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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 de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Piperazinas , Inhibidores de Proteínas Quinasas , Purinas , Piridinas , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Persona de Mediana Edad , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Piridinas/uso terapéutico , Estudios Retrospectivos , Anciano , Piperazinas/uso terapéutico , Aminopiridinas/uso terapéutico , Purinas/uso terapéutico , Taiwán , Inhibidores de Proteínas Quinasas/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Resultado del Tratamiento , Metástasis de la Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pueblo AsiaticoRESUMEN
BACKGROUND: Assessment of breast volume is essential in preoperative planning of immediate breast reconstruction (IBR) surgery to achieve satisfactory cosmetic outcome. This study introduced a breast volume measurement tool that can be used to perform automatic segmentation of magnetic resonance images (MRI) and calculation of breast volume. We compared the accuracy and reliability of this measurement method with four other conventional modalities. METHODS: Patients who were scheduled to undergo mastectomy with IBR between 2016 and 2021 were enrolled in the study. Five different breast volume assessments, including automatic segmentation of MRI, manual segmentation of MRI, 3D surface imaging, mammography, and the BREAST-V formula, were used to evaluate different breast volumes. The results were validated using water displacement volumes of the mastectomy specimens. RESULTS: In this pilot study, a total of 50 female patients met the inclusion criteria and contributed 54 breast specimens to the volumetric analysis. There was a strong linear association between the MRI and water displacement methods (automatic segmentation: r = 0.911, p < 0.001; manual segmentation: r = 0.924, p < 0.001), followed by 3D surface imaging (r = 0.858, p < 0.001), mammography (r = 0.841, p < 0.001), and Breast-V formula (r = 0.838, p < 0.001). Breast volumes measured using automatic and manual segmentation of MRI had lower mean relative errors (30.3% ± 22.0% and 28.9% ± 19.8, respectively) than 3D surface imaging (38.9% ± 31.2), Breast-V formula (44.8% ± 25.8), and mammography (60.3% ± 37.6). CONCLUSION: Breast volume assessment using the MRI methods had better accuracy and reliability than the other methods used in our study. Breast volume measurement using automatic segmentation of MRI could be more efficient compared to the conventional methods.
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Mama , Imagenología Tridimensional , Imagen por Resonancia Magnética , Mamoplastia , Humanos , Femenino , Imagen por Resonancia Magnética/métodos , Mamoplastia/métodos , Persona de Mediana Edad , Proyectos Piloto , Adulto , Mama/diagnóstico por imagen , Mama/cirugía , Mama/patología , Reproducibilidad de los Resultados , Tamaño de los Órganos , Mastectomía/métodos , Estudios Prospectivos , Mamografía/métodos , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , AncianoRESUMEN
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 de la Mama , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Genómica , Mutación , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
BACKGROUND: Surgery is the recommended treatment for breast cancer, the most common cancer in women in Taiwan and the leading cause of cancer-related deaths. Although breast-conserving surgery (BCS) has good prognosis, in some cases, BCS may cause more significant deformities and interfere with the patient's psychosocial well-being. Oncoplastic breast surgery (OBS) is the treatment option in these cases. This study aimed to determine the outcomes of OBS and BCS regardless of clinical and patient-reported esthetic outcomes. METHODS: Between 2015 and 2020, 50 patients who underwent OBS at our hospital after complete treatment were enrolled. With 1:2 matched ratios, 100 patients were enrolled in the BCS control group. Clinical outcomes were analyzed. The BREAST-Q questionnaire was then assessed 6 months after the completion of treatment for subjective patient-reported outcomes. RESULTS: Due to the matching process, no difference was noted between the two groups in terms of demographic data such as age, comorbidities, or tumor characteristics. There were no significant differences in the local recurrence rate, disease-free survival, overall survival, positive margin rate, rewide excision rate, conversion to mastectomy rate, or complication rate (major or minor) between both groups. However, the OBS group showed higher satisfaction with breasts in the BREAST-Q questionnaire ( p < 0.001). The mean follow-up time was 38.77 ± 14.70 months in the BCS group and 29.59 ± 14.06 months in the OBS group. CONCLUSION: OBS seems to be a safe and feasible surgery in breast cancer patients because clinical outcomes are compatible with BCS. Moreover, the OBS group had better patient-reported outcomes in terms of satisfaction.
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Neoplasias de la Mama , Mamoplastia , Humanos , Femenino , Mastectomía , Neoplasias de la Mama/patología , Estudios de Cohortes , Mastectomía Segmentaria/efectos adversos , Medición de Resultados Informados por el Paciente , Estudios RetrospectivosRESUMEN
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 de la Mama , Neutropenia , Piperazinas , Piridinas , Femenino , Humanos , Estudios Retrospectivos , Prevalencia , Receptor ErbB-2/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Neutropenia/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quinasa 4 Dependiente de la CiclinaRESUMEN
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 de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Proteína BRCA1/genética , Taiwán/epidemiología , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/genética , Proteína BRCA2/genética , Genómica , Mutación , Recurrencia , Fosfatidilinositol 3-Quinasa Clase I/genética , Biomarcadores de Tumor/genética , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
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 de la Mama , Humanos , Femenino , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Genes BRCA2 , Prevalencia , Mutación de Línea Germinal , Predisposición Genética a la Enfermedad , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , GenómicaRESUMEN
Organic light-emitting diodes (OLEDs) have outperformed conventional display technologies in smartphones, smartwatches, tablets, and televisions while gradually growing to cover a sizable fraction of the solid-state lighting industry. Blue emission is a crucial chromatic component for realizing high-quality red, green, blue, and yellow (RGBY) and RGB white display technologies and solid-state lighting sources. For consumer products with desirable lifetimes and efficiency, deep blue emissions with much higher power efficiency and operation time are necessary prerequisites. This article reviews over 700 papers covering various factors, namely, the crucial role of blue emission for full-color displays and solid-state lighting, the performance status of blue OLEDs, and the systematic development of fluorescent, phosphorescent, and thermally activated delayed fluorescence blue emitters. In addition, various challenges concerning deep blue efficiency, lifetime, and approaches to realizing deeper blue emission and higher efficacy for blue OLED devices are also described.
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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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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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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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PURPOSE: Invasive lobular cancer (ILC) is the second most common histology type of breast cancer followed by invasive ductal carcinoma (IDC). This study aimed to investigate the characteristic, treatment strategies, and clinical outcomes of ILC based on a national population-based cancer registry. METHODS: This study recruited 2671 ILC and 52,215 IDC patients diagnosed between 2011 and 2017 using the Taiwan Cancer Registry (TCR). Correlations between ILC and IDC subgroups were assessed using 1:4 propensity score matching and compared using the χ2 test. Disease free survival(DFS) and overall survival(OS) were estimated using the Kaplan-Meier method with the log-rank test. The risk of disease relapse and mortality were assessed using Cox proportional hazards model. RESULTS: ILC patients had larger tumor sizes, more positive axillary lymph node involvement, lower tumor grade, and higher cancer stage than IDC patients. After matching, ILC patients had a significantly higher rate of receiving mastectomy (58.93% and 53.85%) and positive surgical margin regardless of surgery type. ILC exhibited a significantly higher rate of distant metastasis than IDC(3.67% and 2.93%), but no difference in local recurrence rate, DFS or OS between the two groups. Higher cancer stage, higher grade, and mastectomy were risk factors for disease relapse and cancer-specific mortality. The hormone receptor-positive and HER2 over-expression subtypes were found to be associated with a reduced risk of disease relapse, while only PR positivity was associated with a decreased risk of mortality. (all P-values < 0.05). CONCLUSION: ILC patients had a higher mastectomy rate, higher surgical margin rate and distant metastasis rate than IDC patients. There is no significant difference in DFS or OS between ILC and IDC patients. Mastectomy was associated with poor outcomes regardless of ILC or IDC.
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Neoplasias de la Mama , Carcinoma Ductal de Mama , Carcinoma Lobular , Humanos , Femenino , Carcinoma Lobular/patología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/terapia , Carcinoma Ductal de Mama/tratamiento farmacológico , Taiwán/epidemiología , Mastectomía , Recurrencia Local de Neoplasia/patología , Resultado del Tratamiento , Sistema de Registros , Estudios RetrospectivosRESUMEN
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.
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Proteína HMGB1 , Neoplasias de la Mama Triple Negativas , Ratones , Humanos , Animales , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Proteína HMGB1/farmacología , Muerte Celular , Adenosina Trifosfato/farmacología , Línea Celular TumoralRESUMEN
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.
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Neoplasias de la Mama , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Hibridación Fluorescente in Situ , Terapia Neoadyuvante , PronósticoRESUMEN
PURPOSE: Trastuzumab, a potent anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody, is conditionally reimbursed by the Taiwan National Health Insurance (NHI) for HER2-positive breast cancer (BC). Trastuzumab-induced cardiotoxicity studies have well characterized heart failure (HF) but fewer addressed arrhythmia, particularly the association of potential life threatening atrial fibrillation (Af) is poorly characterized. We aimed to study the trastuzumab-related risk of Af and HF using the claimed data of Taiwan NHI. METHODS: A nationwide retrospective cohort of patients with BC from the Taiwan NHI reimbursement database from January 2007 to December 2016 was analyzed. Propensity score matching and competing risk model analysis were used for adjusting confounding concurrent medication or comorbidities and competing events. The HF study was used to validate the method used. RESULTS: For Af, 12,472 trastuzumab users were matched with 12,472 non-trastuzumab users. For HF, 12,241 trastuzumab users and 12,241 non-users were enrolled. We found that trastuzumab users had significantly worse HF-free survival but not Af-free survival than non-trastuzumab users. In the competing risk analysis, the use of trastuzumab did not increase the risk of Af (hazard ratio [HR] 0.76, P = 0.0006) but was associated with HF (HR 1.19, P = 0.0052). The risk trends among stratifications by comorbidities and concurrent medication remained in similar directions for both Af and HF. CONCLUSION: Trastuzumab in real-world practice was associated with an increased risk of HF, but was not associated with an increased risk of Af in BC patients. Trastuzumab-induced arrhythmogenic effects may be masked by concurrent heart-protecting measures, more prominent roles of comorbidities or concurrent medications under real-world settings. Further studies are required.
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Fibrilación Atrial , Neoplasias de la Mama , Insuficiencia Cardíaca , Humanos , Femenino , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/epidemiología , Trastuzumab/efectos adversos , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/epidemiología , Estudios Retrospectivos , Puntaje de Propensión , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/epidemiología , Medición de RiesgoRESUMEN
The N-acyl-d-amino acid amidohydrolase (N-d-AAase) of Variovorax paradoxus Iso1 can enantioselectively catalyze the zinc-assisted deacetylation of N-acyl-d-amino acids to yield consistent d-amino acids. A putative FAD-binding glycine/d-amino acid oxidase was located immediately upstream of the N-d-AAase gene. The gene encoding this protein was cloned into Escherichia coli BL21 (DE3)pLysS and overexpressed at 25°C for 6 h with 0.5 mM isopropyl ß-d-1-thiogalactopyranoside induction. After purification, the tag-free recombinant protein was obtained. The enzyme could metabolize glycine, sarcosine, and d-alanine, but not l-amino acids or bulky d-amino acids. Protein modeling further supported these results, demonstrating that glycine, sarcosine, and d-alanine could fit into the pocket of the enzyme's activation site, while l-alanine and d-threonine were out of position. Therefore, this protein was proposed as a glycine oxidase, and we designated it VpGO. Interestingly, VpGO showed low sequence similarity to other well-characterized glycine oxidases. We found that VpGO and N-d-AAase were expressed on the same mRNA and could be transcriptionally induced by various N-acetyl-d-amino acids. Western blotting and zymography showed that both proteins had similar expression patterns in response to different types of inducers. Thus, we have identified a novel glycine oxidase that is co-regulated with N-d-AAase in an operon, and metabolizes N-acyl-d-amino acids in the metabolically versatile V. paradoxus Iso1. IMPORTANCE The Gram-negative bacterium Variovorax paradoxus has numerous metabolic capabilities, including the association with important catabolic processes and the promotion of plant growth. We had previously identified and characterized an N-acyl-d-amino-acid amidohydrolase (N-d-AAase) gene from the strain of V. paradoxus Iso1. The aim of this study was to isolate and characterize (both in vitro and in vivo) another potential gene found in the promoter region of this N-d-AAase gene. The protein was identified as a glycine oxidase, and the gene existed in an operon with N-d-AAase. The structural basis for its FAD-binding potential and substrate stereo-specificity were also elucidated. This study first reported a novel glycine oxidase from V. paradoxus. We believe that our study makes a significant contribution to the literature, because this enzyme has great potential for use as an industrial catalysis, as a biosensor, and in agricultural biotechnology.
Asunto(s)
Flavina-Adenina Dinucleótido , Sarcosina , Flavina-Adenina Dinucleótido/metabolismo , Escherichia coli/metabolismo , Amidohidrolasas/genética , Aminoácidos , Especificidad por Sustrato , AlaninaRESUMEN
BACKGROUND: Upper abdominal surgical treatment may reduce respiratory muscle function and mucociliary clearance, which might be a cause of postoperative pulmonary complications (PPCs). Threshold inspiratory muscle training (IMT) may serve as an effective modality to improve respiratory muscle strength and endurance in patients. However, whether this training could help patients with upper abdominal surgery remains to be determined. The aim of the present investigation was to determine the effect of a fully engaged IMT on PPCs and respiratory function in patients undergoing upper abdominal surgery. We hypothesized that the fully engaged IMT could reduce PPCs and improve respiratory muscle function in patients with upper abdominal surgery. METHODS: This is a randomized controlled trial (RCT) with 28 patients who underwent upper abdominal surgery. Patients were randomly assigned to the control (CLT) group or the IMT group. The CTL group received regular health care. The IMT group received 3 weeks of IMT with 50% of MIP as the initial intensity before the operation. The intensity of MIP increased by 5-10% per week. The IMT was continued for 4 weeks after the operation. The study investigated the outcomes including PPCs, respiratory muscle strength, diaphragmatic function, cardiopulmonary function, and quality of life (QoL). RESULTS: We found that IMT improved respiratory muscle strength and diaphragmatic excursion. IMT also had a beneficial effect on the incidence of postoperative pulmonary complications (PPCs) compared to CLT care. CONCLUSION: The results from this study revealed that IMT provided positive effects on parameters associated with the respiratory muscle function and reduced the incidence of PPCs. We propose that fully engaged IMT should be a part of clinical management in patients with upper abdominal surgery.KEY MESSAGESThe fully engaged inspiratory muscle training reduces postoperative pulmonary complications rate in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases maximal inspiratory pressure in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases diaphragm function in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases the quality of life in patients with upper abdominal surgery.
Asunto(s)
Ejercicios Respiratorios , Músculos Respiratorios , Ejercicios Respiratorios/métodos , Humanos , Pulmón , Fuerza Muscular/fisiología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Músculos Respiratorios/fisiologíaRESUMEN
Selective methane oxidation is difficult chemistry. Here we describe a strategy for the electrocatalysis of selective methane oxidation by immobilizing tricopper catalysts on the cathodic surface. In the presence of dioxygen and methane, the activation of these catalysts above a threshold cathodic potential can initiate the dioxygen chemistry for O atom transfer to methane. The catalytic turnover is completed by facile electron injections into the tricopper catalysts from the electrode. This technology leads to dramatic enhancements in performance of the catalysts toward methane oxidation. Unprecedented turnover frequencies (>40 min-1) and high product throughputs (turnover numbers >30â¯000 in 12 h) are achieved for this challenging chemical transformation in water under ambient conditions. The technology is green and suitable for on-site direct conversion of methane into methanol.