RESUMO
Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1+CD8+ T cells relative to that of PD-1+ regulatory T (Treg) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8+ T cells and Treg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1+CD8+ T cells and enhanced PD-1+ Treg cell-mediated immunosuppression. A profound reactivation of effector PD-1+CD8+ T cells rather than PD-1+ Treg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Antígenos/química , Antígenos/imunologia , Biomarcadores Tumorais , Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunomodulação , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/mortalidade , Peptídeos/química , Peptídeos/imunologia , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Resultado do Tratamento , Microambiente Tumoral/imunologiaRESUMO
Only a small percentage of patients afflicted with gastric cancer (GC) respond to immune checkpoint blockade (ICB). To study the mechanisms underlying this resistance, we examined the immune landscape of GC. A subset of these tumors was characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells. Genomic analyses revealed that these tumors bore mutations in RHOA that are known to drive tumor progression. RHOA mutations in cancer cells activated the PI3K-AKT-mTOR signaling pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. RHOA mutant tumors were resistant to PD-1 blockade but responded to combination of PD-1 blockade with inhibitors of the PI3K pathway or therapies targeting Treg cells. We propose that the metabolic advantage conferred by RHOA mutations enables Treg cell accumulation within GC tumors, generating an immunosuppressive TME that underlies resistance to ICB.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Gástricas/genética , Linfócitos T Reguladores/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Animais , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Quimiocina CXCL10/biossíntese , Quimiocina CXCL11/biossíntese , Ácidos Graxos não Esterificados/biossíntese , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/imunologiaRESUMO
Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole-transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin-18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD-L1). Concurrently, WTS was employed as part of the analyses in MONSTAR-SCREEN-2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD-L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC-positive patients treated with anti-HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression-free survival (ERBB2-high vs. -low: median 9.0 vs. 5.6 months, log-rank p = 0.046). IHC-based molecular profiling revealed significantly high expression of CLDN18 in RTK-negative patients, with 78.4% positive for either CLDN18 or PD-L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC-negative but WTS-positive status may benefit from specific biomarker-targeted therapies.
Assuntos
Biomarcadores Tumorais , Neoplasias Esofágicas , Junção Esofagogástrica , Imuno-Histoquímica , Receptor ErbB-2 , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Masculino , Feminino , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Pessoa de Meia-Idade , Idoso , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Junção Esofagogástrica/patologia , Junção Esofagogástrica/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Claudinas/genética , Claudinas/metabolismo , Adulto , Idoso de 80 Anos ou mais , Transcriptoma , Perfilação da Expressão Gênica/métodosRESUMO
Claudin-18.2 (CLDN18.2) expression evaluated by immunohistochemistry is a new biomarker for gastric and gastroesophageal junction adenocarcinomas that will soon have market authorization for implementation into routine clinical practice. Despite successful testing in the setting of clinical trials, no specific practical testing guidelines have been proposed. Several pre-analytical and analytical variables may interfere with adequate CLDN18.2 staining interpretation, thus this article provides practical guidance on CLDN18.2 testing and scoring in gastric/gastroesophageal junction adenocarcinomas in order to identify patients who may respond to targeted therapy with monoclonal antibodies directed against CLDN18.2. Based on available data, moderate to strong (2+/3+) membrane staining in ≥75% of adenocarcinoma cells is the proposed cut-off for clinical use of the monoclonal antibody anti-CLDN18.2 (zolbetuximab).
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Gastric cancers frequently harbor striking histological complexity and diversity between lesions as well as within single lesions, known as inter- and intratumoral heterogeneity, respectively. The latest World Health Organization Classification of Tumors designated more than 30 histological subtypes for gastric epithelial tumors, assigning 12 subtypes for gastric adenocarcinoma (GAD). Meanwhile, recent advances in genome-wide analyses have provided molecular aspects to the histological classification of GAD, and consequently revealed different molecular traits underlying these histological subtypes. Moreover, accumulating knowledge of comprehensive molecular profiles has led to establishing molecular classifications of GAD, which are often associated with clinical biomarkers for therapeutics and prognosis. However, most of our knowledge of GAD molecular profiles is based on inter-tumoral heterogeneity, and the molecular profiles underlying intratumoral heterogeneity are yet to be determined. In this review, recently established molecular classifications of GAD are introduced in the aspect of pathological diagnosis and are discussed in the context of intratumoral heterogeneity.
Assuntos
Adenocarcinoma , Biomarcadores Tumorais , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/classificação , Adenocarcinoma/patologia , Adenocarcinoma/genética , Adenocarcinoma/classificação , Biomarcadores Tumorais/genética , Heterogeneidade GenéticaRESUMO
BACKGROUND: The aim of this study was to investigate the prognostic impact of mismatch repair (MMR) status, programmed death-ligand 1 (PD-L1) expression, and Epstein-Barr virus (EBV) status in stage II/III gastric cancer after surgery. METHODS: This study included 679 patients diagnosed with pathological stage II/III gastric cancer who underwent curative gastrectomy followed by adjuvant chemotherapy (AC) or observation between 2007 and 2015. Clinical outcomes were retrospectively reviewed and compared with stratification by AC and other clinicopathological factors. RESULTS: Patients were divided into AC (n = 484) or surgery alone (SA; n = 195) groups and were further stratified by MMR and EBV status: MMR-deficient (DMMR) and MMR-proficient (PMMR) groups. Comparing the AC-DMMR group versus the AC-PMMR group, 5-year overall survival was 92.0% versus 74.0% (log-rank p < 0.01), and comparing the SA-DMMR group versus the SA-PMMR group, 5-year overall survival was 71.1% versus 73.7% (log-rank p = 0.89). DMMR (hazard ratio 0.25, 95% confidence interval 0.07-0.81) was identified as an independent prognostic factor in the AC group but not in the SA group. In the subgroup analysis, PD-L1-negative patients among the EBV-positive patients or in the DMMR group had a poor prognosis in both the AC and SA groups. The prognosis of the PMMR and EBV-negative patients was similar regardless of PD-L1 expression. CONCLUSIONS: DMMR was associated with a favorable prognosis in stage II/III gastric cancer after surgery and adjuvant therapy. PD-L1 expression may affect the prognosis of DMMR and EBV-positive gastric cancer.
Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Humanos , Antígeno B7-H1/metabolismo , Herpesvirus Humano 4/metabolismo , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Estudos Retrospectivos , Infecções por Vírus Epstein-Barr/complicações , Prognóstico , Reparo de Erro de Pareamento de DNARESUMO
BACKGROUND: This study aimed to identify patients with upper urinary tract urothelial carcinoma (UTUC) having potential Lynch syndrome (pLS) by immunohistochemistry (IHC) of DNA mismatch repair gene-related proteins (MMRPs) and Amsterdam criteria II and explore their clinical characteristics. METHODS: We retrospectively collected the clinical data of 150 consecutive patients with UTUC who underwent surgical resection at our institution between February 2012 and December 2020, and immunohistochemistry (IHC) of four MMRPs (MLH1, MSH2, MSH6, and PMS2) on all UTUC specimens was performed. Patients who tested positive for Amsterdam criteria (AMS) II and/or IHC screening were classified as having pLS and others as non-pLS, and their characteristics were explored. RESULTS: In this study, 5 (3%) and 6 (4%) patients were positive for AMS II and IHC screening, respectively. Two patient were positive for both AMS II and IHC screening, resulting in 9 (6%) patients with pLS. The pLS group was predominantly female (67% vs. 36%; p = 0.0093) and had more right-sided tumors (100% vs. 43%; p = 0.0009) than the non-pLS group. Of the 6 patients who were positive for IHC screening, 4 showed a combined loss of MSH2/MSH6 (n = 3) and MLH1/PMS2 (n = 1). Other two patients showed single loss of MSH6 and PSM2. CONCLUSIONS: AMS II and IHC screening identified pLS in 6% of patients with UTUC. The IHC screening-positive group tends to have relatively high rate of combined loss, but some patients have single loss. AMS II may overlook patients with LS, and a universal screening may be required for patients with UTUC as well as those with colorectal and endometrial cancer.
Assuntos
Carcinoma de Células de Transição , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Renais , Neoplasias Ureterais , Neoplasias da Bexiga Urinária , Sistema Urinário , Humanos , Feminino , Masculino , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/epidemiologia , Carcinoma de Células de Transição/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Estudos Retrospectivos , Prevalência , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Neoplasias Ureterais/diagnóstico , Neoplasias Ureterais/epidemiologia , Sistema Urinário/metabolismo , Sistema Urinário/patologia , Reparo de Erro de Pareamento de DNARESUMO
Rapid advances are being made in cancer drug therapy. Since molecularly targeted therapy has been introduced, personalized medicine is being practiced, pathological tissue from malignant tumors obtained during routine practice is frequently used for genomic testing. Whereas cytological specimens fixed mainly in alcohol are considered to be more advantageous in terms of preservation of the nucleic acid quality and quantity. This article is aimed to share the information for the proper handling of cytological specimens in practice for genomic medicine based on the findings established in "Guidelines for Handling of Cytological Specimens in Cancer Genomic Medicine (in Japanese)" published by the Japanese Society of Clinical Cytology in 2021. The three-part practical guidelines are based on empirical data analyses; Part 1 describes general remarks on the use of cytological specimens in cancer genomic medicine, then Part 2 describes proper handling of cytological specimens, and Part 3 describes the empirical data related to handling of cytological specimens. The guidelines indicated proper handling of specimens in each fixation, preparation, and evaluation.
Assuntos
Medicina Genômica , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/patologia , Citodiagnóstico , Manejo de EspécimesRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is associated with very poor prognoses. Therefore, new therapies and preclinical models are urgently needed. In the present study, we sought to develop more realistic experimental models for use in PDA research. METHODS: We developed patient-derived xenografts (PDXs), established PDX-derived cell lines (PDCLs), and generated cell line-derived xenografts (CDXs), which we integrated to create 13 matched "trios" - i.e., patient-derived tumor models of PDA. We then compared and contrasted histological and molecular alterations between these three model systems. RESULTS: Orthotopic implantation (OI) of the PDCLs resulted in tumorigenesis and metastases to the liver and peritoneum. Morphological comparisons of OI-CDXs and OI-PDXs with passaged tumors revealed that the histopathological features of the original tumor were maintained in both models. Molecular alterations in PDX tumors (including those to KRAS, TP53, SMAD4, and CDKN2A) were similar to those in the respective PDCLs and CDX tumors. When gene expression levels in the PDCLs, ectopic tumors, and OI tumors were compared, the distant metastasis-promoting gene CXCR4 was specifically upregulated in OI tumors, whose immunohistochemical profiles suggested epithelial-mesenchymal transition and adeno-squamous trans-differentiation. CONCLUSION: These patient-derived tumor models provide useful tools for monitoring responses to antineoplastic agents and for studying PDA biology.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Humanos , Neoplasias Pancreáticas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias PancreáticasRESUMO
BACKGROUND: Although several randomized trials (RCTs) showed survival benefits of immune checkpoint inhibitor (ICI) plus first-line chemotherapy for advanced gastric or gastroesophageal cancer (AGC), these trials could enroll patients who fulfilled the strict eligibility criteria or waited for certain screening period for central assessment of PD-L1 status. METHODS: We retrospectively compared characteristics and clinical outcomes of the patients with AGC who received first-line chemotherapy in control arm of RCTs with ICIs (control group) or clinical practice (practice group) at our institution from February 2016 to April 2019. RESULTS: The control group had a better baseline Eastern Cooperative Oncology Group performance status (PS0, 81.2% vs. 51.4%, p < 0.001) and a longer interval from first visit to first-line chemotherapy initiation (19 days vs. 9 days, p < 0.001) than the practice group. Median overall survival (OS) was 20.3 months in control group and 15.7 months in practice group, with a trend of longer OS in control group than that in practice group (hazard ratio, 0.71; p = 0.062). More patients in control group were treated with subsequent chemotherapy including ICIs. CONCLUSION: Patients with AGC in RCTs of ICIs had a better PS or a higher chance to receive subsequent chemotherapy, resulting in a better prognosis than those treated in clinical practice. This information should be considered when interpreting RCT results and applying new treatments into clinical practice.
Assuntos
Neoplasias Pulmonares , Neoplasias Gástricas , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Prognóstico , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Microsatellite instability-high (MSI-H) is an important biomarker for predicting the effect of immune-checkpoint inhibitors (ICIs) on advanced solid tumors. MSI-H is detected in various cancers, but its frequency varies by cancer type and stage. Therefore, precise frequency is required to plan ICIs therapy. In this study, the results of MSI test actually conducted in clinical practice were investigated. In total, 26,469 samples of various cancers were examined to determine if PD-1 blockade was indicated between December 2018 to November 2019. The results of MSI test were obtained for 26,237 (99.1%) among them. The male to female ratio was 51:49 and mean age was 64.3 years. In all the samples, overall frequency of MSI-H was 3.72%. By gender, the frequency of MSI-H was higher in female patients (4.75%) than in male patients (2.62%) (P < 0.001). A comparison by age revealed that the frequency of MSI-H was significantly higher in patients aged less than 40 years (6.12%) and 80 years or older (5.77%) than in patients aged between 60 and 79 years (3.09%) (P < 0.001). MSI-H was detected in 30 cancer types. Common cancer types were endometrial cancer, 16.85%; small intestinal cancer, 8.63%; gastric cancer, 6.74%; duodenal cancer, 5.60%; and colorectal cancer, 3.78%. MSI-H was detected in cancer derived from a wide variety of organs. The frequency of MSI-H varied by cancer types and onset age. These data should prove especially useful when considering ICI treatment. Supporting Information.
RESUMO
Microsatellite instability-high (MSI-H) is an important biomarker for predicting the effect of immune checkpoint inhibitors (ICIs) on advanced solid tumors. Microsatellite instability-high is detected in various cancers, but its frequency varies by cancer type and stage. Therefore, precise frequency is required to plan ICI therapy. In this study, the results of MSI tests actually carried out in clinical practice were investigated. In total, 26 469 samples of various cancers were examined between December 2018 and November 2019 to determine whether programmed cell death-1 blockade was indicated. The results of MSI tests were obtained for 26 237 (99.1%) of these samples. The male : female ratio was 51:49 and mean age was 64.3 years. In all samples, the overall frequency of MSI-H was 3.72%. By gender, the frequency of MSI-H was higher in female patients (4.75%) than in male patients (2.62%; P < .001). A comparison by age revealed that the frequency of MSI-H was significantly higher in patients younger than 40 years of age (6.12%) and 80 years or older (5.77%) than in patients aged between 60 and 79 years (3.09%; P < .001). Microsatellite instability-high was detected in 30 cancer types. Common cancer types were: endometrial cancer, 16.85%; small intestinal cancer, 8.63%; gastric cancer, 6.74%; duodenal cancer, 5.60%; and colorectal cancer, 3.78%. Microsatellite instability-high was detected in cancer derived from a wide variety of organs. The frequency of MSI-H varied by cancer type and onset age. These data should prove especially useful when considering ICI treatment.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Checkpoint Imunológico/farmacologia , Instabilidade de Microssatélites , Neoplasias/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Estudos de Coortes , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Fatores de Risco , Fatores Sexuais , Adulto JovemRESUMO
The use of patient-derived xenografts (PDXs) has recently attracted attention as a drug discovery platform with a high predictive clinical efficacy and a preserved tumor heterogeneity. Given the racial differences in genetic variations, it would be desirable to establish a PDX library from Japanese cancer patients on a large scale. We thus tried to construct the Japanese PDX (J-PDX) library with a detailed clinical information for further clinical utilization. Between August 2018 and May 2020, a total of 1126 cancer specimens from 1079 patients were obtained at the National Cancer Center Hospital and National Cancer Center Hospital East, Japan, and were immediately transplanted to immunodeficient mice at the National Cancer Center Research Institute. A total of 298 cross-cancer PDXs were successfully established. The time to engraftment varied greatly by cancer subtypes, especially in the first passage. The engraftment rate was strongly affected by the clinical stage and survival time of the original patients. Approximately 1 year was needed from tumor collection to the time when coclinical trials were conducted to test the clinical utility. The 1-year survival rates of the patients who were involved in establishing the PDX differed significantly, from 95.6% for colorectal cancer to 56.3% for lung cancer. The J-PDX library consisting of a wide range of cancer subtypes has been successfully established as a platform for drug discovery and development in Japan. When conducting coclinical trials, it is necessary to consider the target cancer type, stage, and engraftment rate in light of this report.
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Neoplasias/mortalidade , Neoplasias/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Pré-Escolar , Feminino , Humanos , Japão/etnologia , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Transplante de Neoplasias , Especificidade de Órgãos , Modelagem Computacional Específica para o Paciente , Adulto JovemRESUMO
Somatic mutations in human epidermal growth factor receptor 2 (HER2) are present in approximately 3% of breast cancers. Some HER2 mutations are activating, and they represent a mechanism of resistance to conventional anti-HER2 therapies such as trastuzumab and lapatinib. Consistently, in patients with HER2-amplified breast cancer, these mutations are predominantly observed in metastatic tumors obtained after exposure to anti-HER2 systemic therapies, possibly after clonal selection. Therefore, it is rare to find coexistent HER2 mutation and amplification in the early clinical course, and thus, the clinical relevance of HER2 mutation to the sensitivity to HER2-targeted drugs, particularly antibody-drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and the recently approved fam-trastuzumab deruxtecan (T-DXd), remains unclear. In this article, we describe a patient with de novo metastatic breast cancer who exhibited both HER2 amplification and the L755S mutation in the untreated primary breast tumor obtained at the initial diagnosis, and the lesion responded to T-DM1 and T-DXd after exhibiting clinical resistance to other HER2-targeted drugs. Our current case findings suggested that anti-HER2 ADCs should be prioritized over conventional trastuzumab- or lapatinib-based therapies for patients with HER2-amplified and comutated tumors. KEY POINTS: Although HER2 mutations were implicated in resistance to anti-HER2 monoclonal antibodies or HER2 tyrosine kinase inhibitors in preclinical studies, their clinical impact on sensitivity to anti-HER2 drugs is unclear owing to the rarity of concomitant HER2 mutation and HER2 amplification. A case of de novo metastatic breast cancer harboring both HER2 amplification and the L755S mutation in an untreated breast primary tumor displayed clinical resistance to standard trastuzumab- or lapatinib-based therapies but good responses to ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd). Anti-HER2 antibody-drug conjugates such as T-DM1 and T-DXd may be prioritized over conventional trastuzumab- or lapatinib-containing therapies for patients with HER2-amplified and comutated tumors.
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Neoplasias da Mama , Imunoconjugados , Ado-Trastuzumab Emtansina , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Camptotecina/análogos & derivados , Feminino , Humanos , Mutação , TrastuzumabRESUMO
Biliary tract cancer (BTC) is an aggressive cancer with a poor prognosis partially due to the limited success in developing novel therapies, including molecularly targeted therapies and immunotherapies. Programmed cell death-1 (PD-1) blockade therapy is less effective against BTCs, necessitating further studies to understand the detailed immunological status of the tumor microenvironment (TME) in BTC. Here, we examined the immunological status of the TME in 37 BTCs with early- to late-stage disease, especially focusing on PD-1+CD8+ T cells. PD-1+CD8+ T cells, which are reportedly associated with the clinical response to PD-1 blockade therapy, were frequently observed in early-stage BTC and decreased with disease progression. Imaging mass cytometry for representative PD-1+CD8+TIL-high and -low patients demonstrated that tumor-infiltrating PD-1+CD8+ T cells were localized adjacent to tumor cells, whereas PD-1-CD8+ T cells were detected mainly in the stroma of the TME. In a mouse model, PD-1 expression by tumor-infiltrating CD8+ T cells was higher in smaller tumors and decreased with tumor growth. Consequently, large tumors became resistant to PD-1 blockade, while small tumors containing higher numbers of PD-1+CD8+ T cells were sensitive. We propose the important role of tumor-infiltrating PD-1+CD8+ T cells in anti-tumor immunity and the potential application of PD-1 blockade therapy for early-stage BTC.
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Neoplasias do Sistema Biliar/imunologia , Neoplasias do Sistema Biliar/terapia , Linfócitos T CD8-Positivos/imunologia , Imunoterapia , Neoplasias Experimentais/imunologia , Receptor de Morte Celular Programada 1/imunologia , Idoso , Idoso de 80 Anos ou mais , Animais , Neoplasias do Sistema Biliar/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Cancer progression following chemotherapy is a significant barrier to effective cancer treatment. We aimed to evaluate the role of drug-exposed cancer-associated fibroblasts (CAFs) in the growth and progression of drug-exposed gastric cancer (GC) cells and to explore the underlying molecular mechanism. METHODS: The human GC cell line 44As3 and CAFs were treated with 5-fluorouracil and oxaliplatin (5FU + OX). 5FU + OX-pretreated 44As3 cells were then cultured in a conditioned medium (CM) from 5FU + OX-pretreated CAFs, and the growth and migration/invasion ability of the cells were evaluated. We also compared the clinicopathological characteristics of the GC patients treated with S1 + OX in accordance with the properties of their resected specimens, focusing on the number of CAFs. Changes in gene expression in CAFs and 44As3 cells were comprehensively analyzed using RNA-seq analysis. RESULTS: The CM from 5FU + OX-pretreated CAFs promoted the migration and invasion of 5FU + OX-pretreated 44As3 cells. Although the number of cases was relatively small (n = 21), the frequency of positive cases of lymphovascular invasion and the recurrence rate were significantly higher in those with more residual CAF. RNA-seq analysis revealed 5FU + OX-pretreated CAF-derived glycoprotein 130 (gp130) as a candidate factor contributing to the increased migration of 5FU + OX-pretreated 44As3 cells. Administration of the gp130 inhibitor SC144 prevented the increased migration ability of 5FU + OX-pretreated 44As3 cells owing to drug-treated CAFs. CONCLUSIONS: Our findings provide evidence regarding the interactions between GC cells and CAFs in the tumor microenvironment following chemotherapy, suggesting that ligands for gp130 may be novel therapeutic targets for suppressing or preventing metastasis in GC.
Assuntos
Fibroblastos Associados a Câncer/efeitos dos fármacos , Fluoruracila/administração & dosagem , Oxaliplatina/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Hidrazinas/administração & dosagem , Morfolinas/antagonistas & inibidores , Quinoxalinas/administração & dosagem , Estômago/citologia , Estômago/patologiaRESUMO
BACKGROUND: Perioperative treatment is an accepted standard approach for treating locally advanced gastric cancer (LAGC). Histopathological tumor regression with < 10% residual tumor is a globally accepted prognosticator in LAGC patients who received neoadjuvant chemotherapy (NAC) and curative surgery. However, despite a response of the primary tumor, a significant percentage of patients dies from recurrence and identification of those at risk for relapse remains challenging. We re-estimated the value of histopathological tumor regression as a prognosticator alongside other factors, especially posttherapy topographical nodal status, ypN-site. PATIENTS AND METHODS: Individual patient data including clinicopathological variables were used from the four JCOG trials investigating NAC (JCOG0001, JCOG0002, JCOG0210, JCOG0405) for analyzing prognosticators in patients with curative surgery excluding those with type 4 AGC by univariable and multivariable Cox regression analyses. RESULTS: Among 85 patients, 5-year overall survival (OS) was 46.0% [95% confidence interval (CI) 35.0-56.4] with a median follow-up of 3.2 years. On univariable analysis, histopathological tumor regression with ≥ 10% residual tumor and ypN-site 2-3 were negatively associated with OS [≥ 10% residual tumor: hazard ratio (HR) 2.60; 95% CI 1.22-5.54; P = 0.014; ypN2-3: HR 3.59; 95% CI 1.60-8.06; P = 0.002). On multivariable analysis, only ypN-site 2-3 was predictive of OS (HR 3.67; 95% CI 1.55-8.69; P = 0.003), whereas histopathological tumor regression with ≥ 10% residual tumor was not (HR 2.24; 95% CI 0.98-5.10; P = 0.055). CONCLUSIONS: ypN-site may have greater impact on OS than histopathological tumor regression in patients who received NAC plus surgery for non-type 4 LAGC.
Assuntos
Quimioterapia Adjuvante/mortalidade , Gastrectomia/mortalidade , Terapia Neoadjuvante/mortalidade , Neoplasia Residual/patologia , Neoplasias Gástricas/patologia , Adulto , Idoso , Ensaios Clínicos Fase II como Assunto , Feminino , Gastrectomia/métodos , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/mortalidade , Período Pós-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Estômago/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/terapia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Insufficient information is available about the long-term outcomes of patients with Siewert type II adenocarcinoma of the esophagogastric junction (AEG) who undergo laparoscopic transhiatal approach (LTH). Here we evaluated the oncological safety of LTH for patients with Siewert type II AEG compared with the open transhiatal approach (OTH). METHODS: Subjects included 79 patients with Siewert type II AEG who underwent gastrectomy combined with lower esophagectomy from 2008 to 2018 at our institution. Overall survival (OS), recurrence-free survival (RFS), status of adjuvant chemotherapy, late-phase complications, and recurrence patterns were compared between the OTH (n = 29) and LTH groups (n = 43). RESULTS: The median observation periods were 60 months (6-120 months) and 36 months (1-88) for the OTH and LTH groups, respectively. The 5-year OS rates were significantly different: 74% (95% CI 71-77%) and 98% (95% CI 97-99) in the OTH and LTH groups (HR 0.10, 95% CI 0.01-0.83), respectively, though the OTH group included more patients with advanced disease. After stratification, according to pathological stage to adjust for selection bias, the 5-year OS and RFS rates were longer, but not significantly different among patients in the LTH group with pStage III (HR 0.42, 95% CI 0.05-3.47; HR 0.47, 95% CI 0.10-2.12, respectively). Recurrence patterns were similar in the both groups. CONCLUSIONS: Long-term outcomes of the LTH group were not inferior to those of the OTH group, suggesting the possibility of LTH as a treatment option for selected patients with Siewert type II AEG.
Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Junção Esofagogástrica/patologia , Junção Esofagogástrica/cirurgia , Laparoscopia/métodos , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Gastric mesenchymal tumors are relatively rare, and their molecular pathogeneses are poorly understood, except for gastrointestinal stromal tumor, desmoid, and inflammatory myofibroblastic tumors. We report a case of a gastric mesenchymal tumor with prominent smooth muscle cell differentiation and an echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion. On gross section, the tumor was 26 mm at the largest diameter, well-circumscribed, and located in the submucosal and muscular layers of the stomach wall. Histologically, the tumor comprised intersecting fascicles of spindle cells, non-atypical nuclei, and highly eosinophilic cytoplasm. Myxoid changes were observed focally, but inflammatory infiltrates were only evident in limited areas. Immunochemical staining revealed that the tumor was positive for α-smooth muscle actin and desmin. Diffuse positive staining for h-caldesmon was observed throughout the tumor, which suggested smooth muscle cell differentiation. Intracytoplasmic staining for ALK protein was also observed, and fluorescence in situ hybridization using ALK break-apart probes showed split chromosomal signals. RNA-sequencing analysis identified EML4-ALK fusion transcripts. We concluded that the tumor was a gastric mesenchymal tumor with smooth muscle differentiation based on its distinct differential smooth muscle properties, such as highly eosinophilic cytoplasm and diffuse expression of h-caldesmon. Furthermore, activated ALK may underly the tumor's pathogenesis.
Assuntos
Biomarcadores Tumorais/metabolismo , Leiomioma/diagnóstico , Músculo Liso/patologia , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias Gástricas/diagnóstico , Idoso , Diferenciação Celular , Feminino , Humanos , Leiomioma/metabolismo , Leiomioma/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologiaRESUMO
This study aims to determine the correlation between the percent viable tumor cells (%VTC) and the tumor microenvironment in resected non-small cell lung cancer after induction therapy. We enrolled 72 patients with non-small cell lung cancer (NSCLC) who received chemoradiotherapy (CRT) or chemotherapy (CT) prior to surgery. The ratio of the area of viable tumor cells to the total tumor area was calculated to obtain the %VTC. We also examined the number of CD4 (+), CD8 (+), CD20 (+) and FOXP3 (+) tumor-infiltrating lymphocytes (TILs), podoplanin (PDPN) (+) cancer-associated fibroblasts (CAFs), and CD204 (+) tumor-associated macrophages (TAMs) by immunohistochemistry (IHC). In the CRT group (n = 37), the tumors had significantly lower %VTC than the CT group (n = 35) (P < 0.001). In both of the CT group and CRT group, the %VTC showed a significant positive correlation with the number of CD204 (+)-TAMs (P = 0.014 and 0.005, respectively). Only in the CRT group, a higher number of CD204 (+) TAMs was associated with a shorter overall survival (OS) (P = 0.007) and recurrence-free survival (RFS) (P = 0.015). In the CRT group, the number of CD204 (+) TAMs is associated with %VTC and prognosis, suggesting that these cells may have tumor-promoting effects on the residual lung cancer in specific microenvironments after CRT.