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PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. METHODS: This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. RESULTS: Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. CONCLUSION: Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting.
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Aminopiridinas , Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Piperazinas , Inibidores de Proteínas Quinases , Purinas , Piridinas , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Pessoa de Meia-Idade , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Piridinas/uso terapêutico , Estudos Retrospectivos , Idoso , Piperazinas/uso terapêutico , Aminopiridinas/uso terapêutico , Purinas/uso terapêutico , Taiwan , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Resultado do Tratamento , Metástase Neoplásica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Povo AsiáticoRESUMO
Moderate physical activity is related to reduced mortality in hemodialysis patients. However, most hemodialysis patients have low physical activity levels for complex reasons. This study investigated the determinants of moderate-to-high physical activity levels and whether psychosocial correlates are associated with engagement in moderate-to-high physical activity among hemodialysis patients. A cross-sectional survey was conducted with 134 hemodialysis outpatients, aged 64.7 years, in three hemodialysis centers in Taiwan. Data on sociodemographics, comorbidities, lifestyles, and psychosocial correlates, including perceived benefits, barriers, and self-efficacy of physical activity, were collected. Multiple logistic regression analyses were performed. Results showed that patients with moderate-to-high physical activity levels constituted a significantly lower proportion of current smokers and had fewer perceived physical activity barriers and higher self-efficacy of physical activity compared with those with low levels. After adjusting for potential sociodemographic covariates, current employment, nonsmoking status, and high self-efficacy of physical activity were significantly associated with moderate-to-high physical activity levels. Developing strategies to improve the self-efficacy of physical activity, support employment, and enhance anti-smoking campaigns in hemodialysis patients can help them engage in moderate-to-high levels of physical activity.
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Exercício Físico , Diálise Renal , Humanos , Estudos Transversais , Masculino , Feminino , Diálise Renal/psicologia , Diálise Renal/métodos , Diálise Renal/estatística & dados numéricos , Pessoa de Meia-Idade , Taiwan , Exercício Físico/psicologia , Exercício Físico/fisiologia , Idoso , Inquéritos e Questionários , Autoeficácia , Modelos LogísticosRESUMO
Early rehabilitation has beneficial impacts on functional outcomes for patients with acute stroke. However, whether the addition of virtual reality (VR) training could further improve these patients' muscle strength, functional recovery, and psychological health is unknown. A randomized controlled trial was conducted on 33 patients with first-time acute ischemic stroke. The patients were randomly assigned using a 1:1 randomization ratio to either the experimental group (EG) or the comparison group (CG). Both groups received early rehabilitation, and the EG received extra VR training during their stay in the hospital. Muscle strength, functional status, and psychological health were assessed before the intervention and at discharge. Generalized estimating equations were used to examine the intervention effects via the interaction of time and group. After adjusting for potential covariates, the EG showed a more significant decrease in depression at discharge than the CG (ß = 3.77, p = 0.011). There were no differences in muscle strength and functional recovery between groups after intervention. Adding VR training into early rehabilitation facilitates substantial positive effects on psychological health, specifically depression, but not muscle strength and functional recovery, compared to receiving early rehabilitation alone in patients with first-time acute stroke during their hospitalized period.
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BACKGROUND: Telerehabilitation has been developed and applied for years for cardiac and pulmonary diseases with good clinical outcomes. However, its application to participants with long COVID remains limited. OBJECTIVES: To investigate the effectiveness of a 12-week telerehabilitation training program in participants with long COVID. The primary outcome was cardiorespiratory fitness (CRF), and secondary outcomes were physical activity (PA) amounts, exercise self-efficacy, sleep quality, and health-related quality of life (HRQOL). METHODS: A parallel-group, randomized controlled trial was conducted. Eligible participants with long COVID (n = 182) were randomly assigned in a 1:1 ratio to either the experimental group (EG) or the control group (CG). The EG received 12 weeks of telerehabilitation training with weekly remote monitoring for exercise maintenance and support. The CG received PA counseling only. CRF, PA amounts, exercise self-efficacy, sleep quality, and HRQOL were assessed at baseline and 12 weeks. Generalized estimating equations were used to analyze the intervention effects by examining the interaction between time and group. RESULTS: One hundred twenty-two participants (67 %) completed the study, and 182 were included in the intention-to-treat analysis. The EG had greater walking behavior (ß = -763.3, p < 0.001), total amount of PA (ß= -711, p = 0.003), exercise self-efficacy (ß = -1.19, p < 0.001), and better sleep quality (ß = 1.69, p = 0.012) after the 12-weeks of telerehabilitation training than the CG. However, there were no significant differences in any CRF parameters or HRQOL at 12 weeks between the EG and CG. CONCLUSION: Telerehabilitation training offers a personalized and convenient approach that can increase exercise willingness and PA amounts and improve sleep quality. These findings underscore the potential benefits of telerehabilitation training for promoting healthier lifestyles and improving overall health outcomes. CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT05205460) on January 25, 2022.
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COVID-19 , Aptidão Cardiorrespiratória , Qualidade de Vida , Autoeficácia , Telerreabilitação , Humanos , Masculino , Feminino , COVID-19/reabilitação , Pessoa de Meia-Idade , Idoso , Terapia por Exercício/métodos , Qualidade do Sono , Exercício Físico , SARS-CoV-2 , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the association between physical activity (PA) amount and gender differences on cardiorespiratory fitness (CRF), sleep quality, and health-related quality of life (HRQoL) in individuals with long COVID. DESIGN: Cross-sectional study. SETTING: An integrated outpatient clinic for post-COVID-19 at a medical center. PARTICIPANTS: Convenience sample of patients (N=264) diagnosed with long COVID. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: PA amounts, sleep quality, and HRQoL were measured by the International Physical Activity Questionnaire, Pittsburgh Sleep Quality Index, and the World Health Organization Questionnaire on Quality of Life: Short Form, respectively. CRF was evaluated through graded exercise testing. RESULTS: The participants had a mean age of 42.5±13.5 years and a mean duration of post-COVID-19 symptoms of 12.7±6.8 weeks. More than half (n=149, 56.5%) were female patients. Female participants had significantly lower CRF than male participants (P<.05). Older age and higher body mass index were associated with worse CRF and HRQoL (P<.05). Less sitting behavior and greater amounts of vigorous-intensity PA (VPA) or total PA were associated with better CRF (P<.05). In addition, greater total PA and moderate-intensity PA (MPA) were associated with better sleep quality and HRQoL (P<.05), respectively. CONCLUSIONS: Gender differences were found in CRF among patients with long COVID. Greater self-reported VPA or total PA was associated with better CRF, whereas greater total PA and MPA were associated with better sleep quality and HRQoL, respectively, in patients with long COVID. Further research is needed to explore these associations in longitudinal studies.
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The aim of this study was to elucidate molecular profiling in HER2-low tumors based on a promising dataset. A total of 615 consecutive HER2-negative breast cancer samples were assayed. The genomic mutations in the two groups with different HER2 expression levels (HER2-0 vs. HER2-low) were compared. The mutation types obtained via next-generation targeted sequencing were correlated with the clinicopathological features of the patients with HER2-0 and HER2-low breast cancer. The results showed that there was a significantly higher percentage of receptor-positive (ER/PR) tumors and more low-level Ki-67 tumors, but a lower incidence of stage I/II tumors in the HER2-low group compared to the HER2-0 group. There was a significantly higher frequency of 17.62% (65/369) for PIK3CA_SNA in the HER2-low group than in the HER2-0 group, which had a frequency of only 9.35% (23/246) (p = 0.006). When the called gene alterations in the triple-negative breast cancer (TNBC) group were compared with those in the luminal-like breast cancer group, there was a significantly high frequency of 28.17% (140/497) for ERBB2_SNA in a luminal-like group than in the TNBC group(16.95% (20/118)).We conclude that the early detection of PIK3CA mutations is likely to be important and might help therapeutic decision making in patients with HER2-low tumors.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Genômica , Mutação , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
BACKGROUND: The human epidermal growth factor receptor 2 (HER2) negative luminal B1 subtype of breast cancer has been reported with a poorer outcome than luminal A in recent studies. This study aimed to investigate the molecular alterations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of luminal B1 breast cancer in Taiwan. METHODS: We enrolled patients with luminal B1 breast cancer in our study. They were classified as patients who received curative surgery and adjuvant or neoadjuvant chemotherapy as the low-risk group, and who had advanced or metastatic disease or early relapse during the follow-up time as the high-risk group. Using targeted sequencing, we evaluated genomic alterations, interpreting variants with the ESMO Scale of clinical actionability of molecular targets (ESCAT). RESULTS: A total of 305 luminal B1 breast cancer patients underwent targeted sequencing analyses. The high-risk patients reported more actionable genes and called variants than the low-risk group (P < 0.05). PIK3CA (42%), FGFR1 (25%), and BRCA1/2 (10.5%) were the most prevalent ESCAT actionable alterations in luminal B1 breast cancer. There was no difference in the prevalence of actionable mutations between these two groups, except for ERBB2 oncogenic mutations, which were more prevalent among the high-risk than the low-risk group (P < 0.05). Alterations in PTEN, ERBB2, and BRCA1/2 were associated with disease relapse events in luminal B1 breast cancer. CONCLUSIONS: PIK3CA, FGFR1, and BRCA1/2 were the most prevalent actionable alterations among Taiwanese luminal B1 breast cancer. Moreover, PTEN and BRCA1/2 was significantly associated with disease relapse.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Proteína BRCA1/genética , Taiwan/epidemiologia , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Proteína BRCA2/genética , Genômica , Mutação , Recidiva , Classe I de Fosfatidilinositol 3-Quinases/genética , Biomarcadores Tumorais/genética , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
BACKGROUND: CDK4/6 inhibitors (CDK4/6i) have shown great efficacy in prolonging progression-free survival and is the current standard of care for hormone positive (HR(+)) metastatic breast cancer (mBC). Despite well tolerability and ease of use, the most common side effect of CDK4/6i is myelosuppression, with neutropenia the most prevalent adverse effect. Studies show that the prevalence and severity of neutropenia are more marked in Asian patients, although details remain obscure. METHODS: In this study, we retrospectively analyzed 105 Taiwanese patients who received palbociclib for HR(+) HER2(-) mBC at the Taipei Veterans General Hospital. To investigate a possible genetic association for high prevalence of neutropenia, we queried the Taiwan Biobank with publicly available germline databases (ALFA, gnomAD, ExAC, 1000 Genomes project, HapMap), for the allele frequencies of 4 neutropenia-related SNPs (ABCB1_rs1045642, ABCB1_rs1128503, ERCC1_rs3212986, ERCC1_rs11615) and compared between different ethnicities. In addition, one of the patients was a long-term patient with peritoneal dialysis. We quantified the levels of palbociclib in her serum and peritoneal fluid by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Interestingly, in our cohort, early neutropenia nadir (occurred within 56 days of start) was associated with worse treatment outcome, while occurrence of grade 3/4 neutropenia was associated with better outcome. We observed an extremely high incidence of neutropenia (96.2% any grade, 70.4% grade 3/4). In the analyzed germline databases, we discovered a higher SNP frequency of the T allele in ABCB1_rs1128503, a lower frequency of T allele in ABCB1_rs1045642, and a higher SNP frequency of G allele in ERCC1_rs11615. We observed that palbociclib levels in peritoneal dialysate ranged from around 20-50 ppb, and serum levels reached 100-110 ppb during drug administration and decreased to <10 ppb during discontinuation. CONCLUSION: Our retrospective analysis of real world palbociclib use reveals an association with grade 3/4 neutropenia with better outcome and early neutropenia nadir with worse outcome. Our findings of Asian specific SNPs support a predisposition toward profound and prevalent neutropenia in Asian patients under CDK4/6i. We also report the first pharmacokinetics analysis on a patient with peritoneal dialysis receiving CDK4/6i. In summary, our study provides novel clinical and genotypic insights into CDK4/6i associated neutropenia.
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Neoplasias da Mama , Neutropenia , Piperazinas , Piridinas , Feminino , Humanos , Estudos Retrospectivos , Prevalência , Receptor ErbB-2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Neutropenia/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quinase 4 Dependente de CiclinaRESUMO
Importance: The incidence of brain metastasis is increasing in patients with metastatic breast cancer. Treatments to extend the control of brain metastasis are urgently required. Objective: To investigate whether the addition of an induction treatment of bevacizumab, etoposide, and cisplatin (BEEP) improves brain-specific progression-free survival (PFS) after whole-brain radiotherapy (WBRT). Design, Setting, and Participants: This open-label, randomized, multicenter clinical trial assessed patients with brain metastases from breast cancer (BMBC) in Taiwan from September 9, 2014, to December 24, 2018, with survival follow-up until December 31, 2021. Key inclusion criteria included metastatic brain tumors not suitable for focal treatment, WBRT naivety, age 20 to 75 years, and at least 1 measurable brain metastatic lesion. The primary end point was brain-specific PFS, with an expected hazard ratio of 0.60, a 2-sided α ≤ .20, and power of 0.8. Interventions: Eligible patients were randomly assigned at a ratio of 2:1 to the experimental arm, which involved 3 cycles of BEEP followed by WBRT, or the control arm, which involved WBRT alone. Main Outcomes and Measures: The primary end point was the determination of brain-specific PFS by local investigators according to the Response Evaluation Criteria in Solid Tumors, version 1.1, the initiation of other brain-directed treatment after WBRT, or death. Other key end points included brain-specific objective response rate after 8 weeks of BEEP treatment or WBRT and 8-month brain-specific PFS rate, PFS, and overall survival. Results: A total of 118 patients with BMBC were randomized, with the intention-to-treat cohort comprising 112 patients. The median age was 56 years (range, 34-71 years), and 61 patients (54.5%) had ERBB2 (formerly HER2 or HER2/neu)-positive disease. The median (range) brain-specific PFS was 8.1 (0.3-29.5) vs 6.5 (0.9-25.5) months in the experimental and control arms, respectively (hazard ratio, 0.71; 95% CI, 0.44-1.13; P = .15; significant at predefined α ≤ .20). The brain-specific objective response rate at 2 months was not significantly different (BEEP treatment vs WBRT, 41.9% vs 52.6%), but the 8-month brain-specific PFS rate was significantly higher in the experimental group (48.7% vs 26.3%; P = .03). Adverse events were generally manageable with prophylactic granulocyte colony-stimulating factor treatment. Conclusions and Relevance: The findings show that induction BEEP before WBRT may improve the control of BMBC compared with using upfront WBRT, which could address an unmet need for an effective systemic treatment for intractable brain and extracranial metastases from metastatic breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02185352.
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Neoplasias Encefálicas , Neoplasias da Mama , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/uso terapêutico , Encéfalo/patologia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Cisplatino/uso terapêutico , Etoposídeo/uso terapêuticoRESUMO
BACKGROUND: The homologous recombination (HR) repair pathway for DNA damage, particularly the BRCA1 and BRCA2 genes, has become a target for cancer therapy, with poly ADP-ribose polymerase (PARP) inhibitors showing significant outcomes in treating germline BRCA1/2 (gBRCA1/2) mutated breast cancer. Recent studies suggest that some patients with somatic BRCA1/2 (sBRCA1/2) mutation or mutations in HR-related genes other than BRCA1/2 may benefit from PARP inhibitors as well, particularly those with PALB2 mutations. The current analysis aims to evaluate the prevalence of genetic alterations specific to BRCA1, BRCA2, and PALB2 in a large cohort of Taiwanese breast cancer patients through tumor-targeted sequencing. METHODS: A total of 924 consecutive assays from 879 Taiwanese breast cancer patients underwent tumor-targeted sequencing (Thermo Fisher Oncomine Comprehensive Assay v3). We evaluated BRCA1, BRCA2, and PALB2 mutational profiles, with variants annotated and curated by the ClinVAR, the Oncomine™ Knowledgebase Reporter, and the OncoKB™. We also conducted reflex germline testing using either whole exome sequencing (WES) or whole genome sequencing (WGS), which is ongoing. RESULTS: Among the 879 patients analyzed (924 assays), 130 had positive mutations in BRCA1 (3.1%), BRCA2 (8.6%), and PALB2 (5.2%), with a total of 14.8% having genetic alterations. Co-occurrence was noted between BRCA1/BRCA2, BRCA1/PALB2, and BRCA2/PALB2 mutations. In BRCA1-mutated samples, only p.K654fs was observed in three patients, while other variants were observed no more than twice. For BRCA2, p.N372H was the most common (26 patients), followed by p.S2186fs, p.V2466A, and p.X159_splice (5 times each). For PALB2, p.I887fs was the most common mutation (30 patients). This study identified 176 amino acid changes; 60.2% (106) were not documented in either ClinVAR or the Oncomine™ Knowledgebase Reporter. Using the OncoKB™ for annotation, 171 (97.2%) were found to have clinical implications. For the result of reflex germline testing, three variants (BRCA1 c.1969_1970del, BRCA1 c.3629_3630del, BRCA2 c.8755-1G > C) were annotated as Pathogenic/Likely pathogenic (P/LP) variants by ClinVar and as likely loss-of-function or likely oncogenic by OncoKB; while one variant (PALB2 c.448C > T) was not found in ClinVar but was annotated as likely loss-of-function or likely oncogenic by OncoKB. CONCLUSION: Our study depicted the mutational patterns of BRCA1, BRCA2, and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.
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Proteína BRCA1 , Neoplasias da Mama , Humanos , Feminino , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Genes BRCA2 , Prevalência , Mutação em Linhagem Germinativa , Predisposição Genética para Doença , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , GenômicaRESUMO
The use of non-pharmacological strategies to complement pharmacological approaches can enhance cancer pain management by promoting patient autonomy and increasing management effectiveness. This study aimed to explore the required behavioral adaptations and situational barriers that cancer patients encounter when utilizing non-pharmacological strategies to manage pain. We adopted an exploratory-descriptive qualitative research approach, purposive sampling, and semi-structured interview guidelines to conduct face-to-face interviews with 18 cancer patients experiencing moderate or severe levels of worst pain. Data were analyzed using inductive content analysis to explore patients' experiences. Five themes described the behavioral adaptations of patients using non-pharmacological strategies to deal with cancer pain: finding complementary therapies, utilizing assistive skills, adapting to assistive skills, diverting attention, and seeking help. Situational barriers faced by patients include being in the workplace or in a climate-affected environment. Behavioral adaptation is necessary for non-pharmacological strategies to coping with cancer pain. The behavioral skills can help the patients to overcome situational barriers to engagement with these strategies. Thus, health professionals are expected to help the patients acquire adequate behavioral adaptation and skills for self-pain management, and assess the effectiveness of the strategies.
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Neoadjuvant chemotherapy (NACT)-induced pathologic complete response (pCR) is associated with a favorable prognosis for breast cancer. Prior research links tumor-infiltrating lymphocytes with breast cancer chemotherapy response, suggesting the tumor-immune microenvironment's role. The aim of this study was to evaluate the immune-related genes that exhibit associations with the response to NACT. In this study, we analyzed a total of 37 patients (aged 27-67) who received NACT as the first-line treatment for primary breast cancer, followed by surgery. This group consisted of nine patients (24.3 %) with estrogen receptor (ER)-positive/HER2-negative status, ten patients (27.0 %) with ER-positive/HER2-positive status, five patients (13.5 %) with ER-negative/HER2-positive status, and thirteen patients (35.1 %) with triple-negative breast cancer (TNBC). Among these patients, twelve (32.4 %) achieved a pCR, with eight (66.6 %) having HER2-positive tumors, and the remaining four having TNBC. To identify immune-related genes linked with pCR in subjects with breast cancer prior to NACT, we collected fresh tissues for next-generation sequencing. Patients with pCR had higher expressions of eight genes, KLRK1, IGJ, CD69, CD40LG, MS4A1, CD1C, KLRB1, and CA4, compared to non-pCR patients. The 8-gene signature was associated with good prognosis and linked to better relapse-free survival in patients receiving chemotherapy. The expression of these genes was involved in better drug response, displaying a positive correlation with the infiltration of immune cells. In conclusion, we have identified eight immune-related genes that are associated with a favorable prognosis and positive responses to drugs. This 8-gene signature could potentially provide prognostic insights for breast cancer patients undergoing NACT.
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In this study, we evaluated the concordance of targeted sequencing between paired ctDNA and matched tumor samples from early breast cancers treated with curative intention. Molecular profiling was performed using the Oncomine Comprehensive Assay v3 and the Oncomine Breast cfDNA Assay v2. The liquid biopsy detection rate was 39% (all-stage breast cancers, n = 612). Among 246 early-stage patients assayed for both ctDNA and matched tumor, the cfDNA assay detected 73 (29.6%) and the comprehensive assay detected 201 (81.7%) breast cancers with at least one alteration (χ2 test, p = 0.001). In total, 67 (25.6%) cases tested positive on both platforms, while the cfDNA and comprehensive assays detected an additional 10 (4%) and 138 (56%) cases, respectively. The most prevalent mutant genes were TP53 (68.3%) and KRAS (53.5%), while the PIK3CA (39.4%), AKT1 (45.9%), and ERBB2 (17.1%) mutations constituted biomarkers for FDA-approved therapeutics. Our study showed that tumor tissue should be the source of actionable mutation detection for early breast cancers, considering that the concordance rate between tumor and liquid biopsy was only one-quarter.
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Background: Breast cancer is the most common cancer type that affects women. In hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the most frequently mutated gene associated with poor prognosis. This study evaluated the frequency of PIK3CA mutations in the Taiwanese breast cancer population. Methodology: This is a retrospective study; patient data were collected for 2 years from a next-generation sequencing database linked to electronic health records (EHRs). The primary endpoint was the regional prevalence of PIK3CA mutation. The secondary endpoints were to decipher the mutation types across breast cancer subtype, menopausal status, and time to treatment failure after everolimus (an mTOR inhibitor) or cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment. Results: PIK3CA mutations were identified in 278 of 728 patients (38%). PIK3CA mutations were reported in 43% of patients with HR-/HER2+ subtype and 42% of patients with HR+/HER2- postmenopausal status. A lower prevalence of PIK3CA mutations was observed in triple-negative (27%) and HR+/HER2- premenopausal patients (29%). The most common mutation was at exon 20 (H1047R mutation, 41.6%), followed by exon 9 (E545K mutation, 18.9% and E542K mutation, 10.3%). Among patients treated with CDK4/6 inhibitors, the median time to treatment failure was 12 months (95% CI: 7-21 months) in the PIK3CA mutation cohort and 16 months (95% CI: 11-23 months) in the PIK3CA wild-type cohort, whereas patients receiving an mTOR inhibitor reported a median time to treatment failure of 20.5 months (95% CI: 8-33 months) in the PIK3CA mutation cohort and 6 months (95% CI: 2-9 months) in the PIK3CA wild-type cohort. Conclusion: A high frequency of PIK3CA mutations was detected in Taiwanese patients with breast cancer, which was consistent with previous studies. Early detection of PIK3CA mutations might influence therapeutic decisions, leading to better treatment outcomes.
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Trastuzumab deruxtecan (T-DXd)-an antibody-drug conjugate targeting the human epidermal growth factor receptor 2 (HER2)-improved outcomes of patients with HER2-positive and HER2-low metastatic breast cancer. Guidance on monitoring and managing T-DXd-related adverse events (AEs) is an emerging unmet need as translating clinical trial experience into real-world practice may be difficult due to practical and cultural considerations and differences in health care infrastructure. Thus, 13 experts including oncologists, pulmonologists and a radiologist from the Asia-Pacific region gathered to provide recommendations for T-DXd-related AE monitoring and management by using the latest evidence from the DESTINY-Breast trials, our own clinical trial experience and loco-regional health care considerations. While subgroup analysis of Asian (excluding Japanese) versus overall population in the DESTINY-Breast03 uncovered no major differences in the AE profile, we concluded that proactive monitoring and management are essential in maximising the benefits with T-DXd. As interstitial lung disease (ILD)/pneumonitis is a serious AE, patients should undergo regular computed tomography scans, but the frequency may have to account for the median time of ILD/pneumonitis onset and access. Trastuzumab deruxtecan appears to be a highly emetic regimen, and prophylaxis with serotonin receptor antagonists and dexamethasone (with or without neurokinin-1 receptor antagonist) should be considered. Health care professionals should be vigilant for treatable causes of fatigue, and patients should be encouraged to use support groups and practice low-intensity exercises. To increase treatment acceptance, patients should be made aware of alopecia risk prior to starting T-DXd. Detailed monitoring and management recommendations for T-DXd-related AEs are discussed further.
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Imunoconjugados , Doenças Pulmonares Intersticiais , Pneumonia , Humanos , ÁsiaRESUMO
Haemophilia A patients who develop factor VIII inhibitors pose a challenge with respect to bleeding and orthopaedic management. This is particularly relevant in cases requiring amputation. We present here a case of a patient with severe haemophilia A and inhibitors who had a history of multiple surgeries due to periprosthetic joint infection and a non-healing wound which led to above-knee amputation. Following the implementation of appropriate and suitable transfemoral prosthesis and emicizumab therapy, the patient experienced a significant improvement in mobility and quality of life without any adverse events or bleeding episodes. Additional studies are required to more fully understand treatment options for lower limb amputations in the haemophilia population.
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Hemofilia A , Ortopedia , Humanos , Hemofilia A/complicações , Fator VIII , Qualidade de Vida , Amputação CirúrgicaRESUMO
Background: Paclitaxel is widely used for the treatment of metastatic breast cancer (MBC). However, it has a low oral bioavailability due to gut extrusion caused by P-glycoprotein (P-gp). Oral paclitaxel (oPAC) may be more convenient, less resource-intensive, and more tolerable than its intravenous form. Encequidar (E) is a first-in-class, minimally absorbed, gut-specific oral P-gp inhibitor that facilitates the oral absorption of paclitaxel. Objectives: To investigate the pharmacokinetics (PK), overall response rate (ORR), and safety of weekly oral paclitaxel with encequidar (oPAC + E) in patients with advanced breast cancer. Design: This is a multicenter, single-arm, open-label study in six medical centers in Taiwan. Methods: Patients with advanced breast cancer were administered 205 mg/m2 oPAC and 12.9 mg E for 3 consecutive days weekly for up to 16 weeks. Plasma samples were collected at weeks 1 and 4. PK, ORR, and safety were evaluated. Results: In all, 28 patients were enrolled; 27 had MBC; 23 had prior chemotherapy; and 14 had ⩾2 lines of prior chemotherapy. PK were evaluable in 25 patients. Plasma paclitaxel area under the curve (AUC)(0-52 h) at week 1 (3419 ± 1475 ng h/ml) and week 4 (3224 ± 1150 ng h/ml) were equivalent. Best overall response in 28 evaluable patients was partial response (PR) in 11 (39.3%), 13 (46.4%) stable disease (SD), and 1 (3.6%) with progressive disease (PD). No patient achieved complete response (CR). The clinical benefit rate (CR + PR + SD) was 85.7%. Major adverse events among the 28 treated patients were grade 3 neutropenia (25%), grade 4 neutropenia (18%), with febrile neutropenia in 4%, and grade 3 diarrhea (4%). No treatment-related deaths occurred. Grade 2 peripheral neuropathy occurred in 1 (4%) patient and grade 3 peripheral neuropathy in 1 (4%) patient. Conclusions: oPAC + E produced a consistent therapeutic plasma paclitaxel exposure during treatment. There was a high rate of radiologically assessed clinical benefit, and a low rate of neurotoxicity which may provide advantages over IV paclitaxel. Registration: ClinicalTrials.gov Identifier: NCT03165955.
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Damage associated molecular patterns (DAMPs), including calreticulin (CRT) exposure, high-mobility group box 1 protein (HMGB1) elevation, and ATP release, characterize immunogenic cell death (ICD) and may play a role in cancer immunotherapy. Triple negative breast cancer (TNBC) is an immunogenic subtype of breast cancer with higher lymphocyte infiltration. Here, we found that regorafenib, a multi-target angiokinase inhibitor previously known to suppress STAT3 signaling, induced DAMPs and cell death in TNBC cells. Regorafenib induced the expression of HMGB1 and CRT, and the release of ATP. Regorafenib-induced HMGB1 and CRT were attenuated following STAT3 overexpression. In a 4T1 syngeneic murine model, regorafenib treatment increased HMGB1 and CRT expression in xenografts, and effectively suppressed 4T1 tumor growth. Immunohistochemical staining revealed increased CD4+ and CD8+ tumor-infiltrating T cells in 4T1 xenografts following regorafenib treatment. Regorafenib treatment or programmed death-1 (PD-1) blockade using anti-PD-1 monoclonal antibody reduced lung metastasis of 4T1 cells in immunocompetent mice. While regorafenib increases the proportion of MHC II high expression on dendritic cells in mice with smaller tumors, the combination of regorafenib and PD-1 blockade did not show a synergistic effect on anti-tumor activity. These results suggest that regorafenib induces ICD and suppresses tumor progression in TNBC. It should be carefully evaluated when developing a combination therapy with an anti-PD-1 antibody and a STAT3 inhibitor.
Assuntos
Proteína HMGB1 , Neoplasias de Mama Triplo Negativas , Camundongos , Humanos , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Proteína HMGB1/farmacologia , Morte Celular , Trifosfato de Adenosina/farmacologia , Linhagem Celular TumoralRESUMO
Cancer-associated thrombosis (CAT) is a common complication of malignancies. Patients with CAT are at risk of venous thromboembolism recurrence, but also at risk of bleeding while anticoagulated. Taiwanese patients are perceived to have a lower incidence of CAT, likely leading to false reassurance for Taiwanese patients with cancer. Because of this, oncologists and cardiologists from multiple medical institutions in Taiwan have set forth to provide clinical consensus guidelines on the management of CAT, based on local clinical practices and guided by predominant international clinical practice guidelines. This paper aims to describe the current disease burden of cancer-associated venous thromboembolism in Taiwanese cancer patients, and discusses the unmet needs and gaps in the management of this medical complication. It also outlines diagnostic and management strategies relevant to the different treatment options available, such as non-vitamin K antagonist oral anticoagulants.
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BACKGROUND: Neoadjuvant systemic therapy (NST) is conducted in increased number of patients with breast cancer overexpressing human epidermal growth factor receptor 2 (HER2). Whether the intensity of HER2 protein expression determines response to treatment is challenged. This study aims to analyze the impact of HER2 immunohistochemical (IHC) scores on NST response and survival outcome. METHODS: We analyzed a total of 197 patients with HER2-positive breast cancer receiving NST and definite surgery from a prospectively collected database. The analyzed endpoints included pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS). More patients with IHC 2+/ in situ hybridization (ISH)-positive tumors presented positive for hormonal receptors, compared with those with IHC 3+ tumors. No clinicopathological features except tumor necrosis were significantly associated with pCR. RESULTS: Both positive hormone receptors and IHC scores stood on the borderline in statistical analysis. IHC 3+ group tends to present a higher pCR rate than IHC 2+/ISH+ groups (52.5% vs. 34.3%). Patients who achieved pCR had better survival outcome than that of non-pCR group. The impact of pCR on survival reached the statistical significance in the IHC 3+ group both in DFS (90.9% vs. 76.5%; p = 0.004) and OS (97.4% vs. 83.2%; p = 0.002). Multivariate analysis demonstrated IHC scores as an independent predictor of survival outcome with the adjustment of tumor staging and pCR. CONCLUSION: HER2 IHC score is an independent predictor for outcome. IHC 3+ tumors presented a trend of higher pCR rate and better outcome in HER2-positive breast cancer patients who receive NST.