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OBJECTIVES: The study was undertaken to assess the association between certification and volume of breast centres on the one hand and survival on the other in patients with invasive breast cancer (IBC). METHODS: The study comprises a cohort of 46,035 patients diagnosed with IBC between 2014 and 2018, selected from the nation-wide Belgian Cancer Registry (BCR) database, which was linked with health insurance, hospital discharge and vital status data. Overall and relative survival probabilities were obtained with Kaplan-Meier method and an actuarial approach based on Ederer II, respectively. The associations between centre certification/volume and relative survival were assessed using Poisson models, adjusted for potential confounders. RESULTS: Five years after the diagnosis of IBC, the observed and relative survival probabilities for the cohort were 83.4 % (95 %CI: [83.1, 83.8]) and 93.3 % (95 %CI: [92.9, 93.7]), respectively. After adjustment for age and combined tumour stage, the risk to die from BC was 44 % higher (EHR: 1.44, 95 %CI: [1.24, 1.66]) for patients treated in a low-volume centre and 30 % higher (EHR: 1.30, 95 %CI: [1.14, 1.48]) for patients treated in a medium-volume centre, compared to high-volume centres. Likewise, the risk to die from BC was 30 % higher (EHR: 1.30, 95 %CI: [1.15, 1.48], p < 0.001) for patients treated in a non-certified centre (representing 23.8 % of the cohort), compared to patients treated in a coordinating breast clinic. CONCLUSION: This population-based study reveals that BC survival is higher when patients are treated in certified and high-volume breast clinics.
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The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been unequivocally shown in mutant KRAS and are even observed in a majority of wild-type KRAS tumors. Therefore, patient selection based on mutational profiling remains problematic. We previously identified methylglyoxal (MGO), a by-product of glycolysis, as a metabolite promoting tumor growth and metastasis. Mutant KRAS cells under MGO stress show AKT-dependent survival when compared with wild-type KRAS isogenic CRC cells. MGO induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation. Importantly, the sole induction of MGO stress in sensitive wild-type KRAS cells renders them resistant to cetuximab. MGO scavengers inhibit AKT and resensitize KRAS-mutated CRC cells to cetuximab in vivo. This study establishes a link between MGO and AKT activation and pinpoints this oncometabolite as a potential target to tackle EGFR-targeted therapy resistance in CRC.
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Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Depuradores de Radicales Libres/farmacología , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Piruvaldehído/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Carnosina/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cetuximab/farmacología , Células Clonales , Activación Enzimática/efectos de los fármacos , Glucólisis/efectos de los fármacos , Glicosilación/efectos de los fármacos , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Masculino , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Estrés Fisiológico/efectos de los fármacosRESUMEN
BACKGROUND: Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-ß1 has been identified as a key driving force behind metastatic breast cancer, with promising therapeutic implications. METHODS AND FINDINGS: Employing immunohistochemistry (IHC) analysis, we report, to our knowledge for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue. In vitro, asporin is secreted by breast fibroblasts upon exposure to conditioned medium from some but not all human breast cancer cells. While hormone receptor (HR) positive cells cause strong asporin expression, triple-negative breast cancer (TNBC) cells suppress it. Further, our findings show that soluble IL-1ß, secreted by TNBC cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts. Using recombinant protein, as well as a synthetic peptide fragment, we demonstrate the ability of asporin to inhibit TGF-ß1-mediated SMAD2 phosphorylation, epithelial to mesenchymal transition, and stemness in breast cancer cells. In two in vivo murine models of TNBC, we observed that tumors expressing asporin exhibit significantly reduced growth (2-fold; p = 0.01) and metastatic properties (3-fold; p = 0.045). A retrospective IHC study performed on human breast carcinoma (n = 180) demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression (4-fold; p = 0.001). Assessment of asporin expression and patient outcome (n = 60; 10-y follow-up) shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status (area under the curve = 0.87; 95% CI 0.78-0.96; p = 0.0001). Survival analysis, based on gene expression (n = 375; 25-y follow-up), confirmed that low asporin levels are associated with a reduced likelihood of survival (hazard ratio = 0.58; 95% CI 0.37-0.91; p = 0.017). Although these data highlight the potential of asporin to serve as a prognostic marker, confirmation of the clinical value would require a prospective study on a much larger patient cohort. CONCLUSIONS: Our data show that asporin is a stroma-derived inhibitor of TGF-ß1 and a tumor suppressor in breast cancer. High asporin expression is significantly associated with less aggressive tumors, stratifying patients according to the clinical outcome. Future pre-clinical studies should consider options for increasing asporin expression in TNBC as a promising strategy for targeted therapy.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/farmacología , Animales , Biomarcadores de Tumor/metabolismo , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Femenino , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/farmacología , Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Interleucina-1beta/farmacología , Ratones , Persona de Mediana Edad , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Análisis de Supervivencia , Factor de Crecimiento Transformador beta/farmacología , Células Tumorales CultivadasRESUMEN
PURPOSE: To compare breast cancer subtyping with the three centrally assessed microarray-based assays BluePrint, MammaPrint, and TargetPrint with locally assessed clinical subtyping using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). METHODS: BluePrint, MammaPrint, and TargetPrint were all performed on fresh tumor samples. Microarray analysis was performed at Agendia Laboratories, blinded for clinical and pathological data. IHC/FISH assessments were performed according to local practice at each institution; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) assessments were performed on 132 samples, and Ki-67 on 79 samples. RESULTS: The concordance between BluePrint and IHC/FISH subtyping was 94 % for the Luminal-type, 95 % for the HER2-type, and 94 % for the Basal-type subgroups. The concordance of BluePrint with subtyping using mRNA single gene readout (TargetPrint) was 96 % for the Luminal-type, 97 % for the HER2-type, and 98 % for the Basal-type subgroups. The concordance for substratification into Luminal A and B using MammaPrint and Ki-67 was 68 %. The concordance between TargetPrint and IHC/FISH was 97 % for ER, 80 % for PR, and 95 % for HER2. CONCLUSIONS: The implementation of multigene assays such as TargetPrint, BluePrint, and MammaPrint may improve the clinical management of breast cancer patients. High discordance between Luminal A and B substratification based on MammaPrint versus locally assessed Ki-67 or grade indicates that chemotherapy decisions should not be based on the basis of Ki-67 readout or tumor grade alone. TargetPrint serves as a second opinion for those local pathology settings where high-quality standardization is harder to maintain.