 12 patients (38.7%). The median number of metastases was 2.0 [interquartile range (IQR), 1.0-3.0], and the liver was the most common site of metastasis (23 patients, 74.2%). The median TMB was 4.7 (IQR, 3.1-6.3) mutations/Mb, and all tumors were classified as microsatellite stability (MSS). Only one patient had a high TMB (266.4 mutations/Mb), which was a grade 3 neuroendocrine tumor originating from the pancreas. The TMB value did not vary depending on the primary tumor site or World Health Organization (WHO) grade. Conclusions: This analysis showed that, despite very low incidence, there are GEP-NENs with high TMB. For precision medicine, testing for MSI and TMB is needed for this tumor type.
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PURPOSE: To evaluate the efficacy and safety of tucatinib and trastuzumab in patients with previously treated human epidermal growth factor receptor 2-positive (HER2+) metastatic biliary tract cancer (mBTC). METHODS: SGNTUC-019 (ClinicalTrials.gov identifier: NCT04579380) is an open-label phase II basket study evaluating the efficacy and safety of tucatinib and trastuzumab in patients with HER2-altered solid tumors. In the biliary tract cancer cohort, patients had previously treated HER2 overexpressing or amplified (HER2+) tumors (identified with local testing) with no prior HER2-directed therapy. The primary end point was confirmed objective response rate (cORR) per investigator assessment. Patients were treated on a 21-day cycle with tucatinib (300 mg orally twice daily) and trastuzumab (8 mg/kg intravenously followed by 6 mg/kg every 3 weeks). RESULTS: Thirty patients were enrolled. As of data cutoff (January 30, 2023), the median duration of follow-up was 10.8 months. The cORR was 46.7% (90% CI, 30.8 to 63.0), with a disease control rate of 76.7% (90% CI, 60.6 to 88.5). The median duration of response and progression-free survival were 6.0 months (90% CI, 5.5 to 6.9) and 5.5 months (90% CI, 3.9 to 8.1), respectively. At data cutoff, 15 patients (50.0%) had died, and the estimated 12-month overall survival rate was 53.6% (90% CI, 36.8 to 67.8). The two most common treatment-emergent adverse events (TEAEs) were pyrexia (43.3%) and diarrhea (40.0%). Grade ≥3 TEAEs were reported in 18 patients (60.0%), with the most common being cholangitis, decreased appetite, and nausea (all 10.0%), which were generally not treatment related. TEAEs led to treatment regimen discontinuation in one patient, and there were no deaths due to TEAEs. CONCLUSION: Tucatinib combined with trastuzumab had clinically significant antitumor activity and was well tolerated in patients with previously treated HER2+ mBTC.
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Anticuerpos Monoclonales Humanizados , Neoplasias , Humanos , Trastuzumab/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Receptor ErbB-2/metabolismo , Neoplasias/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Background: Although bevacizumab is an important treatment for metastatic colorectal cancer (CRC), not all patients with CRC benefit from it; in unselected patient populations, only modest survival benefits have been reported. Methods: We evaluated clinical outcomes in 110 patients using comprehensive molecular characterization to identify biomarkers for a response to bevacizumab-containing treatment. The molecular analysis comprised whole-exome sequencing, ribonucleic acid sequencing, and a methylation array on patient tissues. Results: Genomic and molecular characterization was successfully conducted in 103 patients. Six of 103 CRC samples were hypermutated, and none of the non-hypermutant tumors were microsatellite unstable. Among those 103 patients, 89 had adenocarcinoma (ADC), 15 were diagnosed with mucinous ADC, and six had signet-ring cell carcinoma (SRCC). Consensus molecular subtype (CMS) 2 was unique to ADC. Of the four SRCCs, two were CMS1, one was CMS4, and the other was CMS3. APC mutation status was a significantly enriched factor in responders to bevacizumab treatment. Fibroblast growth factor receptor (FGFR) 1/2 signaling was upregulated in non-responders, whereas cell cycle, transfer ribonucleic acid processing, nucleotide excision repair, and oxidative phosphorylation pathways were enriched in responders. In addition, IGF1 was differentially expressed in non-responders (log2 fold change = -1.43, p = 4.11 × 10-5, false discovery rate = 0.098), and FLT1 was highly methylated in non-responders (p = 7.55 × 10-3). When the molecular pathways were reanalyzed separately according to the backbone chemotherapy (FOLFOX vs. FOLFIRI), the significance of the molecular pathways varied according to the backbone chemotherapy. Conclusions: This study sought a subset of CRC patients with a distinct clinical response to chemotherapy containing bevacizumab. Our results need to be validated in a large group of homogenous patient cohort and examined according to the different chemotherapy backbones to create personalized therapeutic opportunities in CRC.
Asunto(s)
Adenocarcinoma , Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias del Colon/tratamiento farmacológico , Biomarcadores , Adenocarcinoma/genética , ARN , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pronóstico , Fluorouracilo/uso terapéuticoRESUMEN
BACKGROUND: Programmed death-ligand 1 (PD-L1) is an important screening biomarker to select patients with gastric cancer (GC) for optimized treatment, including immune checkpoint inhibitors (ICI). METHODS: In this single-institution retrospective cohort study, patients with metastatic GC with available PD-L1 results between October 2019 and September 2021 were identified by reviewing their electronic medical records. Genomic data were obtained from the Samsung Medical Center Clinical Sequencing Platform. RESULTS: Among the 399 patients, 276 (69%) had a PD-L1 combined positive score (CPS) ≥1, 155 (39%) had a CPS between 1 and 5, and 121 (30%) had a CPS ≥5. Of the 121 patients with CPS ≥5, 28 (23%) had a known etiology for "inflamed tumor," with Epstein-Barr virus (EBV) positivity (N = 11) or high tumor mutational burden (TMB) (N = 17), which included microsatellite instability (MSI) (N = 9). PD-L1 CPS ≥5 was observed in 11/11 (100%) patients with EBV positivity, 9/12 (75%) patients with MSI, and 17/33 (52%) patients with high TMB. For the 108 patients who received ICI therapy, CPS ≥5 was the only predictor significantly associated with survival in multivariable analyses, including TMB, MSI, or EBV. Objective response rate (ORR) was 49% in patients with CPS ≥5, 30% in patients with 1 ≤ CPS <5, and 19% in patients with CPS <1. Among the 31 responders to ICI therapy, 27 (87%) had a CPS of ≥1. Mutations in TET2, IRS2, DOT1L, PTPRT, and LRP1B were associated with a higher ORR (63%-100%), whereas MDC1 mutations were associated with a low ORR (22%). CONCLUSIONS: PD-L1 expression is an independent and sensitive biomarker for ICI therapy. Considering its significant association with several gene alterations, including PIK3CA mutations and MET amplification, combining ICI therapy with other targeted agents may be a promising therapeutic strategy for GC.
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PURPOSE: The optimal tumor mutational burden (TMB) value for predicting treatment response to programmed cell death-1 (PD-1) checkpoint inhibitors in advanced gastric cancer (AGC) remains unclear. We aimed to investigate the optimal TMB cutoff value that could predict the efficacy of PD-1 checkpoint inhibitors in AGC. MATERIALS AND METHODS: Patients with AGC who received pembrolizumab or nivolumab between October 1, 2020, and July 27, 2021, at Samsung Medical Center in Korea were retrospectively analyzed. The TMB levels were measured using a next-generation sequencing assay. Based on receiver operating characteristic curve analysis, the TMB cutoff value was determined. RESULTS: A total 53 patients were analyzed. The TMB cutoff value for predicting the overall response rate (ORR) to PD-1 checkpoint inhibitors was defined as 13.31 mutations per megabase (mt/Mb) with 56% sensitivity and 95% specificity. Based on this definition, 7 (13.2%) patients were TMB-high (TMB-H). The ORR differed between the TMB-low (TMB-L) and TMB-H (8.7% vs. 71.4%, P=0.001). The progression-free survival and overall survival (OS) for 53 patients were 1.93 (95% confidence interval [CI], 1.600-2.268) and 4.26 months (95% CI, 2.992-5.532). The median OS was longer in the TMB-H (20.8 months; 95% CI, 2.292-39.281) than in the TMB-L (3.31 months; 95% CI, 1.604-5.019; P=0.049). CONCLUSIONS: The TMB cutoff value for predicting treatment response in AGC patients who received PD-1 checkpoint inhibitor monotherapy as salvage treatment was 13.31 mt/Mb. When applying the programmed death ligand-1 status to TMB-H, patients who would benefit from PD-1 checkpoint inhibitors can be selected.
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BACKGROUND/AIM: No standard treatment is currently recommended for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin. We aimed to evaluate the efficacy and safety of a pemetrexed and erlotinib combination in patients with BTC previously treated with gemcitabine. PATIENTS AND METHODS: This phase II, open-label, single-arm study enrolled patients with BTC who had previously failed gemcitabine-based first-line chemotherapy. Patients were treated with pemetrexed as a 500 mg/m2 intravenous infusion on day 1 for three weeks and erlotinib 100 mg daily until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR). RESULTS: The study enrolled 20 patients with BTC, including 12 (60%) with intrahepatic cholangiocarcinoma (IHCC), 3 (15%) with extrahepatic cholangiocarcinoma (EHCC), and 5 (25%) with gallbladder cancer (GBC). The ORR was 5%, and the disease control rate (DCR) was 55%. As of the cutoff point of March 31, 2023, the median progression-free survival (PFS) was 2.3 months [95% confidence interval (CI)=0.00-4.74] and the median overall survival (OS) was 5.6 months (95%CI=2.28-8.87). Patients with EHCC showed longer PFS and OS compared to patients with IHCC or GBC, but the differences were not significant. A baseline CEA greater than the upper normal limit was the only significant prognostic factor for a worse OS rate. The only treatment-related adverse event (TRAE) with severity grade ≥3 was anemia (5%). CONCLUSION: Salvage chemotherapy with pemetrexed plus erlotinib was well-tolerated and showed marginal clinical activity in BTC patients after failure to gemcitabine-based chemotherapy.