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BACKGROUND: HER2-low populations constitute a heterogeneous group, and the cytotoxic anticancer agent efficacy based on HER2 status remains unclear. This study evaluated the clinicopathological features and outcomes of patients with advanced breast cancer showing HER2-low expression treated with eribulin or capecitabine, two treatment options after anthracycline and taxane treatment. METHODS: We retrospectively evaluated patients who were treated with eribulin or capecitabine between 2011 and 2015. HER2 status was evaluated according to the ASCO/CAP guidelines. RESULTS: No significant difference was observed in overall survival (OS; eribulin: hazard ratio [HR], 0.66; 95% CI 0.40-1.10; capecitabine: HR, 0.76; 95% CI 0.45-1.30) or progression-free survival (PFS; eribulin: HR, 1.13; 95% CI 0.72-1.78; capecitabine: HR, 0.90; 95% CI 0.56-1.44) between patients receiving eribulin (HER2-null: 35, HER2-low: 44) and those receiving capecitabine (HER2-null: 41, HER2-low: 33). Subgroup analysis revealed no significant differences in OS between the two groups in the hormone-positive and -negative populations for eribulin and capecitabine. HER2-null and HER2-low patients showed objective response rates (ORRs) of 22.5% and 9.1% (p = 0.09) overall, and 32.0% and 10.5% (p = 0.03), respectively, in hormone-positive cases among eribulin-treated patients. No response was observed in hormone-negative patients. Capecitabine treatment in HER2-null and HER2-low patients had overall ORRs of 26.8% and 15.2% (p = 0.23), respectively, with 27.3% and 16.1% (p = 0.28) for hormone-positive cases; and 25.0% and 0% (p = 1.0), respectively, for hormone-negative cases. CONCLUSIONS: Eribulin and capecitabine sensitivity may vary based on HER2 expression in patients with HER2-low and HER2-null breast cancer. Prognosis was similar between the HER2-low and the HER2-null groups.
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Aim: To understand the real-world use of abemaciclib in Japanese patients with early breast cancer (EBC). Methods: This retrospective observational study was conducted using a Japanese administrative claims database in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative EBC who received abemaciclib adjuvant therapy from December 2021-March 2023. Patient characteristics and treatment patterns were summarized. Results: Among 374 patients, 38.2, 51.6 and 63.4% patients received neoadjuvant chemotherapy, adjuvant chemotherapy and radiotherapy, respectively; 13.1% were chemotherapy naive. Tamoxifen (37.7%), letrozole (35.6%), anastrozole (24.3%) were the commonly prescribed concomitant adjuvant endocrine therapies. Abemaciclib dose reductions were observed in 42.0% patients. Conclusion: Use of abemaciclib for treatment of high-risk EBC was described, which could help inform patient selection and treatment patterns.
Abemaciclib (150 mg twice daily) is prescribed with hormonal therapy for the treatment of early breast cancer (EBC) with high risk of recurrence. We used a big database from Japan that has anonymized information about 44 million patients from 480 hospitals. We aim to describe the characteristics of patients with EBC who receive abemaciclib and their treatment patterns in Japan.We included 374 patients with EBC who had breast cancer surgery and were prescribed abemaciclib with hormonal therapy between December 2021 and March 2023. The median age of patients is 54 years, almost all (99.2%) are female. The most commonly prescribed hormonal therapy with abemaciclib is tamoxifen (37.7%), letrozole (35.6%) and anastrozole (24.3%).Of the 374 patients who were prescribed abemaciclib, 38.2% patients received chemotherapy before surgery, 51.6% received chemotherapy after surgery and 63.4% received radiation therapy after surgery; whereas, 13.1% received no perioperative chemotherapy before abemaciclib therapy. Around 42% of patients reduced their dose from starting dose of abemaciclib. Higher proportion of older patients and patients with low body weight, had dose reduction. Majority of the patients are prescribed either an antidiarrheal agent or probiotic within a day of starting abemaciclib.This is the first study describing patient characteristics and treatment patterns of Japanese patients who are prescribed abemaciclib in the clinical practice. The results will help understand who can benefit from abemaciclib, and to choose the most appropriate patients to receive abemaciclib for the treatment of EBC.
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Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare endocrine malignancies with limited effective treatment options. The association between the tumor microenvironment (TME) with somatostatin receptor 2 (SSTR2) and hypoxia-induced factor-2α (HIF-2α) in PPGLs, critical for optimizing combination therapeutic strategies with immunotherapy, remains largely unexplored. To evaluate the association of SSTR2 and HIF-2α immunoreactivity with the TME in patients with PPGLs, we analyzed the expression of SSTR2A, HIF-2α, and TME components, including tumor-infiltrating lymphocytes (CD4 and CD8), tumor-associated macrophages (CD68 and CD163), and PD-L1, using immunohistochemistry in patients with PPGLs. The primary outcome was to determine the association of the immune profiles with SSTR2A and HIF-2α expression. Among 45 patients with PPGLs, SSTR2A and HIF2α were positively expressed in 21 (46.7%) and 14 (31.1%) patients, respectively. The median PD-L1 immunohistochemical score (IHS) was 2.0 (interquartile range: 0-30.0). Positive correlations were observed between CD4, CD8, CD68, and CD163 levels. A negative correlation was found between the CD163/CD68 ratio (an indicator of M2 polarization) and SSTR2A expression (r = -0.385, p = 0.006). HIF-2α expression showed a positive correlation with PD-L1 IHS (r = 0.348, p = 0.013). The co-expression of PD-L1 (HIS > 10) and HIF-2α was found in seven patients (15.6%). No associations were observed between SDHB staining results and the CD163/CD68 ratio, PD-L1, or SSTR2A expression. Our data suggest the potential of combination therapy with immunotherapy and peptide receptor radionuclide therapy or HIF-2α inhibitors as a treatment option in selected PPGL populations.
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Folate receptor α (FRα) is a cell-surface protein and an attractive target for cancer treatment. We investigated the association between FRα expression and the tumor immune microenvironment in patients with cervical cancer. We examined whole tumor sections of 123 patients with cervical cancer: 67 and 56 sections of squamous cell carcinoma (SCC) and non-SCC, respectively. FRα expression was assessed using immunohistochemical staining with the anti-FRα monoclonal antibody clone 26B3. Programmed death-ligand 1 (PD-L1) expression was assessed using a combined positive score (CPS). The intratumoral CD3 and CD8 cell densities were calculated as the average number of positive cells in five independent areas. FRα-positivity was identified in 72.4% of the patients, and it differed by histology (SCC vs. non-SCC; 55.2% vs. 92.9%, P<0.001). PD-L1 status was positive (CPS ≥1) in 75.6% and was more commonly expressed in patients with SCC (SCC vs. non-SCC; 83.5% vs. 66.1%, P=0.02). FRα expression had a weak correlation with PD-L1 expression (r=-0.22, P<0.001) and CD8-positive cells (r=-0.19, P=0.03). FRα-positivity was more frequently observed in the PD-L1 CPS <10 group than in the PD-L1 CPS ≥10 group (81% vs. 64%, P=0.03). FRα-high was significantly associated with poor prognosis, especially in the PD-L1 CPS ≥10 groups (hazard ratio: 4.10, 95% confidence interval: 1.39-12.06, P=0.01). In conclusion, FRα expression was higher in patients with cervical cancer and PD-L1 CPS <10 than in those with CPS ≥10. Targeting FRα expression may be a potential therapeutic strategy for cervical cancer patients with low or negative PD-L1 expression.
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Histological diagnosis of sarcomas (malignant bone and soft tissue tumors) is challenging due to their rarity, morphological diversity, and constantly evolving diagnostic criteria. In this study, we aimed to assess the concordance in histological diagnosis of bone and soft tissue tumors between referring hospitals and a tertiary sarcoma center and analyzed the clinical impact of the diagnostic alteration. We analyzed 628 consecutively accessioned specimens from 624 patients who visited a specialized sarcoma center for treatment. The diagnoses at referring hospitals and those at the sarcoma center were compared and classified into four categories: agreed, disagreed, specified, and de-specified. Of the 628 specimens, the diagnoses agreed in 403 (64.2%) specimens, whereas some changes were made in 225 (35.8%) specimens: disagreed in 153 (24.3%), specified in 52 (8.3%), and de-specified in 20 (3.2%) cases. The benign/intermediate/malignant judgment changed for 92 cases (14.6%). The diagnostic change resulted in patient management modification in 91 cases (14.5%), including surgical and medical treatment changes. The main inferred reason for the diagnostic discrepancies was a different interpretation of morphological findings of the tumor, which accounted for 48.9% of the cases. This was followed by the unavailability of specialized immunohistochemical antibodies and the unavailability of genetic analysis. In summary, our study clarified the actual clinical impact of diagnostic discrepancy in bone and soft tissue tumors. This may underscore the value of pathology consultation, facilitating access to specialized diagnostic tools, and continued education. These measures are expected to improve diagnostic precision and ultimately benefit patients.
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Neoplasias Óseas , Derivación y Consulta , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/diagnóstico , Sarcoma/patología , Sarcoma/diagnóstico , Masculino , Femenino , Neoplasias Óseas/patología , Neoplasias Óseas/diagnóstico , Persona de Mediana Edad , Adulto , Anciano , Adolescente , Adulto Joven , Niño , Anciano de 80 o más Años , Errores Diagnósticos , Centros de Atención Terciaria , PreescolarRESUMEN
OBJECTIVE: Trophoblast Cell Surface Antigen 2 (Trop-2) is a transmembrane glycoprotein that is overexpressed in various cancers, with immunological significance as a target for tumor-reactive T-cells. We aimed to investigate the association between the expression of Trop-2 and the tumor immune microenvironment in cervical cancer. METHODS: The study included 123 patients with cervical cancer who underwent primary surgery between 2000 and 2020 in our hospital. Trop-2 expression was evaluated using anti-Trop-2 monoclonal antibody clone MAB650. Immune biomarkers, including PD-L1 (22C3), CD3 (PS1), and CD8 (4B11), were also evaluated. Trop-2 and PD-L1 positivity were defined by an H-score ≥ 10 and a combined positive score (CPS) ≥1, respectively. Tumor-infiltrating lymphocytes (TILs) were assessed in the five selected independent areas. The correlation between Trop-2 expression and immune biomarkers was analyzed. RESULTS: The cohort comprised patients with squamous cell carcinoma (SCC) (54.5%) and non-SCC (45.5%). Trop-2 was positive in 84.6% of samples and more commonly expressed in SCC (SCC vs. non-SCC; 97.0% vs. 69.6%, p < 0.001). Intratumoral CD3+ and CD8 + TILs were significantly more common in Trop-2-positive cases (CD3, Mann-Whitney U = 383, p < 0.0001; CD8, U = 442, p < 0.0001). Additionally, significant positive correlations were found between the Trop-2 H-score and immune markers (CD3 + TILs, r = 0.295, p < 0.001; CD8 + TILs, r = 0.267, p = 0.001; PD-L1 CPS, r = 0.178, p = 0.025). No significant associations were detected between TILs and other clinicopathological features, including prognosis. CONCLUSION: Expression of Trop-2 in cervical cancer is associated with increased levels of intratumoral TILs, indicating the potential of Trop-2 targeted therapy alone or in combination with immune checkpoint inhibitors.
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Antígenos de Neoplasias , Moléculas de Adhesión Celular , Linfocitos Infiltrantes de Tumor , Microambiente Tumoral , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patología , Microambiente Tumoral/inmunología , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/biosíntesis , Persona de Mediana Edad , Antígenos de Neoplasias/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Adulto , Anciano , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Antígeno B7-H1/inmunología , Antígeno B7-H1/biosíntesis , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismoRESUMEN
OBJECTIVE: The efficacy of pembrolizumab in patients with microsatellite instability (MSI)-high cancers has been reported; however, the differences in efficacy according to the subtypes of MSI-high endometrial cancers (ECs) remain unclear. MSI-high ECs are classified into at least 3 groups based on their molecular characteristics: MLH1 hypermethylated, Lynch-like syndrome (LLS)-associated, and Lynch syndrome (LS)-associated cancers. This study aimed to investigate whether the efficacy of pembrolizumab differs among these 3 groups, and if so, whether EPM2AIP1 immunohistochemistry (IHC), which correlates with MLH1 promoter methylation, can be used to rule out MLH1 methylation cases. METHODS: This study included 12 patients with MSI-high EC who received pembrolizumab treatment. Patients were categorized into 3 groups based on MLH1 methylation analysis and the Amsterdam Criteria: MLH1 hypermethylated (sporadic [SP]), LLS-associated, and LS-associated. Patients' medical records were retrospectively reviewed, and the efficacy of treatment was evaluated based on the response rate using the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: The overall response rate was 75% (3/4) in the SP group, while it was 100% including one complete response patient in the LLS-associated and the LS-associated group, respectively. The sensitivity and positive predictive value of EPM2AIP1 IHC for MLH1 methylation were 100% and 66.7%, respectively. CONCLUSION: Pembrolizumab may be more effective in LLS and LS-associated groups. EPM2AIP1 IHC was less predictive than MLH1 methylation analysis; however, it may be useful for ruling out MLH1 methylation cases due to its high sensitivity. Further studies are needed to determine whether EPM2AIP1 IHC can predict pembrolizumab efficacy.
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Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. Exposure: TIL abundance in breast tissue from resected primary tumors. Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.
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Linfocitos Infiltrantes de Tumor , Neoplasias de la Mama Triple Negativas , Adulto , Humanos , Persona de Mediana Edad , Adyuvantes Inmunológicos , Colombia Británica , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Estudios Retrospectivos , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/mortalidad , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/terapiaRESUMEN
BACKGROUND/AIM: Trabectedin is used as a treatment for advanced-stage soft tissue sarcomas (STSs), particularly liposarcoma and leiomyosarcoma. Aside from its direct effect on tumor cells, trabectedin can affect the immune system in the tumor microenvironment. This study aimed to evaluate whether inflammatory biomarkers predict trabectedin efficacy in STSs. PATIENTS AND METHODS: We retrospectively reviewed the clinical features and outcomes of patients with STS treated with trabectedin at our institution between 2016 and 2020. The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation response index (SIRI=neutrophil × monocyte/lymphocyte) were calculated based on the blood samples obtained prior to trabectedin treatment initiation. Analyses of overall survival (OS) and progression-free survival (PFS) were performed according to various factors. RESULTS: Of the 101 patients identified, 54 had L-sarcoma (leiomyosarcoma: 30; liposarcoma: 24), and 47 had other types of STSs. Elevated SIRI, NLR, PLR, LMR, and C-reactive protein (CRP) were associated with worse PFS (p<0.001, p=0.008, p=0.027, p=0.013, and p<0.001, respectively) according to the results of the univariate analysis. Multivariate analysis showed that elevated SIRI, other histology, and CRP were associated with poor PFS (p=0.007, p=0.008, and p=0.029, respectively). In addition, the multivariate analysis of OS showed that SIRI was an independent prognostic factor (hazard ratio=2.16, p=0.006). CONCLUSION: Pretreatment SIRI can be considered a biomarker for the prognostic prediction of patients with STS treated with trabectedin.
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Sarcoma , Trabectedina , Humanos , Trabectedina/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Sarcoma/sangre , Adulto , Estudios Retrospectivos , Antineoplásicos Alquilantes/uso terapéutico , Biomarcadores de Tumor/sangre , Anciano de 80 o más Años , Linfocitos/patología , Inflamación/tratamiento farmacológico , Inflamación/sangre , Inflamación/patología , Neutrófilos/patología , Pronóstico , Adulto Joven , Supervivencia sin Progresión , Monocitos/patología , Resultado del Tratamiento , Liposarcoma/tratamiento farmacológico , Liposarcoma/patología , Liposarcoma/sangreRESUMEN
BACKGROUND: Skeletal-related events (SREs), including the pathological fracture, surgical treatment or radiation of bone lesions, malignant spinal cord compression, hypercalcemia, are important considerations when managing metastatic bone tumors; however, owing to their rarity, the incidence of SREs in patients with Ewing sarcoma remains unknown. METHODS: We retrospectively reviewed the clinical data from 146 patients with Ewing sarcoma treated at a single institution from 2005 to 2019. The median age at diagnosis was 22.7 years. Fifty patients (34.2%) had metastatic disease at diagnosis. The primary outcome was the SRE-free rate among patients with Ewing sarcoma. Moreover, we identified the risk factors for SREs using univariate or multivariate analyses. RESULTS: During the observational period (median, 2.6 years), SREs occurred in 23 patients. Radiation to the bone, malignant spinal cord compression, and hypercalcemia were documented as the initial SREs in 12 patients (52.2%), 10 patients (43.5%), and one patient (4.3%), respectively. The SRE-free rate was 94.2 ± 2.0, 87.3 ± 3.0, and 79.6 ± 3.8% at 1, 2, and 3 years after the initial visit, respectively. Multivariate analysis revealed bone metastasis at diagnosis (hazard ratio [HR] = 4.41, p = 0.007), bone marrow invasion (HR = 34.08, p < 0.001), and local progression or recurrence after definitive treatment (HR = 3.98, p = 0.012) as independent risk factors for SREs. CONCLUSIONS: SREs are non-rare events that can occur during the treatment course for Ewing sarcoma, with an especially high incidence of malignant spinal cord compression. Patients with metastatic disease at diagnosis, especially in the bone or bone marrow, or with local progression or recurrence after definitive treatment, should be carefully monitored for the occurrence of SREs. The most effective methods to monitor the occurrence of SREs and new preventative therapies for SREs should be investigated in the future.
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Hipercalcemia , Neoplasias Primarias Secundarias , Sarcoma de Ewing , Compresión de la Médula Espinal , Humanos , Adulto Joven , Adulto , Sarcoma de Ewing/epidemiología , Sarcoma de Ewing/terapia , Estudios Retrospectivos , Japón/epidemiología , Incidencia , Compresión de la Médula Espinal/epidemiología , Compresión de la Médula Espinal/etiologíaRESUMEN
PURPOSE: TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated. METHODS: This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity. RESULTS: Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response. CONCLUSION: Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition. TRIAL REGISTRATION: jRCT2080222728 (January 29, 2015).
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Relación Dosis-Respuesta a Droga , Neoplasias , Proteínas Proto-Oncogénicas c-akt , Humanos , Masculino , Femenino , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Persona de Mediana Edad , Anciano , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Adulto , Dosis Máxima Tolerada , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Anciano de 80 o más Años , Regulación Alostérica/efectos de los fármacos , Pirazoles , TiofenosRESUMEN
Background: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations. Methods: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]. Findings: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2-7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5-12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs. Interpretation: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. Funding: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).
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Inflammatory rhabdomyoblastic tumors (IRMTs) are newly recognized skeletal muscle tumors with uncertain malignant potential. We investigated 13 IRMTs using clinicopathologic, genetic, and epigenetic methods. The cohort included 7 men and 6 women, aged 23 to 80 years (median, 50 years), of whom 2 had neurofibromatosis type 1. Most tumors occurred in the deep soft tissues of the lower limbs, head/neck, trunk wall, and retroperitoneum/pelvis. Two tumors involved the hypopharyngeal submucosa as polypoid masses. Eight tumors showed conventional histology of predominantly spindled cells with nuclear atypia, low mitotic activity, and massive inflammatory infiltrates. Three tumors showed atypical histology, including uniform epithelioid or plump cells and mitotically active histiocytes. The remaining 2 tumors demonstrated malignant progression to rhabdomyosarcoma; one had additional IRMT histology and the other was a pure sarcoma. All 11 IRMTs without malignant progression exhibited indolent behavior at a median follow-up of 43 months. One of the 2 patients with IRMTs with malignant progression died of lung metastases. All IRMTs were positive for desmin and PAX7, whereas myogenin and MyoD1 were expressed in a subset of cases. Targeted next-generation sequencing identified pathogenic mutations in NF1 (5/8) and TP53 (4/8). All TP53 mutations co-occurred with NF1 mutations. TP53 variant allele frequency was much lower than that of NF1 in 2 cases. These tumors showed geographic (subclonal) strong p53 immunoreactivity, suggesting the secondary emergence of a TP53-mutant clone. DNA methylation-based copy number analysis conducted in 11 tumors revealed characteristic flat patterns with relative gains, including chromosomes 5, 18, 20, 21, and/or 22 in most cases. Widespread loss of heterozygosity with retained biparental copies of these chromosomes was confirmed in 4 tumors analyzed via allele-specific profiling. Based on unsupervised DNA methylation analysis, none of the 11 tumors tested clustered with existing reference entities but formed a coherent group, although its specificity warrants further study.
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Neoplasias de los Músculos , Neurofibromatosis 1 , Rabdomiosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Masculino , Humanos , Femenino , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Rabdomiosarcoma/genética , Rabdomiosarcoma/patología , Sarcoma/patología , Neoplasias de los Tejidos Blandos/genéticaRESUMEN
CONTEXT: Cancer pain is a common complication that is frequently undertreated in patients with cancer. OBJECTIVES: This study is aimed at assessing the time needed to achieve cancer pain management goals through specialized palliative care (SPC). METHODS: This was a multicenter, prospective, longitudinal study of inpatients with cancer pain who received SPC. Patients were continuously followed up until they considered cancer pain management successful, and we estimated this duration using the Kaplan-Meier method. We investigated the effectiveness of pain management using multiple patient-reported outcomes (PROs) and quantitative measures, including pain intensity change in the Brief Pain Inventory. A paired-sample t-test was used to compare the pain intensity at the beginning and end of the observation period. RESULTS: Cancer pain management based on the PROs was achieved in 87.9% (385/438) of all cases. In 94.5% (364/385) of these cases, cancer pain management was achieved within 1 week, and the median time to pain management was 3 days (95% confidence interval [CI], 2-3). The mean worst pain intensity in the last 24 h at the start and end of observation were 6.9 ± 2.2 and 4.0 ± 2.3, respectively, with a difference of -2.9 (95% CI, -3.2 to -2.6; p < 0.01). Overall, 81.6% of the patients reported satisfaction with cancer pain management, and 62 adverse events occurred. CONCLUSION: SPC achieved cancer pain management over a short period with a high level of patient satisfaction resulting in significant pain reduction and few documented adverse events.
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Dolor en Cáncer , Neoplasias , Humanos , Manejo del Dolor , Cuidados Paliativos/métodos , Pacientes Internos , Dolor en Cáncer/terapia , Dolor en Cáncer/complicaciones , Estudios Longitudinales , Estudios Prospectivos , Dolor/complicaciones , Neoplasias/complicaciones , Neoplasias/terapiaRESUMEN
Cancer genomic medicine using next-generation sequencers has been developing. However, the number of patients who could receive genomically matched therapy is limited because off-label use or patient-oriented compassionate use was not permitted under National Health Insurance in Japan. To improve patient drug accessibility, we initiated a biomarker-based basket-type clinical trial (NCCH1901) in October 2019 under patient-proposed healthcare services. We listed the drugs that had high medical needs but were not covered by National Healthcare Insurance. Then we included these drugs before patient proposal so that they could access off-label drugs soon after they had the results of CGP tests. All drugs were provided free of charge by pharmaceutical companies. The objective was to administer off-label drugs and to collect efficacy and safety data for these drugs. The primary endpoint was the response rate based on the best overall response for up to 16 weeks. As of January 31, 2022, we included 18 drug cohorts and 295 patients were treated in this study. The most common cancer was brain tumor, followed by carcinoma of endocrine organs and colorectal cancer. BRAF mutations and ERBB2 amplifications were the frequent genomic abnormalities to be enrolled. This study was one way to access off-label drugs, and contributed significantly to providing treatment opportunities for patients in Japan.
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Neoplasias , Informe de Investigación , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Biomarcadores , JapónRESUMEN
BACKGROUND: Precision medicine has transformed cancer treatment by focusing on personalized approaches based on genomic abnormalities. However, comprehensive genomic profiling (CGP) and access to targeted therapies are limited in Japan. This study investigates the BELIEVE trial, which aims to improve drug accessibility for patients with actionable genetic abnormalities through off-label drug administration. METHODS: The BELIEVE trial is a platform trial with a single master protocol, conducted under the Clinical Trials Act and the patient-proposed health services (PPHS) scheme. Eligible patients with solid tumors exhibiting actionable alterations were enrolled, and CGP tests covered by national health insurance were employed. Treatment selection, study drugs from collaborating pharmaceutical companies, and treatment schedules adhered to predefined protocols. Primary and secondary endpoints were evaluated, and statistical analysis was conducted based on patient response rates. RESULTS: The BELIEVE trial offered treatment opportunities for patients with relapse/refractory disease who lacked standard therapies or clinical trial options. This study addresses unmet medical needs and contributes to the establishment of precision medicine systems. Similar trials like NCI-MATCH and TAPUR are being conducted globally. The BELIEVE trial provides a platform for off-label drug administration, collects essential clinical data, and contributes to drug approval applications. CONCLUSION: The BELIEVE trial provides hope for patients with actionable genetic abnormalities by facilitating access to targeted therapies through off-label drug administration. It establishes a regulatory framework and promotes collaboration between industry and academia by expanding organ-specific and cross-organ biomarker-based treatments.
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Neoplasias , Uso Fuera de lo Indicado , Humanos , Neoplasias/tratamiento farmacológico , Preparaciones Farmacéuticas , Genómica/métodos , Atención a la SaludRESUMEN
Background: Most cervical adenocarcinomas are associated with human papillomavirus (HPV). Gastric-type cervical adenocarcinoma (GAS), an HPV-independent adenocarcinoma, shows an aggressive clinical feature, resulting in a poor prognosis. Resistance to chemotherapy poses a difficulty in managing patients with metastatic GAS. We aimed to establish patient-derived xenografts (PDXs) of tumors from two patients with GAS and evaluated protein biomarkers for drug development using immunohistochemistry. Methods: Two PDXs were established 78 and 48 days after transplanting the patient's tumor tissues into immunodeficient mice, respectively. PDX and patient's tumor samples were stained for HER2, HER3, PMS2, MSH6, PanTrk, and ARID1A to evaluate biomarkers for therapeutic targets. In addition, whole exome sequencing and RNA sequencing were performed on available samples. Results: The pathological findings in morphological features and immunohistochemical profiles from the established PDXs were similar to those from the patients' surgical tumor specimens. HER3 was overexpressed in the patient's tumors, and the corresponding PDX tumors and HER2 was weakly stained in both types of tumor samples. In all PDX and patient tumor samples, PMS2, MSH6, and ARID1A were retained, and PanTrk was not expressed. In addition, a total of 10 samples, including tumor tissue samples from 8 other GAS patients, were evaluated for HER3 expression scores, all of which were 2 + or higher. Conclusions: In summary, we evaluated biomarkers for therapeutic targets using newly established PDX models of GAS. Frequent HER3 overexpression and HER2 expression in GAS tumors suggest the possibility of new treatments for patients with GAS by targeting HER3 and HER2.
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PURPOSE: Although opioids have been shown to be effective for cancer pain, opioid-induced adverse events (AEs) are common. To date, little is known about the differences in risks of AEs by opioid type. This study was performed to compare the prevalence of AEs across opioids commonly used for analgesic treatment in Japan. METHODS: This study was conducted as a preplanned secondary analysis of a multicenter prospective longitudinal study of inpatients with cancer pain who received specialized palliative care for cancer pain relief. We assessed daily AEs until termination of follow-up. We rated the severity of AEs based on the Common Terminology Criteria for Adverse Events version 5.0. We computed adjusted odds ratios for each AE (constipation, nausea and vomiting, delirium, and drowsiness) with the following variables: opioid, age, sex, renal dysfunction, and primary cancer site. RESULTS: In total, 465 patients were analyzed. Based on the descriptive analysis, the top four most commonly used opioids were included in the analysis: oxycodone, hydromorphone, fentanyl, and tramadol. With respect to the prevalence of AEs among all analyzed patients, delirium (n = 25, 6.3%) was the most frequent, followed by drowsiness (n = 21, 5.3%), nausea and vomiting (n = 19, 4.8%), and constipation (n = 28, 4.6%). The multivariate logistic analysis showed that no single opioid was identified as a statistically significant independent predictor of any AE. CONCLUSION: There was no significant difference in the prevalence of AEs among oxycodone, fentanyl, hydromorphone, and tramadol, which are commonly used for analgesic treatment in Japan.
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Dolor en Cáncer , Delirio , Tramadol , Humanos , Analgésicos Opioides/efectos adversos , Oxicodona , Hidromorfona/efectos adversos , Dolor en Cáncer/tratamiento farmacológico , Dolor en Cáncer/epidemiología , Dolor en Cáncer/inducido químicamente , Estudios Prospectivos , Japón/epidemiología , Prevalencia , Estudios Longitudinales , Fentanilo , Estreñimiento/inducido químicamente , Náusea/inducido químicamente , Vómitos/inducido químicamente , Delirio/tratamiento farmacológicoRESUMEN
The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer were updated to the 2022 edition through a process started in 2018. The updated guidelines consist of 12 background questions (BQs), 33 clinical questions (CQs), and 20 future research questions (FRQs). Multiple outcomes including efficacy and safety were selected in each CQ, and then quantitative and qualitative systematic reviews were conducted to determine the strength of evidence and strength of recommendation, which was finally determined through a voting process among designated committee members. Here, we describe eight selected CQs as important updates from the previous guidelines, including novel practice-changing updates, and recommendations based on evidence that has emerged specifically from Japanese clinical trials.