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Mesenchymal stromal cells (MSCs) display heterogeneity in origin and functional role in tissue homeostasis. Subsets of MSCs derived from the neural crest express nestin and serve as niches in bone marrow, but the possibility of coaxing MSCs into nestin-expresing cells for enhanced supportive activity is unclear. In this study, as an approach to the chemical coaxing of MSC functions, we screened libraries of clinically approved chemicals to identify compounds capable of inducing nestin expression in MSCs. Out of 2000 clinical compounds, we chose vorinostat as a candidate to coax the MSCs into neural crest-like fates. When treated with vorinostat, MSCs exhibited a significant increase in the expression of genes involved in the pluripotency and epithelial-mesenchymal transition (EMT), as well as nestin and CD146, the markers for pericytes. In addition, these nestin-induced MSCs exhibited enhanced differentiation towards neuronal cells with the upregulation of neurogenic markers, including SRY-box transcription factor 2 (Sox2), SRY-box transcription factor 10 (Sox10) and microtubule associated protein 2 (Map2) in addition to nestin. Moreover, the coaxed MSCs exhibited enhanced supporting activity for hematopoietic progenitors without supporting leukemia cells. These results demonstrate the feasibility of the drug repositioning of MSCs to induce neural crest-like properties through the chemical coaxing of cell fates.
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Diferenciación Celular , Reposicionamiento de Medicamentos , Células Madre Mesenquimatosas , Nestina , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Nestina/metabolismo , Nestina/genética , Humanos , Diferenciación Celular/efectos de los fármacos , Reposicionamiento de Medicamentos/métodos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Células Cultivadas , Cresta Neural/citología , Cresta Neural/metabolismo , Cresta Neural/efectos de los fármacosRESUMEN
BACKGROUND: Anti-HER2 therapies, including the HER2 antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have led to improved survival outcomes in patients with HER2-overexpressing (HER2+) metastatic breast cancer. However, intrinsic or acquired resistance to anti-HER2-based therapies remains a clinical challenge in these patients, as there is no standard of care following disease progression. The purpose of this study was to elucidate the mechanisms of resistance to T-DM1 and T-DXd in HER2+ BC patients and preclinical models and identify targets whose inhibition enhances the antitumor activity of T-DXd in HER2-directed ADC-resistant HER2+ breast cancer in vitro and in vivo. METHODS: Targeted DNA and whole transcriptome sequencing were performed in breast cancer patient tissue samples to investigate genetic aberrations that arose after anti-HER2 therapy. We generated T-DM1 and T-DXd-resistant HER2+ breast cancer cell lines. To elucidate their resistance mechanisms and to identify potential synergistic kinase targets for enhancing the efficacy of T-DXd, we used fluorescence in situ hybridization, droplet digital PCR, Western blotting, whole-genome sequencing, cDNA microarray, and synthetic lethal kinome RNA interference screening. In addition, cell viability, colony formation, and xenograft assays were used to determine the synergistic antitumor effect of T-DXd combinations. RESULTS: We found reduced HER2 expression in patients and amplified DNA repair-related genes in patients after anti-HER2 therapy. Reduced ERBB2 gene amplification in HER2-directed ADC-resistant HER2+ breast cancer cell lines was through DNA damage and epigenetic mechanisms. In HER2-directed ADC-resistant HER2+ breast cancer cell lines, our non-biased RNA interference screening identified the DNA repair pathway as a potential target within the canonical pathways to enhance the efficacy of T-DXd. We validated that the combination of T-DXd with ataxia telangiectasia and Rad3-related inhibitor, elimusertib, led to significant breast cancer cell death in vitro (P < 0.01) and in vivo (P < 0.01) compared to single agents. CONCLUSIONS: The DNA repair pathways contribute to HER2-directed ADC resistance. Our data justify exploring the combination treatment of T-DXd with DNA repair-targeting drugs to treat HER2-directed ADC-resistant HER2+ breast cancer in clinical trials.
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Neoplasias de la Mama , Reparación del ADN , Resistencia a Antineoplásicos , Inmunoconjugados , Receptor ErbB-2 , Trastuzumab , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Animales , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Ratones , Receptor ErbB-2/metabolismo , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Camptotecina/análogos & derivados , Camptotecina/farmacología , Camptotecina/uso terapéutico , Sinergismo FarmacológicoRESUMEN
Purpose: Considering the high disease burden and unique features of Asian patients with breast cancer (BC), it is essential to have a comprehensive view of genetic characteristics in this population. An institutional targeted sequencing platform was developed through the Korea Research-Driven Hospitals project and was incorporated into clinical practice. This study explores the use of targeted next-generation sequencing (NGS) and its outcomes in patients with advanced/metastatic BC in the real world. Materials and Methods: We reviewed the results of NGS tests administered to BC patients using a customized sequencing platform - FiRST Cancer Panel (FCP) - over seven years. We systematically described clinical translation of FCP for precise diagnostics, personalized therapeutic strategies, and unraveling disease pathogenesis. Results: NGS tests were conducted on 548 samples from 522 patients with BC. 97.6% of tested samples harbored at least one pathogenic alteration. The common alterations included mutations in TP53(56.2%), PIK3CA(31.2%), GATA3(13.8%), BRCA2(10.2%), and amplifications of CCND1(10.8%), FGF19(10.0%), and ERBB2(9.5%). NGS analysis of ERBB2 amplification correlated well with HER2 immunohistochemistry and in situ hybridization. RNA panel analyses found potentially actionable and prognostic fusion genes. FCP effectively screened for potentially germline pathogenic/likely pathogenic mutation. 10.3% of BC patients received matched therapy guided by NGS, resulting in a significant overall survival advantage (p=0.022), especially for metastatic BCs. . Conclusion: Clinical NGS provided multifaceted benefits, deepening our understanding of the disease, improving diagnostic precision, and paving the way for targeted therapies. The concrete advantages of FCP highlight the importance of multi-gene testing for BC, especially for metastatic conditions.
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BACKGROUND/AIM: Atezolizumab plus bevacizumab and lenvatinib are currently available as first-line therapy for the treatment of unresectable hepatocellular carcinoma (HCC). However, comparative efficacy studies are still limited. This study aimed to investigate the effectiveness of these treatments in HCC patients with portal vein tumor thrombosis (PVTT). METHODS: We retrospectively included patients who received either atezolizumab plus bevacizumab or lenvatinib as first-line systemic therapy for HCC with PVTT. Primary endpoint was overall survival (OS), and secondary endpoints included progressionfree survival (PFS) and disease control rate (DCR) determined by response evaluation criteria in solid tumors, version 1.1. RESULTS: A total of 52 patients were included: 30 received atezolizumab plus bevacizumab and 22 received lenvatinib. The median follow-up duration was 6.4 months (interquartile range, 3.9-9.8). The median OS was 10.8 months (95% confidence interval [CI], 5.7 to not estimated) with atezolizumab plus bevacizumab and 5.8 months (95% CI, 4.8 to not estimated) with lenvatinib (P=0.26 by log-rank test). There was no statistically significant difference in OS (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.34-1.49; P=0.37). The median PFS was similar (P=0.63 by log-rank test), with 4.1 months (95% CI, 3.3-7.7) for atezolizumab plus bevacizumab and 4.3 months (95% CI, 2.6-5.8) for lenvatinib (aHR, 0.93; 95% CI, 0.51-1.69; P=0.80). HRs were similar after inverse probability treatment weighting. The DCRs were 23.3% and 18.2% in patients receiving atezolizumab plus bevacizumab and lenvatinib, respectively (P=0.74). CONCLUSION: The effectiveness of atezolizumab plus bevacizumab and lenvatinib was comparable for the treatment of HCC with PVTT.
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Purpose: This study aimed to investigate clinical practices and factors related to the outcomes of T-DM1 use in patients with HER2-positive metastatic breast cancer (mBC). Methods: We included patients with HER2-positive mBC who received T-DM1 as a palliative therapy between August 2017 and December 2018. The safety and outcomes of T-DM1, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) for mortality or progression to HER2-positive mBC. Results: In total, 824 patients were enrolled during the study period. The mean age of patients was 58 years, and 516 (62.6%) patients relapsed after curative treatment. Excluding a history of endocrine therapy, 341 (41.4%) patients previously received none or first-line chemotherapy, 179 (21.7%) received second-line therapy, and 303 (36.9%) received third-or later-line chemotherapy before T-DM1 therapy. During a median follow-up of 16.8 months, the ORR was 35%, the median PFS was 6.6 months, and the median OS was not reached. The clinical factors associated with the hazard of progression were age (<65 years), poor performance status (⩾2), advanced line of palliative chemotherapy (⩾2), prior pertuzumab use, and treatment duration of palliative trastuzumab (<10 months). Common grade 3-4 adverse events were thrombocytopenia (n = 107, 13.2%), neutropenia (n = 23, 2.8%), anemia (n = 21, 2.6%), and elevated liver enzyme (n = 20, 2.5%). Hypokalemia (⩽3.0 mmol/L) and any-grade bleeding events occurred in 25 (3.1%) and 94 (22.6%) patients, respectively. Conclusion: This is the first nationwide real-world study of T-DM1 use in patients with HER2-positive mBC in Korea. The effectiveness and toxicity profiles of T-DM1 in real-world practice were comparable to those in randomized trials. Moreover, patient factors and previous anti-HER2 therapy could predict the outcomes of T-DM1 therapy.
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INTRODUCTION: Metastatic breast cancer refractory to anthracycline and taxanes often shows rapid progression. The development of effective and tolerable combination regimens for these patients is needed. This phase II trial investigated the efficacy of pemetrexed plus vinorelbine in patients with metastatic breast cancer. METHODS: This randomized, open-label, phase II trial was conducted in 17 centers in Korea. Patients with advanced breast cancer who had previously been treated with anthracyclines and taxanes were randomly assigned in a 1:1 ratio to receive either vinorelbine or pemetrexed plus vinorelbine. Randomization was stratified by prior capecitabine treatment and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included the objective response rate, overall survival, safety, and quality of life. RESULTS: Between March 2017 and August 2019, a total of 125 patients were enrolled. After a median follow-up duration of 14.1 months, 118 progression events and 88 death events had occurred. Sixty-two patients were assigned to the pemetrexed plus vinorelbine arm, and 63 were assigned to the vinorelbine arm. Pemetrexed plus vinorelbine significantly prolonged PFS compared to vinorelbine (5.7 vs. 1.5 months, p < 0.001). The combination arm had higher disease control rate (76.8% vs. 45.9%, p = 0.001) and a tendency toward longer overall survival (16.8 vs. 10.5 months, p = 0.102). Anemia was more frequent in the pemetrexed plus vinorelbine arm per cycle compared with vinorelbine (7.9% vs. 1.9%, p < 0.001), but there was no difference in the incidence of grade 3-4 neutropenia per cycle between the pemetrexed plus vinorelbine arm and the vinorelbine single arm (14.7% vs. 19.5%, p = 0.066). CONCLUSIONS: This phase II study showed that pemetrexed plus vinorelbine led to a longer PFS than vinorelbine. Adverse events of pemetrexed plus vinorelbine were generally manageable.
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Neoplasias de la Mama , Pemetrexed , Vinorelbina , Femenino , Humanos , Antraciclinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Pemetrexed/uso terapéutico , Calidad de Vida , Taxoides/uso terapéutico , Vinorelbina/uso terapéuticoRESUMEN
BACKGROUND: The role of HER2 amplification level in predicting the effectiveness of HER2-directed therapies has been established. However, its association with survival outcomes in advanced HER2-positive breast cancer treated with dual HER2-blockade remains unexplored. METHODS: This is a single-center retrospective study of patients with advanced HER2-positive breast cancer treated with first-line pertuzumab, trastuzumab, and docetaxel. The primary objective was to ascertain the relationship between treatment outcomes and the level of HER2 amplification by in situ hybridization (ISH). RESULTS: A total of 152 patients were included with a median follow-up duration of 50.0 months. Among the 78 patients who received ISH, a higher HER2/CEP17 ratio correlated significantly with longer PFS (HR 0.50, p = 0.022) and OS (HR 0.28, p = 0.014) when dichotomized by the median. A higher HER2 copy number also correlated significantly with better PFS (HR 0.35, p < 0.001) and OS (HR 0.27, p = 0.009). In multivariate analysis, the HER2/CEP17 ratio was an independent predictive factor for PFS (HR 0.66, p = 0.004) and potentially for OS (HR 0.64, p = 0.054), along with HER2 copy number (PFS HR 0.85, p = 0.004; OS HR 0.84, p = 0.049). Furthermore, the correlation between HER2 amplification level by ISH with PFS and OS was consistent across the HER2 IHC 1+/2+ and 3+ categories. CONCLUSIONS: This is the first study to report that a higher level of HER2 amplification by ISH is associated with improved PFS and OS in advanced HER2-positive breast cancer treated with dual HER2-blockade. Notably, HER2 amplification level had a predictive role regardless of IHC results. Even in patients with HER2 protein expression of 3+, treatment outcome to HER2-directed therapy was dependent on the level of HER2 gene amplification.
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Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Femenino , Trastuzumab/uso terapéutico , Docetaxel , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudios Retrospectivos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Hibridación in Situ , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Hormone receptor-positive (HR+) disease is the most frequently diagnosed subtype of breast cancer. Among tumor subtypes, natural course of HR+ breast cancer is indolent with favorable prognosis compared to other subtypes such as human epidermal growth factor protein 2-positive disease and triple-negative disease. HR+ tumors are dependent on steroid hormone signaling and endocrine therapy is the main treatment option. Recently, the discovery of cyclin-dependent kinase 4/6 inhibitors and their synergistic effects with endocrine therapy has dramatically improved treatment outcome of advanced HR+ breast cancer. The demonstrated efficacy of additional nonhormonal agents, such as targeted therapy against mammalian target of rapamycin and phosphatidylinositol 3-kinase signaling, poly(ADP-ribose) polymerase inhibitors, antibody-drug conjugates, and immunotherapeutic agents have further expanded the available therapeutic options. This article reviews the latest advancements in the treatment of HR+ breast cancer, and in doing so discusses not only the development of currently available treatment regimens but also emerging therapies that invite future research opportunities in the field.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Pronóstico , Resultado del Tratamiento , Sirolimus , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
OBJECTIVES: Immunohistochemistry (IHC) for the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) biomarkers has prognostic and therapeutic value in breast cancer, while it facilitates molecular subtyping. This study aimed to identify subtype discordance and its clinical significance among different phases of breast cancer evolution, focusing on effusion cytology samples diagnosed with malignancy. METHODS: Our electronic archive was searched for all effusion cases diagnosed as breast carcinomas within a pre-defined period (January 2018-October 2021), and their cell blocks (CBs) were subjected to ER, PR, and HER2 IHC or in situ hybridization. Furthermore, information regarding the same biomarkers from previously obtained tissue specimens of these patients was extracted. RESULTS: Only 2/76 (2.6%) of the breast cancer patients analyzed showed a malignant effusion at their initial presentation. The triple negative breast cancer (TNBC) phenotype was found significantly more often at effusion CBs, compared to their paired biopsies received during initial diagnosis (30/70 vs 16/70; p<0.001). In addition, the presence of TNBC subtype was significantly associated with an earlier development of a malignant effusion, more specifically at initial diagnosis (P<0.001; log-rank test), at first recurrence/metastasis (either solid or effusion) (P=0.012; log-rank test), at effusion (P=0.007; log-rank test), and at any tumor evolution phase (P=0.009; log-rank test). CONCLUSION: Serous effusion cytology provides high-quality material for ancillary techniques, especially when CBs are prepared, reflecting cancer heterogeneity.
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BACKGROUND: For locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) may enhance tumour response, reduce recurrence, and improve patient compliance compared to upfront surgery. Recent studies have shown that chemoradiotherapy (CRT) followed by consolidation chemotherapy leads to higher rate of pathologic complete response (pCR) than induction chemotherapy followed by CRT. However, an optimal TNT regimen that maximise the pCR rate and minimise toxicity has not been established. Therefore, the aim of this trial was to investigate whether preoperative short-course radiotherapy followed by chemotherapy with four cycles of CAPOX can double the pCR rate compared to a standard schedule of long-course preoperative CRT in patients with LARC. METHODS: This is a multi-centre, prospective, open label, randomised controlled trial. Patients with clinical primary tumour stage 3 and higher or regional node-involved rectal cancer located within 10 cm from the anal verge were randomly assigned equally to short-course radiotherapy (25 Gy in 5 fractions over 1 week) followed by four cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) (TNT) or CRT (50.4 Gy in 28 fractions over 5 weeks, concurrently with concomitant oral capecitabine 825 mg/m2 twice a day). After preoperative treatment, total mesorectal excision was performed 2-4 weeks in the TNT group and 6-10 weeks in the CRT group, followed by optional additional adjuvant chemotherapy. The primary endpoint is the pCR rate, and secondary endpoints include disease-related treatment failure, quality of life, and cost-effectiveness. Assuming a pCR rate of 28% and 15% in the TNT and CRT groups, respectively, and one-side alpha error rate of 0.025 and power of 80%, 348 patients will be enrolled considering 10% dropout rate. DISCUSSION: The TV-LARK trial will evaluate the superiority of employed TNT regimen against the standard CRT regimen for patients with LARC. We aimed to identify a TNT regimen that will improve the pCR rate and decrease systemic recurrence in these patients. TRIAL REGISTRATION: Cris.nih.go.kr ID: KCT0007169 (April 08, 2022). The posted information will be updated as needed to reflect the protocol amendments and study progress.
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Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Terapia Neoadyuvante/métodos , Capecitabina/uso terapéutico , Resultado del Tratamiento , Estudios Prospectivos , Calidad de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estadificación de Neoplasias , Neoplasias del Recto/patología , Quimioradioterapia/métodos , República de Corea/epidemiología , Fluorouracilo , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. METHODS: Tissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. RESULTS: Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. CONCLUSIONS: We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Multiómica , Receptor ErbB-2/genética , Receptor ErbB-2/análisis , Receptor ErbB-2/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptores de Estrógenos/genética , Receptores de Estrógenos/análisis , Receptores de Estrógenos/uso terapéutico , Estrógenos/uso terapéuticoRESUMEN
OBJECTIVE: To investigate the association of clinical, pathologic, and magnetic resonance imaging (MRI) variables with progressive disease (PD) during neoadjuvant chemotherapy (NAC) and distant metastasis-free survival (DMFS) in patients with triple-negative breast cancer (TNBC). MATERIALS AND METHODS: This single-center retrospective study included 252 women with TNBC who underwent NAC between 2010 and 2019. Clinical, pathologic, and treatment data were collected. Two radiologists analyzed the pre-NAC MRI. After random allocation to the development and validation sets in a 2:1 ratio, we developed models to predict PD and DMFS using logistic regression and Cox proportional hazard regression, respectively, and validated them. RESULTS: Among the 252 patients (age, 48.3 ± 10.7 years; 168 in the development set; 84 in the validation set), PD was occurred in 17 patients and 9 patients in the development and validation sets, respectively. In the clinical-pathologic-MRI model, the metaplastic histology (odds ratio [OR], 8.0; P = 0.032), Ki-67 index (OR, 1.02; P = 0.044), and subcutaneous edema (OR, 30.6; P = 0.004) were independently associated with PD in the development set. The clinical-pathologic-MRI model showed a higher area under the receiver-operating characteristic curve (AUC) than the clinical-pathologic model (AUC: 0.69 vs. 0.54; P = 0.017) for predicting PD in the validation set. Distant metastases occurred in 49 patients and 18 patients in the development and validation sets, respectively. Residual disease in both the breast and lymph nodes (hazard ratio [HR], 6.0; P = 0.005) and the presence of lymphovascular invasion (HR, 3.3; P < 0.001) were independently associated with DMFS. The model consisting of these pathologic variables showed a Harrell's C-index of 0.86 in the validation set. CONCLUSION: The clinical-pathologic-MRI model, which considered subcutaneous edema observed using MRI, performed better than the clinical-pathologic model for predicting PD. However, MRI did not independently contribute to the prediction of DMFS.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Adulto , Persona de Mediana Edad , Neoplasias de la Mama Triple Negativas/diagnóstico por imagen , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Estudios Retrospectivos , Terapia Neoadyuvante/métodos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Mama/patología , Imagen por Resonancia Magnética/métodosRESUMEN
BACKGROUND: The importance of clinical staging in breast cancer has increased owing to the wide use of neoadjuvant systemic therapy (NST). This study aimed to investigate the current practice patterns regarding clinical nodal staging in breast cancer in real-world settings. MATERIALS AND METHODS: A web-based survey was administered to board-certified oncologists in Korea, including breast surgical, medical, and radiation oncologists, from January to April 2022. The survey included 19 general questions and 4 case-based questions. RESULTS: In total, 122 oncologists (45 radiation, 44 surgical, and 33 medical oncologists) completed the survey. Among them, 108 (88%) responded that clinical staging before NST was primarily performed by breast surgeons. All the respondents referred to imaging studies during nodal staging. Overall, 64 (52.5%) responders determined the stage strictly based on the radiology reports, whereas 58 (47.5%) made their own decision while noting radiology reports. Of those who made their own decisions, 88% referred to the number or size of the suspicious node. Of the 75 respondents involved in prescribing regimens for neoadjuvant chemotherapy, 58 (77.3%) responded that the reimbursement regulations in the selection of NST regimens affected nodal staging in clinical practice. In the case-based questions, high variability was observed among the clinicians in the same cases. CONCLUSIONS: Diverse assessments by specialists owing to the lack of a clear, harmonized staging system for the clinical nodal staging of breast cancer can lead to diverse practice patterns. Thus, practical, harmonized, and objective methods for clinical nodal staging and for the outcomes of post-NST response are warranted for appropriate treatment decisions and accurate outcome evaluation.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Terapia Neoadyuvante , Metástasis Linfática , Estadificación de Neoplasias , Encuestas y Cuestionarios , Pautas de la Práctica en MedicinaRESUMEN
Ocean warming and acidification can induce oxidative stress in marine species, resulting in cellular damage and apoptosis. However, the effects of pH and water temperature conditions on oxidative stress and apoptosis in disk abalone are poorly understood. This study investigated, for the first time, the effects of different water temperatures (15, 20, and 25 °C) and pH levels (7.5 and 8.1) on oxidative stress and apoptosis in disk abalone by estimating levels of H2O2, malondialdehyde (MDA), dismutase (SOD), catalase (CAT), and the apoptosis-related gene caspase-3. We also visually confirmed apoptotic effects of different water temperatures and pH levels via in situ hybridization and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. The levels of H2O2, MDA, SOD, CAT, and caspase-3 increased under low/high water temperature and/or low pH conditions. Expression of the genes was high under high temperature and low pH conditions. Additionally, the apoptotic rate was high under high temperatures and low pH conditions. These results indicate that changes in water temperature and pH conditions individually and in combination trigger oxidative stress in abalone, which can induce cell death. Specifically, high temperatures induce apoptosis by increasing the expression of the apoptosis-related gene caspase-3.
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Let-7 miRNAs have pleiotropic cellular functions in cell proliferation, migration, and regenerative processes. Here, we investigate whether the inhibition of let-7 miRNAs with antisense oligonucleotides (ASOs) can be a transient and safe strategy enhancing the therapeutic potential of mesenchymal stromal cells (MSCs) to overcome their limitations in cell therapeutic trials. We first identified major subfamilies of let-7 miRNAs preferentially expressed in MSCs, and efficient ASO combinations against these selected subfamilies that mimic the effects of LIN28 activation. When let-7 miRNAs were inhibited with an ASO combination (anti-let7-ASOs), MSCs exhibited higher proliferation with delayed senescence during the passaging into a culture. They also exhibited increased migration and enhanced osteogenic differentiation potential. However, these changes in MSCs were not accompanied by cell-fate changes into pericytes or the additional acquisition of stemness, but instead occurred as functional changes accompanied by changes in proteomics. Interestingly, MSCs with let-7 inhibition exhibited metabolic reprogramming characterized by an enhanced glycolytic pathway, decreased reactive oxygen species, and lower transmembrane potential in mitochondria. Moreover, let-7-inhibited MSCs promoted the self-renewal of neighboring hematopoietic progenitor cells, and enhanced capillary formation in endothelial cells. These findings together show that our optimized ASO combination efficiently reprograms the MSC functional state, allowing for more efficient MSC cell therapy.
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Células Madre Mesenquimatosas , MicroARNs , Osteogénesis , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos Antisentido/metabolismo , Células Endoteliales/metabolismo , Células Madre Mesenquimatosas/metabolismo , Diferenciación Celular/genética , MicroARNs/metabolismoRESUMEN
PURPOSE: Several previous studies and case reports have reported ethanol-induced symptoms in patients receiving anticancer drugs containing ethanol. Most docetaxel formulations contain ethanol as a solvent. However, there are insufficient data on ethanol-induced symptoms when docetaxel-containing ethanol is administered. The primary purpose of this study was to investigate the frequency and pattern of ethanol-induced symptoms during and after docetaxel administration. The secondary purpose was to explore the risk factors for ethanol-induced symptoms. MATERIALS AND METHODS: This was a prospective, multicenter, observational study. The participants filled out ethanol-induced symptom questionnaire on the day of chemotherapy and the following day. RESULTS: Data from 451 patients were analyzed. The overall occurrence rate of ethanol-induced symptoms was 44.3% (200/451 patients). The occurrence rate of facial flushing was highest at 19.7% (89/451 patients), followed by nausea in 18.2% (82/451 patients), and dizziness in 17.5% (79/451 patients). Although infrequent, unsteady walking and impaired balance occurred in 4.2% and 3.3% of patients, respectively. Female sex, presence of underlying disease, younger age, docetaxel dose, and docetaxel-containing ethanol amount were significantly associated with the occurrence of ethanol-induced symptoms. CONCLUSION: The occurrence of ethanol-induced symptoms was not low in patients receiving docetaxel-containing ethanol. Physicians need to pay more attention to the occurrence of ethanol-induced symptoms and prescribe ethanol-free or low-ethanol-containing formulations to high-risk patients.
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Antineoplásicos , Neoplasias de la Mama , Humanos , Femenino , Docetaxel/efectos adversos , Etanol/efectos adversos , Estudios Prospectivos , Antineoplásicos/efectos adversos , Pacientes , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológicoRESUMEN
PURPOSE: Circulating tumor DNA (ctDNA) is emerging as a valuable non-invasive tool to identify tumor heterogeneity and tumor burden. This study investigated ctDNA dynamics in metastatic colorectal cancer patients treated with regorafenib. Materials and Methods: In this prospective biomarker study, plasma cell-free DNA (cfDNA) samples obtained at baseline, at the first response evaluation after 2 cycles of treatment, and at the time of progressive disease were sequenced using a targeted next-generation sequencing platform which included 106 genes. RESULTS: A total of 285 blood samples from 110 patients were analyzed. Higher baseline cfDNA concentration was associated with worse progression-free survival (PFS) and overall survival (OS). After 2 cycles of treatment, variant allele frequency (VAF) in the majority of ctDNA mutations decreased with a mean relative change of -31.6%. Decreases in the VAF of TP53, APC, TCF7L2, and ROS1 after 2 cycles of regorafenib were associated with longer PFS. We used the sum of VAF at each time point as a surrogate for the overall ctDNA burden. A reduction in sum (VAF) of ≥ 50% after 2 cycles was associated with longer PFS (6.1 vs. 2.7 months, p=0.002), OS (11.3 vs. 5.9 months, p=0.001), and higher disease control rate (86.3% vs. 51.1%, p < 0.001). VAF of the majority of the ctDNA mutations increased at the time of disease progression, and VAF of BRAF increased markedly. CONCLUSION: Reduction in ctDNA burden as estimated by sum (VAF) could be used to predict treatment outcome of regorafenib.
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Ácidos Nucleicos Libres de Células , ADN Tumoral Circulante , Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , ADN Tumoral Circulante/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Resultado del Tratamiento , Neoplasias del Colon/patología , Biomarcadores de Tumor/genética , Mutación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genéticaRESUMEN
Mesenchymal stromal cells derived from induced pluripotent stem cells (iMSCs) have been proposed as alternative sources of primary MSCs with various advantages for cell therapeutic trials. However, precise evaluation of the differences between iMSCs and primary MSCs is lacking due to individual variations in the donor cells, which obscure direct comparisons between the two. In this study, we generated donor-matched iMSCs from individual bone marrow-derived MSCs and directly compared their cell-autonomous and paracrine therapeutic effects. We found that the transition from primary MSCs to iMSCs is accompanied by a functional shift towards higher proliferative activity, with variations in differentiation potential in a donor cell-dependent manner. The transition from MSCs to iMSCs was associated with common changes in transcriptomic and proteomic profiles beyond the variations of their individual donors, revealing expression patterns unique for the iMSCs. These iMSC-specific patterns were characterized by a shift in cell fate towards a pericyte-like state and enhanced secretion of paracrine cytokine/growth factors. Accordingly, iMSCs exhibited higher support for the self-renewing expansion of primitive hematopoietic progenitors and more potent immune suppression of allogenic immune responses than MSCs. Our study suggests that iMSCs represent a separate entity of MSCs with unique therapeutic potential distinct from their parental MSCs, but points to the need for iMSC characterization in the individual basis.
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Células Madre Pluripotentes Inducidas , Células Madre Mesenquimatosas , Proteómica , Diferenciación Celular/fisiología , Transducción de Señal , Células Madre Mesenquimatosas/metabolismoRESUMEN
BACKGROUND: Germline mutations of breast cancer susceptibility gene BRCA1 and BRCA2 (gBRCA1/2) are associated with elevated risk of breast cancer in young women in Asia. BRCA1 and BRCA2 proteins contribute to genomic stability through homologous recombination (HR)-mediated double-strand DNA break repair in cooperation with other HR-related proteins. In this study, we analyzed the targeted sequencing data of Korean breast cancer patients with gBRCA1/2 mutations to investigate the alterations in HR-related genes and their clinical implications. MATERIALS AND METHODS: Data of the breast cancer patients with pathogenic gBRCA1/2 mutations and qualified targeted next-generation sequencing, SNUH FiRST cancer panel, were analyzed. Single nucleotide polymorphisms, small insertions, and deletions were analyzed with functional annotations using ANNOVAR. HR-related genes were defined as ABL1, ATM, ATR, BARD1, BRCA1, BRCA2, CDKN1A, CDKN2A, CHEK1, CHEK2, FANCA, FANCD2, FANCG, FANCI, FANCL, KDR, MUTYH, PALB2, POLE, POLQ, RAD50, RAD51, RAD51D, RAD54L, and TP53. Mismatch-repair genes were MLH1, MSH2, and MSH6. Clinical data were analyzed with cox proportional hazard models and survival analyses. RESULTS: Fifty-five Korean breast cancer patients with known gBRCA1/2 mutations and qualified targeted NGS data were analyzed. Ethnically distinct mutations in gBRCA1/2 genes were noted, with higher frequencies of Val1833Ser (14.8%), Glu1210Arg (11.1%), and Tyr130Ter (11.1%) in gBRCA1 and Arg2494Ter (25.0%) and Lys467Ter (14.3%) in gBRCA2. Considering subtypes, gBRCA1 mutations were associated with triple-negative breast cancers (TNBC), while gBRCA2 mutations were more likely hormone receptor-positive breast cancers. At least one missense mutation of HR-related genes was observed in 44 cases (80.0%). The most frequently co-mutated gene was TP53 (38.1%). In patients with gBRCA1/2 mutations, however, genetic variations of TP53 occurred in locations different from the known hotspots of those with sporadic breast cancers. The patients with both gBRCA1/2 and TP53 mutations were more likely to have TNBC, high Ki-67 values, and increased genetic mutations, especially of HR-related genes. Survival benefit was observed in the TP53 mutants of patients with gBRCA2 mutations, compared to those with TP53 wild types. CONCLUSION: Our study showed genetic heterogeneity of breast cancer patients with gBRCA1 and gBRCA2 mutations in the Korean populations. Further studies on precision medicine are needed for tailored treatments of patients with genetic diversity among different ethnic groups.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama Triple Negativas/genética , Reparación del ADN por Recombinación/genética , Mutación , Reparación del ADN , Mutación de Línea Germinal/genética , Células Germinativas/patología , Predisposición Genética a la Enfermedad , Proteína p53 Supresora de Tumor/genética , Proteína BRCA1/genéticaRESUMEN
PURPOSE: This single-arm phase II trial investigate the efficacy and safety of S-1 plus oxaliplatin (SOX) in patients with metastatic breast cancer. Materials and Methods: Patients with metastatic breast cancer previously treated with anthracyclines and taxanes were enrolled. Patients received S-1 (40-60 mg depending on patient's body surface area, twice a day, day 1-14) and oxaliplatin (130 mg/m2, day 1) in 3 weeks cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumor 1.1. Secondary endpoints included time-to-progression (TTP), duration-of-response (DoR), overall survival (OS), and adverse events. RESULTS: A total of 87 patients were enrolled from 11 institutions in Korea. Hormone receptor was positive in 54 (62.1%) patients and six (6.9%) had human epidermal growth factor receptor 2-positive disease. Forty-eight patients (85.1%) had visceral metastasis and 74 (55.2%) had more than three sites of metastases. The ORR of SOX regimen was 38.5% (95% confidence interval [CI], 26.9 to 50.0) with a median TTP of 6.0 months (95% CI, 5.1 to 6.9). Median DoR and OS were 10.3 months (95% CI, 5.5 to 15.1) and 19.4 (95% CI, not estimated) months, respectively. Grade 3 or 4 neutropenia was reported in 28 patients (32.1%) and thrombocytopenia was observed in 23 patients (26.6%). CONCLUSION: This phase II study showed that SOX regimen is a reasonable option in metastatic breast cancer previously treated with anthracyclines and taxanes.