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On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2023 Annual Conference. The conference was held in-person, 31 May-2 June 2023, in Halifax, Nova Scotia at the Westin Nova Scotian hotel. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 1 June, and oral abstract authors were featured during the oral abstract session in the afternoon of Friday, 2 June 2023. Twenty-three (23) abstracts were selected for presentation as posters and four (4) as oral presentations. Abstracts were submitted within four categories: (1) Basic/Translational Sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support. The top four (4) oral abstracts and top four (4) poster abstracts were selected to receive an award. All of these were marked as "Award Recipient" within the relevant category. We congratulate all the presenters on their research and contributions to the field.
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Background and purpose: Capecitabine can be used as first-line treatment for advanced breast cancer. However, real-world data on efficacy of capecitabine in this setting is sparse. The purpose of the study is to evaluate outcomes of patients with Human Epidermal Growth Factor Receptor (HER2)-normal advanced breast cancer treated with capecitabine monotherapy as first-line treatment. MATERIAL AND METHODS: The study utilized the Danish Breast Cancer Group (DBCG) database and was conducted retrospectively across all Danish oncology departments. Inclusion criteria were female patients, with HER2-normal advanced breast cancer treated with capecitabine monotherapy as the first-line treatment from 2010 to 2020. The primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 494 patients were included. Median OS was 16.4 months (95% confidence interval [CI]: 14.5-18.0), and median PFS was 6.0 months (95% CI: 5.3-6.7). Patients with estrogen receptor (ER)-positive disease had significantly longer OS (median: 22.8 vs. 10.5 months, p < 0.001) and PFS (median: 7.4 vs. 4.9 months, p = 0.003), when compared to ER-negative patients. Stratifying by age, patients under 45 years displayed a median PFS of 4.1 months, while those aged 45-70 years and over 70 years had median PFS of 5.7 and 7.2 months, respectively (p = 0.01). INTERPRETATION: In this nationwide study, the efficacy of capecitabine as a first-line treatment for HER2-normal advanced breast cancer is consistent with other, mainly retrospective, studies. However, when assessed against contemporary and newer treatments, its effectiveness appears inferior to alternative chemotherapies or targeted therapies.
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Neoplasias de la Mama , Capecitabina , Receptor ErbB-2 , Humanos , Capecitabina/uso terapéutico , Capecitabina/administración & dosificación , Femenino , Estudios Retrospectivos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Anciano , Adulto , Antimetabolitos Antineoplásicos/uso terapéutico , Anciano de 80 o más Años , Dinamarca , Supervivencia sin Progresión , Receptores de Estrógenos/metabolismoRESUMEN
BACKGROUND: Primary metastatic breast cancer (pMBC) accounts for 5-10% of annual breast cancers with a median survival of 3-4 years, varying among subtypes. In Denmark, the incidence of breast cancer increased until 2010, followed by a stabilisation. Several factors influencing pMBC incidence and survival, including screening prevalence, staging methods, and classification standards, remain pivotal but inadequately documented. MATERIAL AND METHOD: This retrospective observational study involving pMBC patients diagnosed between 2000 and 2020 encompassed all Danish oncology departments. Data from the Danish Breast Cancer Group database and the National Patient Register included diagnosis specifics, demographics, treatment, and follow-up. RESULTS: Between 2000 and 2020, 3,272 patients were diagnosed with pMBC, a rise from 355 patients in 2000-2004 to 1,323 patients in 2015-2020. The increase was particularly observed in patients aged 70 years or older. Changes in tumour subtypes were observed, notably with a rise in human epidermal growth factor receptor 2 (HER2)-positive cases but a steady distribution of estrogen receptor (ER) status. Diagnostic practices changed over the two decades, with 6% evaluated with PET/CT (positron emission tomography-computed tomography) or CT (computed tomography) with a bone evaluation in 2000-2004 and 65% in 2015-2020. Overall survival (OS) improved from 23 months in 2000-2004 to 33 months in 2015-2020. In patients with ER-positive and HER2-positive disease, the multivariable model showed improved survival by year of diagnosis, and further, patients with ER-negative/HER2-negative disease fared worse the first 2 years after diagnosis. INTERPRETATION: Our study delineates changes in the treatment and survival of pMBC over two decades. Stage migration, screening introduction, and changes in registration practice, however, prevent a valid assessment of a possible causal relationship.
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Neoplasias de la Mama , Detección Precoz del Cáncer , Estadificación de Neoplasias , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/epidemiología , Femenino , Dinamarca/epidemiología , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Incidencia , Adulto , Anciano de 80 o más Años , Tasa de Supervivencia , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/análisis , Metástasis de la Neoplasia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Receptor ErbB-2/metabolismo , Receptor ErbB-2/análisisRESUMEN
Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs). RECs are defined by CD74/CD68 expression, and although derived from leukemic stem cells (LSCs), are devoid of stem/progenitor capacity. Based on REC in situ proximity to CD34-expressing cells identified using spatial transcriptomics on AML patient bone marrow samples, RECs demonstrate the ability to augment or reduce leukemic regeneration in vivo based on transfusion or depletion, respectively. Furthermore, RECs are prognostic for patient survival as well as predictive of treatment failure in AML cohorts. Our study reveals RECs as a previously unknown functional catalyst of LSC-driven regeneration contributing to the non-canonical framework of AML regeneration.
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Perfilación de la Expresión Génica , Leucemia Mieloide Aguda , Humanos , Pronóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Células Madre/metabolismoRESUMEN
BACKGROUNDIntrinsic molecular subtypes define distinct biological breast cancers and can be used to further improve diagnosis and risk allocation.METHODSThe Copenhagen Breast Cancer Genomics Study (CBCGS) prospectively included women diagnosed with breast cancer at Rigshospitalet from 2014 to 2021. Eligible patients were females with a primary invasive breast cancer (T1c, if N0M0; otherwise, any T, any N, or any M stage) and no prior malignancy. All patients underwent molecular profiling with the CIT256 and PAM50 molecular profile.RESULTSIn the study period, 2,816 patients were included in the CBCGS. Molecular subtyping showed an increase in nonluminal (molecular-apocrine, luminal C, and Basal-like) as compared with luminal (luminal A, luminal B, and Normal-like) subtypes with increasing stage from I to IV. Across all stages, we found a significant difference in survival among subtypes; 91% of patients with LumA were alive at 5 years compared with 91% for LumB, 84% for LumC, 82% for mApo, and 80% for Basal-like. We identified 442 tumors (16%) that were discordant in subtype between CIT256 and IHC. Discordant subtype proved to be a risk factor of death among patients with IHC luminal breast cancer (hazard ratio [HR], 2.08; 95% CI, 1.51-2.86) in a multivariable Cox regression analysis. Discordance occurred more often among patients with N3, stage IV, or grade III disease.CONCLUSIONOur findings indicate that molecular subtypes are a predominant classification for survival. Assessment is particularly crucial for patients with IHC luminal breast cancer with known high-risk factors, since they are at an increased risk of harboring an aggressive molecular subtype.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Biomarcadores de Tumor/genética , Pronóstico , GenómicaRESUMEN
Metastatic breast cancer claims the lives of 1,000 Danish women each year. Current guidelines are focused on the three major immunohistochemical subtypes in breast cancer. This review covers current Danish guidelines for the treatment of advanced breast cancer and highlights the potential future treatments for Danish patients.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , PredicciónRESUMEN
Importance: Validation of a new method for prognostication of de novo metastatic breast cancer (dnMBC) to better reflect the heterogenecity of the disease. Objective: To perform external methodological validation of the Plichta staging system, a novel prognostic system for de novo metastatic breast cancer (dnMBC). Design, Setting, and Participants: This retrospective cohort study used a multicenter, nationwide, population-based Danish Breast Cancer Group database to validate the new method. Participants were patients with dnMBC diagnosed between 2010 and 2019. Data were analyzed from April to June 2023. Main outcomes and measures: A recursive partitioning analysis (RPA) was performed, as demonstrated by Plichta and colleagues, to group patients with similar overall survival (OS) based on clinical factors. The main outcome was to group patients into 4 prognostic groups based on 3-year OS as stage IVa, greater than 70%; stage IVb, 50% to 70%; stage IVc, 25% to less than 50%; or stage IVd, less than 25%. Bootstrapping was applied for 1000 iterations, with final stage assignments based on the most commonly occurring assignment. Results: A total of 1859 women were included with a median (IQR) age of 69 (57-77) years. With a median potential follow-up of 89.9 (95% CI, 86.4-95.1) months and a median OS of 31.7 (95% CI, 29.5-34.1) months, the RPA stratified patients into 10 groups, with organ sites, estrogen receptor status, and human epidermal growth factor receptor 2 status as the key clinical factors. Three-year survival rates ranged from 62% (95% CI, 56%-69%) to 8% (95% CI, 3%-21%), which were further combined into 3 stage groups: IVb, 59.4% (95% CI, 56.2%-62.8%); IVc, 39.4% (95% CI, 36.2%-43.0%); and IVd, 15.4% (95% CI, 11.2%-21.3%) (P < .001). Following bootstrapping, an IVa group emerged, resulting in 4 stage groups with separate 3-year OS rates identified as IVa, 75.8% (95% CI, 67.8%-84.7%); IVb, 58.8% (95% CI, 55.5%-62.3%); IVc, 39.2% (95% CI, 35.8%-43.0%); and IVd, 14.4% (95% CI, 10.8%-19.4%) (P < .001). Conclusions and relevance: These findings provide external and independent validation of the methods applied in the novel Plichta staging system for dnMBC. This could guide future revisions of the current American Joint Committee on Cancer staging guidelines and may be incorporated as a stratification factor in clinical trials.
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Neoplasias de la Mama , Anciano , Femenino , Humanos , Mama , Bases de Datos Factuales , Estudios Retrospectivos , Persona de Mediana Edad , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND: Breast cancer incidence is now the highest among all cancers and accountable for 6.6% of all cancer-related deaths worldwide. Studies of the prognostic utility of plasma C-reactive protein (CRP) measurement in early-stage breast cancer have given discrepant results. METHODS: We identified 6,942 patients in the Danish Breast Cancer Cooperative Group database with early-stage breast cancer diagnosed between 2002 and 2016 who had a measure of pretreatment plasma CRP. Outcomes were recurrence-free interval and survival for a period up to 10 years. We analyzed associations with plasma CRP using Fine-Gray proportional subdistribution hazards model with recurrence-free interval. Data on plasma CRP were analyzed per doubling of concentration and in relation to CRP levels of <3 mg/L, 3 to 10 mg/L, and >10 mg/L and stratified according to standard clinical parameters in sensitivity analyses. RESULTS: A doubling of the plasma CRP concentration was associated with increased risk of recurrence (multivariate adjusted HR, 1.05; 95% CI, 1.01-1.08) and shorter survival (HR, 1.13; 95% CI, 1.09-1.16) in multivariate analyses. Survival was shorter in patients with plasma CRP levels of 3 to 10 and >10 mg/L versus <3 mg/L, with multivariate adjusted HRs of 1.30; 95% CI, 1.17-1.45 and 1.65; 95% CI, 1.39-1.95, respectively. CONCLUSIONS: Elevated plasma CRP measured before treatment in patients with early-stage breast cancer is an independent biomarker of increased risk of recurrence and early death. IMPACT: CRP measures before treatment might be used to individualize follow-up of patients with early-stage breast cancer.
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Neoplasias de la Mama , Proteína C-Reactiva , Humanos , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Persona de Mediana Edad , Pronóstico , Anciano , Estadificación de Neoplasias , Biomarcadores de Tumor/sangre , Adulto , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/epidemiología , Dinamarca/epidemiologíaAsunto(s)
Leucemia Promielocítica Aguda , Complicaciones Neoplásicas del Embarazo , Femenino , Humanos , Embarazo , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Complicaciones Neoplásicas del Embarazo/diagnóstico , Complicaciones Neoplásicas del Embarazo/tratamiento farmacológicoRESUMEN
High metabolic flexibility is pivotal for the persistence and therapy resistance of acute myeloid leukemia (AML). In 20-30% of AML patients, activating mutations of FLT3, specifically FLT3-ITD, are key therapeutic targets. Here, we investigated the influence of FLT3-ITD on AML metabolism. Nuclear Magnetic Resonance (NMR) profiling showed enhanced reshuffling of pyruvate towards the tricarboxylic acid (TCA) cycle, suggesting an increased activity of the pyruvate dehydrogenase complex (PDC). Consistently, FLT3-ITD-positive cells expressed high levels of PDP1, an activator of the PDC. Combining endogenous tagging of PDP1 with genome-wide CRISPR screens revealed that FLT3-ITD induces PDP1 expression through the RAS signaling axis. PDP1 knockdown resulted in reduced cellular respiration thereby impairing the proliferation of only FLT3-ITD cells. These cells continued to depend on PDP1, even in hypoxic conditions, and unlike FLT3-ITD-negative cells, they exhibited a rapid, PDP1-dependent revival of their respiratory capacity during reoxygenation. Moreover, we show that PDP1 modifies the response to FLT3 inhibition. Upon incubation with the FLT3 tyrosine kinase inhibitor quizartinib (AC220), PDP1 persisted or was upregulated, resulting in a further shift of glucose/pyruvate metabolism towards the TCA cycle. Overexpression of PDP1 enhanced, while PDP1 depletion diminished AC220 resistance in cell lines and peripheral blasts from an AC220-resistant AML patient in vivo. In conclusion, FLT3-ITD assures the expression of PDP1, a pivotal metabolic regulator that enhances oxidative glucose metabolism and drug resistance. Hence, PDP1 emerges as a potentially targetable vulnerability in the management of AML.
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Leucemia Mieloide Aguda , Inhibidores de Proteínas Quinasas , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutación , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Piruvatos/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/uso terapéuticoRESUMEN
BACKGROUND: Considering the recent advancements in the treatment of breast cancer with low expression of human epidermal growth factor receptor 2 (HER2), we aimed to examine inter-laboratory variability in the assessment of HER2-low breast cancer across all Danish pathology departments. METHODS: From the Danish Breast Cancer Group, we obtained data on all women diagnosed with primary invasive breast cancer in 2007-2019 who were subsequently assigned for curatively intended treatment. RESULTS: Of 50,714 patients, HER2 score and status were recorded for 48,382, among whom 59.2% belonged to the HER2-low group (score 1+ or 2+ without gene amplification), 26.8% had a HER2 score of 0, and 14.0% were HER2 positive. The proportion of HER2-low cases ranged from 46.3 to 71.8% among pathology departments (P < 0.0001) and from 49.3 to 65.6% over the years (P < 0.0001). In comparison, HER2 positivity rates ranged from 11.8 to 17.2% among departments (P < 0.0001) and from 12.6 to 15.7% over the years (P = 0.005). In the eight departments with the highest number of patients, variability in HER2-low cases increased from 2011 to 2019, although the same immunohistochemical assay was used. By multivariable logistic regression, the examining department was significantly related to both HER2 score 0 and HER2 positivity (P < 0.0001) but showed greater dispersion in odds ratios in the former case (range 0.25-1.41 vs. 0.84-1.27). CONCLUSIONS: Our data showed high inter-laboratory variability in the assessment of HER2-low breast cancer. The findings cast doubt on whether the current test method for HER2 is robust and reliable enough to select HER2-low patients for HER2-targeted treatment in daily clinical practice.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Sistema de Registros , Dinamarca/epidemiologíaRESUMEN
Background: Metastatic triple-negative breast cancer (mTNBC) is an aggressive subtype of breast cancer with poor survival. Currently, the literature lacks comprehensive real-world evidence on locally recurrent and mTNBC patients. To validate the optimal treatment for patients with mTNBC, real-world evidence in combination with data from clinical trials must be evaluated as complementary. Objectives: The objective of the study is to examine outcomes and treatment patterns of patients with advanced triple-negative breast cancer (TNBC) utilizing real-world data of patients from all oncology sites across Denmark. Design: This is a retrospective, non-interventional, multi-site, population-based observational study conducted across all oncology departments in Denmark. Methods: We included all women diagnosed with metastatic or locally recurrent TNBC from January 1, 2017, to December 31, 2019, using the national Danish Breast Cancer Group database. The primary endpoints were overall survival (OS) and progression-free survival (PFS) in the first to third treatment line. Results: The study included 243 women diagnosed with metastatic or recurrent TNBC. The median OS (mOS) was 11.6 months after the first line of treatment, 6.5 months after the second line, and 6.5 months after the third line. De novo mTNBC was associated with shorter OS (mOS: 8.3 vs 14.2 months), and those with a relapse within 18 months of primary diagnosis had shorter OS than those with a relapse after 18 months (mOS: 10.0 vs 18.2). In the first line, taxane was the preferred choice of treatment for patients with de novo mTNBC, whereas capecitabine was preferred for patients with recurrent TNBC. Conclusions: This real-world, nationwide study demonstrated poor OS among patients with metastatic or recurrent TNBC, with a mOS of 11.6 months (95% CI, 9.9-17.3). Patients who presented with de novo mTNBC or who had a relapse of their breast cancer within 18 months of primary diagnosis had shorter OS. Registration: The study was registered and approved by the Danish Capital Regions research overview (P-2021-605).
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INTRODUCTION: We examined the role of receptor profiles and other prognostic factors in survival outcomes after stereotactic radiosurgery (SRS) for brain metastases in breast cancer patients, to help improve selection of candidates for SRS. MATERIAL AND METHODS: We included 149 consecutive patients who received SRS between 2012 and 2019 at the University Hospital of Copenhagen, Rigshospitalet, Denmark. Overall survival (OS) following SRS was determined through the Kaplan-Meier method, while CNS progression-free survival (CNS-PFS) was determined through competing risk analysis. Prognostic factors for both OS and CNS-PFS were evaluated through uni- and multivariate Cox regression and Fine-Gray models, respectively. The proportional hazards assumptions were tested through Schoenfeld residuals, and non-proportionality was accounted for by the inclusion of time-dependent variables. RESULTS: Median OS was 14.8 months for the entire cohort and was as follows for the four receptor profiles: 33.3 months for ER+/HER2+ (ER: estrogen receptor, HER2: human epidermal growth factor receptor 2), 11.0 months for ER+/HER2-, 17.7 months for ER-/HER2+, and 5.3 months for ER-/HER2-. In the multivariate model, the ER-/HER2- receptor profile (hazard ratio (HR): 2.00, 95% confidence interval (CI): 1.09-3.67) and the presence of extracranial visceral metastases (HR: 2.90, 95% CI: 1.53-5.50) were associated with worse OS. The ER+/HER2+ receptor profile (HR: 0.43, 95% CI: 0.19-0.96) and 5+ lines of treatment (HR: 0.40, 95% CI: 0.20-0.82) were both associated with improved OS. For CNS-PFS, 5+ lines of treatment (sub-distributional hazard ratio (SHR): 2.88, 95% CI: 1.06-7.81) was associated with worse CNS-PFS, while extracranial visceral metastases (SHR: 0.54, 95% CI: 0.30-0.97) was associated with reduced risk of CNS progression - which is primarily due to patients with extracranial metastases dying before developing new CNS progression. CONCLUSION: Extracranial visceral disease and the ER-/HER2- receptor profile were associated with poor survival outcomes following SRS.
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Neoplasias Encefálicas , Neoplasias de la Mama , Radiocirugia , Humanos , Femenino , Neoplasias de la Mama/patología , Radiocirugia/métodos , Pronóstico , Estudios Retrospectivos , Neoplasias Encefálicas/secundarioRESUMEN
Radiotherapy is a non-invasive standard treatment for prostate cancer (PC). However, PC develops radio-resistance, highlighting a need for agents to improve radiotherapy response. Canagliflozin, an inhibitor of sodium-glucose co-transporter-2, is approved for use in diabetes and heart failure, but is also shown to inhibit PC growth. However, whether canagliflozin can improve radiotherapy response in PC remains unknown. Here, we show that well-tolerated doses of canagliflozin suppress proliferation and survival of androgen-sensitive and insensitive human PC cells and tumors and sensitize them to radiotherapy. Canagliflozin blocks mitochondrial respiration, promotes AMPK activity, inhibits the MAPK and mTOR-p70S6k/4EBP1 pathways, activates cell cycle checkpoints, and inhibits proliferation in part through HIF-1α suppression. Canagliflozin mediates transcriptional reprogramming of several metabolic and survival pathways known to be regulated by ETS and E2F family transcription factors. Genes downregulated by canagliflozin are associated with poor PC prognosis. This study lays the groundwork for clinical investigation of canagliflozin in PC prevention and treatment in combination with radiotherapy.
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Insuficiencia Cardíaca , Neoplasias de la Próstata , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Masculino , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , MitocondriasRESUMEN
INTRODUCTION: The Danish Medicines Council recommends that patients with estrogen receptor and human epidermal growth factor receptor 2-negative, programmed death-ligand 1 (PD-L1)-positive advanced breast cancer receive atezolizumab in combination with nab-paclitaxel. The approval was largely based on results from Impassion130 that showed a beneficial progression-free survival (PFS) and overall survival (OS) in PD-L1-positive patients who received atezolizumab and nab-paclitaxel. METHODS: We conducted a retrospective, population-based study that included patients who received atezolizumab for advanced breast cancer from October 2019 to September 2022. The primary endpoints were PFS and OS. RESULTS: This study included 74 advanced breast cancer patients. Their median age was 54.5 years, and 21 (28.4%) of the patients had de novo advanced disease. Most patients received first-line treatment with atezolizumab (83.8%). The median PFS was 6.0 months (95% confidence interval (CI): 4.7-8.4 months) and the median OS was 14.3 months (95% CI: 9.9-22.2 months). A total of 48 patients received atezolizumab and nab-paclitaxel in accordance with guidelines from the Danish Medicines Council. CONCLUSIONS: This real-world study expectedly showed numerically lower survival outcomes than the phase III trial Impassion130, but met the standards of efficacy set by real-world studies in other countries. A need exists for increased attention to the criteria for receiving atezolizumab. FUNDING: none. TRIAL REGISTRATION: The study was approved by the Oncological Committee of the DBCG, the Research Overview of the Capital (P-2022-828) and the Centre for Health of the Capital Region (R-22060674).
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Neoplasias de la Mama , Humanos , Persona de Mediana Edad , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Antígeno B7-H1 , Estudios Retrospectivos , DinamarcaRESUMEN
Non-small cell lung cancer (NSCLC) has a poor prognosis, and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA-seq), real-time quantitative PCR (RT-qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown, and protein expression assays were used in mechanistic analyses. We found that canagliflozin inhibited proliferation and clonogenic survival of NSCLC cells and augmented the efficacy of radiotherapy to mediate these effects and inhibit NSCLC xenograft growth. Canagliflozin treatment alone moderately inhibited mitochondrial oxidative phosphorylation and exhibited greater antiproliferative capacity than specific mitochondrial complex-I inhibitors. The treatment downregulated genes mediating hypoxia-inducible factor (HIF)-1α stability, metabolism and survival, activated adenosine monophosphate-activated protein kinase (AMPK) and inhibited mTOR, a critical activator of hypoxia-inducible factor-1α (HIF-1α) signaling. HIF-1α knockdown and stabilization experiments suggested that canagliflozin mediates antiproliferative effects, in part, through suppression of HIF-1α. Transcriptional regulatory network analysis pinpointed histone deacetylase 2 (HDAC2), a gene suppressed by canagliflozin, as a key mediator of canagliflozin's transcriptional reprogramming. HDAC2 knockdown eliminated HIF-1α levels and enhanced the antiproliferative effects of canagliflozin. HDAC2-regulated genes suppressed by canagliflozin are associated with poor prognosis in several clinical NSCLC datasets. In addition, we include evidence that canagliflozin also improves NSCLC response to chemotherapy. In summary, canagliflozin may be a promising therapy to develop in combination with cytotoxic therapy in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Línea Celular Tumoral , Serina-Treonina Quinasas TOR/metabolismo , ARN Interferente Pequeño/genéticaRESUMEN
We systematically investigate functional and molecular measures of stemness in patients with acute myeloid leukemia (AML) using a cohort of 121 individuals. We confirm that the presence of leukemic stem cells (LSCs) detected through in vivo xenograft transplantation is associated with poor survival. However, the measurement of leukemic progenitor cells (LPCs) through in vitro colony-forming assays provides an even stronger predictor of overall and event-free survival. LPCs not only capture patient-specific mutations but also retain serial re-plating ability, demonstrating their biological relevance. Notably, LPC content represents an independent prognostic factor in multivariate analyses including clinical guidelines of risk stratification. Our findings suggest that LPCs provide a robust functional measure of AML, enabling quantitative and rapid assessment of a wide range of patients. This highlights the potential of LPCs as a valuable prognostic factor in AML management.
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Leucemia Mieloide Aguda , Humanos , Pronóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genéticaRESUMEN
The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. We therefore established a DNA-based hybrid capture NGS assay and an associated bioinformatic pipeline that fulfils our institution's specific needs. The assay´s target regions cover the full exonic territory of relevant cancer-related genes and HRR genes and more than 20,000 evenly distributed single nucleotide polymorphism (SNP) loci to allow for the detection of genome-wide allele specific copy number alterations (CNA). To determine GI status, we implemented an %CNA score that is robust across a broad range of tumor cell content (25-85%) often found in routine FFPE samples. The assay was established using high-grade serous ovarian cancer samples for which BRCA1 and BRCA2 mutation status as well as Myriad MyChoice homologous repair deficiency (HRD) status was known. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS (GI-Score) v1 assay was clinically validated on more than 400 samples of the ENGOT PAOLA-1 clinical trial as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative. The "NOGGO GIS v1 assay" performed using highly robust hazard ratios for progression-free survival (PFS) and overall survival (OS), as well a significantly lower dropout rate than the Myriad MyChoice clinical trial assay supporting the clinical utility of the assay. We also provide proof of a modular and scalable routine diagnostic method, that can be flexibly adapted and adjusted to meet future clinical needs, emerging biomarkers, and further tumor entities.
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BACKGROUND: The purpose was to investigate the treatment flow of patients with HER2-positive metastatic breast cancer (mBC), progression-free survival (PFS) and overall survival (OS) across treatment lines and adherence to guidelines (defined as trastuzumab, pertuzumab and chemotherapy first line, where 85% received vinorelbine as backbone and T-DM1 second line). Furthermore, we identified clinical markers to predict the risk of developing brain metastases. MATERIAL AND METHODS: Patients with HER2-positive mBC, diagnosed between 01.01.2014-31.12.2019, registered in the database of the Danish Breast Cancer Group were included in this real-word study. Clinical follow-up was assessed until 01.10.2020 and complete follow-up for overall survival until 01.10.2021. Survival data were analyzed using the Kaplan-Meier method with guidelines adherence analyzed as a time-varying covariate, and the risk of CNS metastasis was estimated by the cumulative incidence function. RESULTS: 631 patients were included. 329 (52%) patients followed the guidelines. The median OS for all patients was 42.3 months (95% Cl, 38.2-48.4), and significantly higher for the patients who followed guidelines; NA (95% CI, 78.2-NA). The median PFS for all patients was 13.4 months (95% Cl, 12.1-14.8), 6.6 (95% Cl, 5.8-7.6) and 5.8 (95% Cl, 4.9-6.9) for first, second and third line of treatment, respectively. Patients with ER-negative mBC had a higher risk of developing brain metastases and patients with high tumor burden had a higher risk of developing brain metastases with an adjusted HR of 0.69 (95% CI, 0.49-0.98), p = 0.047 and 2.69 (95% CI, 1.45-5.00), p = 0.002, respectively. CONCLUSION: We found that only half of the patients with HER2-positive mBC, received first and second-line treatment according to national guidelines. Patients receiving treatment according to guidelines had a significantly higher median OS compared to patients who did not. We also found that patients with ER-negative disease or high tumor burden had a significantly higher risk of developing brain metastases.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Receptor ErbB-2 , Trastuzumab/uso terapéutico , Ado-Trastuzumab Emtansina , Dinamarca/epidemiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: The recommended first-line treatment for advanced, ER+/HER2 negative breast cancer is a CDK 4/6 inhibitor in combination with an endocrine backbone. This study investigated the use of palbociclib, as first- or second-line therapy for advanced breast cancer patients in a real-world setting. MATERIAL AND METHODS: This retrospective, population-based study included all Danish, advanced breast cancer patients with ER+/HER2 negative disease who initiated first- or second-line treatment with palbociclib from January 1st, 2017, until December 31st, 2020. The primary outcomes were PFS and OS. RESULTS: The study included 1054 advanced breast cancer patients with a mean age of 66.8 years. Median OS was 51.7 months (95% CI, 44.9-54.6) for all patients in the first-line setting (n = 728) and median PFS was 24.3 months (95% CI, 21.7-27.8). Patients treated in second line (n = 326) had a median OS of 32.5 months (95% CI, 29.9-35.9) and a median PFS of 13.6 months (95% CI, 11.5-15.7). In first-line setting, the PFS and OS were significantly different for endocrine sensitive patients treated with AI (aromatase inhibitor) (n = 423) vs. fulvestrant (n = 158) as endocrine backbone to palbociclib (median PFS AI 31.3 months vs fulvestrant 19.9 months, p = 0.002 and median OS AI 56.9 months vs. fulvestrant 43.6 months, p = 0.001). In endocrine resistant patients (n = 145), no statistically significant difference in PFS was shown (median PFS AI 21.5 months vs. fulvestrant 12.0 months, p = 0.09), whereas OS was significantly different (median OS AI 43.5 months vs. fulvestrant 28.8 months, p = 0.02). CONCLUSION: In this real-world study, treatment with palbociclib combination therapy met the standards of efficacy set by the phase III trials, PALOMA-2 and PALOMA-3, and the standards set by real-world studies in other countries. The study showed significantly different outcomes in terms of PFS and OS in endocrine sensitive patients comparing AI vs. fulvestrant as endocrine backbone to palbociclib as first-line therapy.