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BACKGROUND: Breast cancer (BC) is a complex disease with profound genomic aberrations. However, the underlying molecular disparity influenced by age and ethnicity remains elusive. METHODS: In this study, we aimed to investigate the molecular properties of 843 primary and metastatic BC patients enrolled in the K-MASTER program. By categorizing patients into two distinct age subgroups, we explored their unique molecular properties. Additionally, we leveraged large-scale genomic data from the TCGA and MSK-IMPACT studies to examine the ethnic-driven molecular and clinical disparities. RESULTS: We observed a high prevalence of PI3KCA mutations in K-MASTER HER2 + tumors, particularly in older patients. Moreover, we identified increased mutation rates in DNA damage response molecules, including ARID1A, MSH6, and MLH1. The K-MASTER patients were mainly comprised of triple-negative breast cancer (TNBC) and HER2-positive tumors, while the TCGA and MSK-IMPACT cohorts exhibited a predominance of hormone receptor-positive (HR +) subtype tumors. Importantly, GATA3 mutations were less frequently observed in East Asian patients, which correlated with poor clinical outcomes. In addition to characterizing the molecular disparities, we developed a gradient-boosting multivariable model to identify a new molecular signature that could predict the therapeutic response to platinum-based chemotherapy. CONCLUSIONS: Our findings collectively provide unprecedented insights into the significance of age and ethnicity on the molecular and clinical characteristics of BC patients.
Assuntos
Neoplasias da Mama , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Fatores Etários , Neoplasias da Mama/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , População do Leste Asiático/genética , Fator de Transcrição GATA3/genética , Receptor ErbB-2/genéticaRESUMO
BACKGROUND: After neoadjuvant chemotherapy (NAC), the SLN identification rate is lower and has a higher false-negative rate than that at upfront surgery. This clinical trial aimed to confirm the effectiveness of sentinel lymph node (SLN) surgery by determining the lymph node identification rate using multimodal SLN marker methods in patients with advanced breast cancer undergoing NAC. PATIENTS AND METHODS: This clinical study is a prospective single-center randomized controlled trial involving patients with breast cancer receiving NAC. Patients are randomized (1:1:1) into arm A that involves the use of radioisotope (RI) plus indocyanine green fluorescence (ICG-F); arm B, RI plus vital dye; and, arm C, ICG-F plus vital dye. A total of 348 patients are needed. An interim analysis was performed on 50% of the patients enrolled. The primary outcome of this trial was the SLN identification rate. RESULTS: Among the 164 total patients (median age 51 years), T2 and N1 were the most common clinical stages. The identification rate of SLN was 95% in arm A, 92% in arm B, and 79% in arm C. To assess superior efficacy, the one-sided endpoint was set at α < 0.0056. Arms A and C showed a difference of 0.1597 in the detection rate (p = 0.0055). CONCLUSIONS: The use of ICG-F plus vital dye for SLNB was the least effective. The results show that the choice of tracer should be radioisotope in combination with one of the other tracers to have the highest SLN identification rate when SLNB cannot be implemented conventionally due to the circumstances of each institution.
Assuntos
Neoplasias da Mama , Verde de Indocianina , Terapia Neoadjuvante , Biópsia de Linfonodo Sentinela , Linfonodo Sentinela , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Pessoa de Meia-Idade , Estudos Prospectivos , Biópsia de Linfonodo Sentinela/métodos , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Linfonodo Sentinela/diagnóstico por imagem , Verde de Indocianina/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico , Seguimentos , Corantes/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Quimioterapia Adjuvante , Metástase LinfáticaRESUMO
The phase 2 LEO study showed that everolimus (EVE) plus letrozole (LET) with ovarian suppression increased progression-free survival (PFS) in tamoxifen-exposed premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer with visceral metastases. Here we report final survival outcomes from the LEO study, and the results of exploratory analyses of bone turnover marker changes and bone-specific progressive disease. Patients who were exposed to or progressed on tamoxifen as adjuvant/palliative treatments were randomly assigned (2:1) to the EVE (leuprorelin + LET + EVE, n = 92) or LET (leuprorelin + LET, n = 45) arm. In a median 51-months of follow-up, the median PFS was 17.5 and 13.8 months in the EVE and LET arms, respectively (P = .245). Patients in the EVE arm with baseline visceral (median PFS 16.4 vs 9.5 months, P = .040) and bone (median PFS 17.1 vs 10.9, P = .003) metastases had greater PFS compared to the LET arm. No differences in overall survival (OS) were observed (median OS, 48.3 vs 50.8 months, P = .948). The 1-year cumulative incidences of bone-specific disease progression were 6.0% and 23.4% in the EVE and LET arms, respectively (hazard ratio 0.26, P < .001). Bone turnover markers at 6 and 12 weeks after treatment decreased in the EVE arm but were increased or stationary in the LET arm. Skeletal-related events occurred in 6.5% and 11.1% of patients in the EVE and LET arms, respectively. EVE + LET with ovarian suppression prolonged PFS in patients with baseline visceral or bone metastases and offered bone-protective effects in the overall study population. However, these clinical benefits did not translate into an OS benefit.
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BACKGROUND: Advanced cancers are associated with more severe symptoms and greater impairment. Although most patients with metastatic cancer would benefit from rehabilitation, few patients receive appropriate rehabilitation therapy. We explored the use of rehabilitation therapy by cancer patients. Our data represented the entire population of Korea. The analyses were performed according to cancer type and stage. METHODS: We extracted rehabilitation utilization data of patients newly diagnosed with cancer in the period of 2011-2015 from the Korea Central Cancer Registry, which is linked to the claims database of the National Health Insurance Service (n = 958,928). RESULTS: The utilisation rate increased during the study period, from 6.0% (11,504) of 192,835 newly diagnosed patients in 2011 to 6.8% (12,455) of 183,084 newly diagnosed patients in 2015. Patients with central nervous system (28.4%) and bone (27.8%) cancer were most likely to undergo physical rehabilitation. The rehabilitation rate was higher in patients with metastatic than localised or regional cancer (8.7% vs. 5.3% vs. 5.5%). CONCLUSION: This claims-based study revealed that rehabilitation therapy for cancer patients is underutilised in Korea. Although patients with metastasis underwent more intensive rehabilitation than patients with early stage cancer, those without brain and bone tumours (the treatment of which is covered by insurance) were less likely to use rehabilitation services. Further efforts to improve the use of rehabilitation would improve the outcomes of cancer patients.
Assuntos
Neoplasias/reabilitação , Modalidades de Fisioterapia/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/reabilitação , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/reabilitação , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Sistema de Registros , República da CoreiaRESUMO
We performed a genome-wide association study to investigate the association between single nucleotide polymorphisms and anthracycline-induced cardiotoxicity (ACT) in patients diagnosed with early breast cancer. From January 2000 to December 2015, 8490 patients underwent breast surgery at the National Cancer Center in Korea. Patients who received doxorubicin (cumulative dose 240 mg/m2 -300 mg/m2 ) with or without trastuzumab as a neoadjuvant/adjuvant therapy were included in our cohort. Sixty-seven patients in our cohort were diagnosed with ACT. Clinical data, including age, body weight, height, cancer stage, trastuzumab treatment, comorbidities, and concomitant medications, were collected retrospectively. Patients were classified as having either persistent or transient ACT based on their clinical course. In total, 346 946 single nucleotide polymorphisms in 42 cases and 215 controls were tested in this study. Body mass index (BMI) ≥25 kg/m2 [odds ratio (OR) = 2.45, 95% confidence interval (CI), 1.23-4.88, P = .011] and trastuzumab use (OR = 2.40, 95% CI, 1.11-5.17, P = .026) were identified as significant risk factors. We found 7 genetic variants for ACT including rs17530621 (SHISA3, P = 3.10E-06), rs11894115 (MPP4, P = 4.71E-06), rs58328254 (RPL7, P = 6.09E-06), and rs117299725 (PRUNE2, P = 8.53E-06), although none of these variants reached the Bonferroni-corrected significance level when adjusted for BMI and trastuzumab use ( = α1.44E-07 based on 0.05/346 946). rs117299725 was a common variant when only the persistent ACT group was analyzed separately. It is meaningful that our study analyzed comprehensively the influence of genetic variation on ACT, along with some clinical factors in Asian breast cancer patients who received anthracycline with or without trastuzumab. Further research will be needed on candidate genetic variants found in this study.
Assuntos
Antraciclinas/efeitos adversos , Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Cardiotoxicidade/etiologia , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Antraciclinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/epidemiologia , Estudos de Casos e Controles , Comorbidade , Feminino , Estudos de Associação Genética/métodos , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Vigilância da População , República da CoreiaRESUMO
PURPOSE: Cardiotoxicities are adverse effects often reported in chemotherapy-treated breast cancer patients. This study evaluated the potential risk factors and cumulative incidence of doxorubicin-induced cardiotoxicity in Korean breast cancer patients. METHODS: We retrospectively analyzed the data of 613 breast cancer patients who underwent a multigated acquisition (MUGA) scan or echocardiography prior to chemotherapy and at least one post-chemotherapy follow-up MUGA scan/echocardiography between 2007 and 2016 at National Cancer Center, Korea. The Cox proportional hazards models were used to evaluate cardiotoxicity risks. Competing risks analyses were performed to estimate cumulative incidence of cardiotoxicity. RESULTS: Risk factors associated with cardiotoxicity within 2 years of doxorubicin administration included age [adjusted hazard ratio (aHR) = 1.02, 95% confidence interval (CI) 1.00-1.04; p = 0.05], metastasis (aHR = 2.66; 95% CI 1.36-5.20; p < 0.01), and concomitant trastuzumab (aHR = 4.08; 95% CI 2.31-7.21; p < 0.01). The cumulative incidence of patients with cardiotoxicity was 6.1% at 2 years (without substantial change from about 9 months)and 20.2% at 2 years (without substantial change from about 15 months) after initiation of doxorubicin-containing therapy without and with trastuzumab, respectively. CONCLUSIONS: Susceptibility to chemotherapy-induced cardiotoxicity within 2 years of doxorubicin initiation in breast cancer patients was elevated with old age, metastasis, and concomitant trastuzumab. Regular imaging monitoring at least up to 9 months after doxorubicin initiation in patients treated without concomitant trastuzumab, and 15 months in patients treated with concomitant trastuzumab, is needed for early detection of chemotherapy-induced cardiotoxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/terapia , Cardiotoxicidade/epidemiologia , Doxorrubicina/efeitos adversos , Trastuzumab/efeitos adversos , Adulto , Idoso , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Quimiorradioterapia Adjuvante/efeitos adversos , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Relação Dose-Resposta a Droga , Ecocardiografia , Feminino , Seguimentos , Humanos , Incidência , Mastectomia , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: As the survival rate of cancer patients increases, the clinical importance of rehabilitation provided by healthcare professionals also increases. However, the evidence supporting the relevance of rehabilitation programs is insufficient. This study aimed to review the literature on effectiveness in physical function, quality of life (QOL) or fatigue of supervised physical rehabilitation in patients with advanced cancer. METHODS: A systematic review and meta-analysis was conducted following the Cochrane guidelines. We narratively described the results when meta-analysis was not applicable or appropriate. Literature databases including Ovid-MEDLINE, Ovid-EMBASE, and the Cochrane Library, as well as several Korean domestic databases, were searched up to June 2017 for studies that investigated the effectiveness of supervised physical rehabilitation programs on physical function, QOL or fatigue in patients with advanced cancer. The quality of the selected studies was evaluated independently by paired reviewers. RESULTS: Eleven studies with 922 participants were finally selected among 2,459 articles. The meta-analysis revealed that after physical exercise, the physical activity level and strength of patients with advanced cancer increased significantly. The QOL showed a statistically significant improvement after physical rehabilitation according to the European Organization for Research and Treatment of Cancer version C30. Though some of measurements about cardiovascular endurance or strength in several studies were not able to be synthesized, each study reported that they were significantly improved after receiving rehabilitation. CONCLUSION: Supervised physical rehabilitation for patients with advanced cancer is effective in improving physical activity, strength, and QOL. However, more trials are needed to prove the effectiveness of supervised exercise and to strengthen the evidence.
Assuntos
Exercício Físico , Neoplasias/reabilitação , Antineoplásicos/uso terapêutico , Bases de Dados Factuais , Fadiga , Humanos , Neoplasias/tratamento farmacológico , Equilíbrio Postural , Qualidade de Vida , Testes de Função RespiratóriaRESUMO
BACKGROUND: The continuum of anti-HER2 agents is a standard treatment of HER2 + metastatic breast cancer (MBC). This study evaluated the efficacy of lapatinib plus vinorelbine in patients progressed on both trastuzumab and lapatinib treatments. METHODS: A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n = 75; lapatinib, 1000 mg daily; vinorelbine 20 mg/m2 D1, D8 q3w) or vinorelbine (V) (n = 74; 30 mg/m2 D1, D8 q3w). The primary endpoint was progression-free survival (PFS) rate at 18 weeks. RESULTS: The median number of previous anti-HER2 therapies was 2 (range 2-5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (45.9% vs 38.9%, p = 0.40). ORR was 19.7% in LV arm, and 16.9% in V arm (p = 0.88). PFS and OS did not differ between two arms (LV vs V; median PFS, 16 vs 12 weeks, HR = 0.86, 95% CI 0.61-1.22; median OS, 15.0 vs 18.9 months, HR = 1.07, 95% CI 0.72-1.58). Toxicity profiles were similar in both arms and all were manageable. CONCLUSIONS: Lapatinib plus vinorelbine treatment was tolerable; however, it failed to demonstrate the clinical benefits over vinorelbine alone in patients with HER2 + MBC after progression on both trastuzumab and lapatinib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT01730677.
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Neoplasias da Mama/tratamento farmacológico , Lapatinib/administração & dosagem , Trastuzumab/administração & dosagem , Vinorelbina/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2/genéticaAssuntos
Neoplasias da Mama , Terapia Neoadjuvante , Biópsia de Linfonodo Sentinela , Linfonodo Sentinela , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Biópsia de Linfonodo Sentinela/métodos , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Linfonodo Sentinela/diagnóstico por imagem , PrognósticoRESUMO
BACKGROUND: This study aimed to compare the sentinel lymph node (SLN) identification rates for breast cancer patients after neoadjuvant chemotherapy (NAC) between the dual method (DM) of indocyanine green fluorescence (ICG-F) plus a radioisotope (RI) and RI alone. METHODS: This randomized study enrolled 130 patients who received NAC for breast cancer and 122 patients who received SLN biopsy (SLNB) using either DM (n = 58) or RI only (n = 64). The study compared the identification rate, number of SLNs, and detection time of SLNB. RESULTS: Among the 122 patients, 113 (92.6%) were clinically node-positive before NAC. The SLN identification rate was 98.3% in the DM group and 93.8% in the RI group (p = 0.14). The DM group and the RI group were similar in the average number of SLNs (2.2 ± 1.13 vs. 1.9 ± 1.33; p = 0.26) and the time to detection of the first SLN (8.7 ± 4.98 vs. 8.3 ± 4.31 min; p = 0.30). In the DM group, transcutaneous lymphatic drainage was visualized by fluorescence imaging for 65.5% (38 of 58) of the patients. The SLN identification rate was 94.7% using ICG-F and 93% using RI (p = 0.79). During and after the operation, no complications, including allergic reactions or skin necrosis, occurred. CONCLUSIONS: This study is the first randomized trial to use ICG-F for SLNB in breast cancer patients after NAC. The DM including ICG-F could be a feasible and safe method for SLNB in initially node-positive breast cancer patients with NAC.
Assuntos
Neoplasias da Mama/patologia , Fluorescência , Verde de Indocianina , Terapia Neoadjuvante , Compostos Radiofarmacêuticos , Biópsia de Linfonodo Sentinela/métodos , Linfonodo Sentinela/patologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/patologia , Corantes , Feminino , Seguimentos , Humanos , Linfonodos , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Prognóstico , Estudos Prospectivos , Linfonodo Sentinela/cirurgiaRESUMO
PURPOSE: We assessed the use of chemotherapy in breast cancer patients to investigate the factors that changed trends in chemotherapy following the adoption of the 21-gene expression assay in tumor genomic profiling. METHODS: Our study used 2033 patients from the National Cancer Center in Korea diagnosed with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (tumor size of 0.5 cm or larger and 0-3 node metastases) from 2010 to 2015. We analyzed use of the 21-gene expression assay, changes in frequency of adjuvant chemotherapy use, and clinicopathological factors related to adjuvant chemotherapy to assess the impact of the 21-gene expression assay. RESULTS: Adjuvant chemotherapy use declined from 33.33% (2011) to 13.59% (2015) [relative risk (RR), 0.71; 95% CI 0.56-0.89; ptrend = 0.004] in patients with 21-gene expression assay data. Among patients without assay data, adjuvant chemotherapy use decreased from 76.79 to 40.17% between 2010 and 2015 (RR 0.87; 95% CI 0.84-0.91; ptrend < 0.001), especially for patients with node-negative/micrometastasis (RR 0.85; 95% CI 0.81-0.89; ptrend < 0.001). The frequency of adjuvant chemotherapy was significantly decreased after introduction of the 21-gene expression assay (p < 0.001). Tumor size (p < 0.001), progesterone receptor (PgR) status (p = 0.001), and proliferation index (Ki-67) levels (p < 0.001) were important factors for chemotherapy decision-making in node-negative/micrometastasis patients who did not undergo the assay. CONCLUSIONS: For HR-positive, HER2-negative breast cancer patients with 0-1 node metastases, chemotherapy use declined significantly after the adoption of the 21-gene assay. PgR status and Ki-67 were useful for chemotherapy decision-making in cases without the 21-gene assay.
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Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Antígeno Ki-67/genética , Adulto , Idoso , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Tomada de Decisões , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , República da Coreia , TranscriptomaRESUMO
Inhibition of the Janus kinase (JAK)-STAT pathway has been implicated as a treatment option for extranodal natural killer/T-cell lymphoma, nasal type (NTCL). However, JAK-STAT pathway alterations in NTCL are variable, and the efficacy of JAK-STAT pathway inhibition has been poorly evaluated. JAK3 mutation and STAT3 genetic alterations were investigated by direct sequencing and immunohistochemistry in 84 patients with newly diagnosed NTCL. Five of 71 patients with NTCL (7.0%) had JAK3 mutations in the pseudokinase domain: two JAK3A573V, two JAK3H583Y, and one JAK3G589D mutation. Proliferation of Ba/F3 cells transduced with novel JAK3 mutations (JAK3H583Y and JAK3G589D) was independent of IL-3 and was inhibited by the JAK3 inhibitor tofacitinib (means ± SD drug concentration causing a 50% inhibition of the desired activity, 85 ± 10 nmol/L and 54 ± 9 nmol/L). Ribbon diagrams revealed that these JAK3 pseudokinase domain mutations were located at the pseudokinase-kinase domain interface. Although phosphorylated STAT3 was overexpressed in 35 of 68 patients with NTCL (51.4%), a STAT3 mutation (p.Tyr640Phe; STAT3Y640F) at the SRC homology 2 domain was detected in 1 of the 63 patients (1.5%). A STAT3 inhibitor was active against STAT3-mutant SNK-6 and YT cells. Novel JAK3 mutations are oncogenic and druggable in NTCL. The JAK3 or STAT3 signal was altered in NTCL, and pathway inhibition might be a therapeutic option for patients with JAK3- or STAT3-mutant NTCL.
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Janus Quinase 3/genética , Linfoma Extranodal de Células T-NK/genética , Mutação/genética , Neoplasias Nasais/genética , Adolescente , Adulto , Idoso , Criança , Óxidos S-Cíclicos/farmacologia , Feminino , Humanos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Masculino , Pessoa de Meia-Idade , Fosforilação/genética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células Tumorais Cultivadas , Adulto JovemRESUMO
BACKGROUND: Urachal cancer is a rare cancer that develops in the urachus. Because of its rarity, standard treatment therapies for urachal cancer are not established, and chemotherapeutic regimens for bladder cancer have been unsuccessful for patients with urachal cancer. Hence, we aim to understand a systematic molecular characterisation of urachal cancer. METHODS: We identified somatic single-nucleotide variations (SNVs)/indels and somatic copy number aberrations (SCNAs) in the 17 patients by using whole-exome sequencing (WES) and OncoScan platform (Affymetrix) as follows: tumour-normal paired sequencing (WES, n=10), tumour-only sequencing (WES, n=1; targeted deep sequencing, n=16), and OncoScan (n=17). RESULTS: Our analyses identified 27 genes with somatic SNVs and indels, as well as six genes (APC, COL5A1, KIF26B, LRP1B, SMAD4 and TP53) that were recurrent in at least two patients. By analysing the SCNAs, we found that the extent of chromosomal amplification was highly associated with the patient's cancer stage. Interestingly, 35% (6/17) of the patients had focal DNA amplifications in fibroblast growth factor receptor family genes. The integration of somatic SNVs, indels and SCNAs revealed significant alterations in the mitogen-activated protein kinase signalling pathways. CONCLUSIONS: Our genome-wide analysis of urachal cancer suggests that molecular characteristics may be important for the treatment of urachal cancer.
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Genoma Humano/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Variações do Número de Cópias de DNA/genética , Estudo de Associação Genômica Ampla , Humanos , Mutação INDEL/genética , Sistema de Sinalização das MAP Quinases/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Bexiga Urinária/fisiopatologia , Sequenciamento do ExomaRESUMO
BACKGROUND: Although adolescent and young adult (AYA) cancers are characterized by biological features and clinical outcomes distinct from those of other age groups, the molecular profile of AYA cancers has not been well defined. In this study, we analyzed cancer genomes from rare types of metastatic AYA cancers to identify driving and/or druggable genetic alterations. METHODS: Prospectively collected AYA tumor samples from seven different patients were analyzed using three different genomics platforms (whole-exome sequencing, whole-transcriptome sequencing or OncoScan™). Using well-known bioinformatics tools (bwa, Picard, GATK, MuTect, and Somatic Indel Detector) and our annotation approach with open access databases (DAVID and DGIdb), we processed sequencing data and identified driving genetic alterations and their druggability. RESULTS: The mutation frequencies of AYA cancers were lower than those of other adult cancers (median = 0.56), except for a germ cell tumor with hypermutation. We identified patient-specific genetic alterations in candidate driving genes: RASA2 and NF1 (prostate cancer), TP53 and CDKN2C (olfactory neuroblastoma), FAT1, NOTCH1, and SMAD4 (head and neck cancer), KRAS (urachal carcinoma), EML4-ALK (lung cancer), and MDM2 and PTEN (liposarcoma). We then suggested potential drugs for each patient according to his or her altered genes and related pathways. By comparing candidate driving genes between AYA cancers and those from all age groups for the same type of cancer, we identified different driving genes in prostate cancer and a germ cell tumor in AYAs compared with all age groups, whereas three common alterations (TP53, FAT1, and NOTCH1) in head and neck cancer were identified in both groups. CONCLUSION: We identified the patient-specific genetic alterations and druggability of seven rare types of AYA cancers using three genomics platforms. Additionally, genetic alterations in cancers from AYA and those from all age groups varied by cancer type.
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Descoberta de Drogas , Perfilação da Expressão Gênica , Genômica , Neoplasias/genética , Neoplasias/patologia , Adolescente , Adulto , Fatores Etários , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Instabilidade Cromossômica , Biologia Computacional/métodos , Inibidor de Quinase Dependente de Ciclina p18/genética , Inibidor de Quinase Dependente de Ciclina p18/metabolismo , Exoma , Feminino , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Masculino , Terapia de Alvo Molecular , Taxa de Mutação , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Via de Sinalização Wnt , Adulto Jovem , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
BACKGROUND: Pre-operative chemoradiotherapy (CRT) is the standard treatment in clinical stage T3/4 or node positive rectal cancer. However, there are no established biomarkers that can predict the pathological response and clinical outcome to CRT. METHODS: Immunohistochemical staining was performed in tissue arrays constructed from core tissue specimens taken before treatment and from operative specimens from 112 patients who received 5-FU based pre-operative CRT and surgery. Expression of Ki67, TS, BAX, EpCAM, p53, p21, EGFR, CD44, CD133, CD166, HIF1α and ALDH1 were assessed and correlated with tumor regression grades and disease free survival. RESULTS: Of the 112 patients (M/F 74/38, median age: 62), 20 (17.9%) patients achieved pathologic complete remission (pCR). In analyzing the associations between marker expressions and tumor regression grades, high p21 expression at the pretreatment biopsy was significantly associated with non-pCR (p = 0.022) and poor disease free survival (median DFS - low vs high p21: 75.8 vs 58.1 months, p = 0.002). In the multivariate analysis, high p21 expression level at the pre-treatment biopsy was significantly associated with poor DFS (p = 0.001, HR 6.14; 95% CI 2.03, 18.55). High CD166 expression level at the pretreatment biopsy was also associated with poor DFS (p = 0.003; HR 5.61; 95% CI 1.81, 17.35). CONCLUSION: These show high p21 and CD166 expression at the pretreatment biopsy were associated with tumor regression and poor prognosis in patients treated with 5-FU based CRT. Larger, prospective and functional studies are warranted to determine the role of p21 and CD166 as predictive biomarker of response to CRT.
Assuntos
Antígenos CD/biossíntese , Biomarcadores Tumorais/biossíntese , Moléculas de Adesão Celular Neuronais/biossíntese , Proteínas Fetais/biossíntese , Neoplasias Retais/genética , Proteínas rho de Ligação ao GTP/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Biomarcadores Tumorais/genética , Moléculas de Adesão Celular Neuronais/genética , Quimiorradioterapia , Intervalo Livre de Doença , Feminino , Proteínas Fetais/genética , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Proteínas rho de Ligação ao GTP/genéticaRESUMO
OBJECTIVES: Unequal access to cancer clinical trials is an important issue, given the potential benefits of participation for cancer patients. We evaluated regional disparities in access to cancer clinical trials in Korea. METHODS: From the Ministry of Food and Drug Safety database, we extracted 2,465 records of all cancer clinical trials approved between January 2012 and April 2023. To measure disparities in cancer clinical trial access, we calculated the ratio of clinical trials open to non-capital areas relative to those open to capital areas. We then analyzed temporal trends in this ratio, which we termed the trial geographical equity index (TGEI). RESULTS: Disparities in access to cancer clinical trials, as indicated by the TGEI, did not significantly improve during the study period (regression coefficient, 0.002; p=0.59). However, for phase II/III trials sponsored by global pharmaceutical companies, the TGEI improved significantly (regression coefficient, 0.021; p<0.01). In contrast, the TGEI deteriorated for trials initiated by investigators or those testing domestically developed therapeutics (regression coefficient, -0.015; p=0.05). Furthermore, the increasing trend of TGEI for phase II/III trials sponsored by global companies began to reverse after 2019, coinciding with the outbreak of coronavirus disease 2019 (COVID-19). CONCLUSIONS: Over the past decade, access to cancer clinical trials has improved in Korea, particularly for phase II/III trials evaluating therapeutics from global companies. However, this increase in accessibility has not extended to trials initiated by investigators or those assessing domestically developed therapeutics. Additionally, the impact of COVID-19 on disparities in clinical trial access should be closely monitored.
Assuntos
COVID-19 , Neoplasias , Humanos , Neoplasias/epidemiologia , Neoplasias/terapia , República da Coreia/epidemiologiaRESUMO
The role of combining neoadjuvant endocrine therapy with conventional chemotherapy remains unclear; therefore, we conducted an open-label, single-center, nonrandomized phase II trial to assess the effect of this combination. Patients with previously untreated stage II or III HR-positive, HER2-negative breast cancer received concurrent letrozole 2.5 mg with standard neoadjuvant chemotherapy. The primary endpoint was pathologic complete response (pCR) at the time of surgery. We used Simon's minimax two-stage design; a pCR rate > 6% was necessary at the first stage to continue. Between November 2017 and November 2020, 53 women were enrolled in the first stage of the trial. Their median age was 49 years (range, 33-63), and 60% of them were premenopausal. Subsequently, 66% and 34% of patients with clinical stages II and III, respectively, were included; 93% had clinically node-positive disease. Two patients (4%) achieved pCR after neoadjuvant chemo-endocrine treatment, which did not satisfy the criteria for continuing to the second stage. The overall response rate was 83%. During the median follow-up of 53.7 months, the 3-year disease-free survival and overall survival rates were 87% and 98%, respectively. Neutropenia was the most common grade 3/4 adverse event (40%), but rarely led to febrile neutropenic episodes (4%). Myalgia (32%), nausea (19%), constipation (17%), heartburn (11%), oral mucositis (9%), and sensory neuropathy (9%) were frequently observed, but classified as grade 1 or 2. No deaths occurred during preoperative treatment. The addition of letrozole to standard neoadjuvant chemotherapy was safe and beneficial in terms of overall response rate, but did not provide a higher pCR rate in locally advanced HR-positive, HER2-negative breast cancer. Further research is needed to enhance neoadjuvant treatment strategies for this cancer subtype.
RESUMO
PURPOSE: Triple-negative breast cancer (TNBC) is a particularly challenging subtype of breast cancer, with a poorer prognosis compared to other subtypes. Unfortunately, unlike luminal-type cancers, there is no validated biomarker to predict the prognosis of patients with early-stage TNBC. Accurate biomarkers are needed to establish effective therapeutic strategies. MATERIALS AND METHODS: In this study, we analyzed gene expression profiles of tumor samples from 184 TNBC patients (training cohort, n=76; validation cohort, n=108) using RNA sequencing. RESULTS: By combining weighted gene expression, we identified a 10-gene signature (DGKH, GADD45B, KLF7, LYST, NR6A1, PYCARD, ROBO1, SLC22A20P, SLC24A3, and SLC45A4) that stratified patients by risk score with high sensitivity (92.31%), specificity (92.06%), and accuracy (92.11%) for invasive disease-free survival. The 10-gene signature was validated in a separate institution cohort and supported by meta-analysis for biological relevance to well-known driving pathways in TNBC. Furthermore, the 10-gene signature was the only independent factor for invasive disease-free survival in multivariate analysis when compared to other potential biomarkers of TNBC molecular subtypes and T-cell receptor ß diversity. 10-gene signature also further categorized patients classified as molecular subtypes according to risk scores. CONCLUSION: Our novel findings may help address the prognostic challenges in TNBC and the 10-gene signature could serve as a novel biomarker for risk-based patient care.
Assuntos
Biomarcadores Tumorais , Perfilação da Expressão Gênica , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Feminino , Prognóstico , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Perfilação da Expressão Gênica/métodos , Estadiamento de Neoplasias , Transcriptoma , Adulto , Regulação Neoplásica da Expressão Gênica , IdosoRESUMO
Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib-tamoxifen in patients with HR+/HER2- advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib-tamoxifen or placebo-tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1-32.4) with palbociclib-tamoxifen and 11.1 months (95% CI, 7.4-14.6) with placebo-tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43-0.85; P = 0.002). Palbociclib-tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44-1.21) with palbociclib-tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib-tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo-tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2- advanced breast cancer, palbociclib-tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib-tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018.