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BACKGROUND: Trastuzumab emtansine (T-DM1) has demonstrated improvements in survival and neurological symptoms in patients with breast cancer with brain metastases (BCBM). This real-world study investigated the effectiveness of T-DM1 versus lapatinib plus capecitabine (LC) in patients with BCBM. METHODS: This retrospective, observational study evaluated patients with HER2-positive BCBM using a real-world database. Eligible patients had initiated T-DM1 or LC with a prior diagnosis of brain metastasis and ≥1 prior metastatic breast cancer treatment. The primary endpoint was overall survival (OS); secondary endpoints were time to next relevant treatment or death (TTNT) and real-world progression-free survival (rwPFS). An inverse probability of treatment weighting (IPTW) approach was used to account for differences in potential baseline characteristics between treatment groups. Outcomes were described using the Kaplan-Meier method, and the average treatment effect of initiating T-DM1 versus LC was estimated using weighted Cox proportional hazard models and hazard ratio (HR). RESULTS: A total of 214 patients were available for analysis (T-DM1, n = 161; LC, n = 53). Demographics and baseline characteristics were generally well-balanced between treatment groups after weighting. After weighting, median OS was 17.7 (T-DM1) versus 9.6 (LC) months (HR, 0.55 [95% CI, 0.34-0.89]; P=0.013). Median TTNT was 9.0 (T-DM1) versus 6.0 (LC) months (HR, 0.55 [95% CI, 0.36-0.85]; P = 0.005). After weighting, median rwPFS was 6.0 (T-DM1) versus 4.0 (LC) months (HR, 0.50 [95% CI, 0.36-0.69]; P < 0.001). CONCLUSIONS: These results support the superior effectiveness and clinical relevance of T-DM1 versus LC in patients with HER2-positive BCBM in the real world.
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Neoplasias Encefálicas , Neoplasias de la Mama , Maitansina , Humanos , Femenino , Ado-Trastuzumab Emtansina/uso terapéutico , Neoplasias de la Mama/patología , Lapatinib , Capecitabina/uso terapéutico , Trastuzumab/uso terapéutico , Estudios Retrospectivos , Receptor ErbB-2 , Maitansina/uso terapéutico , Quinazolinas/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Real-world studies have suggested decreased trastuzumab emtansine (T-DM1) effectiveness in patients with metastatic breast cancer (mBC) who received prior trastuzumab plus pertuzumab (H + P). However, these studies may have been biased toward pertuzumab-experienced patients with more aggressive disease. Using an electronic health record-derived database, patients diagnosed with mBC on/after 1 January 2011 who initiated T-DM1 in any treatment line (primary cohort) or who initiated second-line T-DM1 following first-line H ± P (secondary cohort) from 22 February 2013 to 31 December 2019 were included. The primary outcome was time from index date to next treatment or death (TTNT). In the primary cohort (n = 757), the percentage of patients with prior P increased from 37% to 73% across the study period, while population characteristics and treatment effectiveness measures were generally stable. Among P-experienced patients from the secondary cohort (n = 246), median time from mBC diagnosis to T-DM1 initiation increased from 10 to 14 months (2013-2019), and median TTNT increased from 4.4 to 10.2 months (2013-2018). Over time, prior H + P prevalence significantly increased with no observable impact on T-DM1 effectiveness. Drug approval timing should be considered when assessing treatment effectiveness within a sequence.
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Heterogeneity of carcinoma-associated fibroblasts (CAF) has long been recognized, but the functional significance remains poorly understood. Here, we report the distinction of two CAF subtypes in oral squamous cell carcinoma (OSCC) that have differential tumor-promoting capability, one with a transcriptome and secretome closer to normal fibroblasts (CAF-N) and the other with a more divergent expression pattern (CAF-D). Both subtypes supported higher tumor incidence in nonobese diabetic/severe combined immunodeficient (NOD/SCID) Ilγ2(null) mice and deeper invasion of malignant keratinocytes than normal or dysplasia-associated fibroblasts, but CAF-N was more efficient than CAF-D in enhancing tumor incidence. CAF-N included more intrinsically motile fibroblasts maintained by high autocrine production of hyaluronan. Inhibiting CAF-N migration by blocking hyaluronan synthesis or chain elongation impaired invasion of adjacent OSCC cells, pinpointing fibroblast motility as an essential mechanism in this process. In contrast, CAF-D harbored fewer motile fibroblasts but synthesized higher TGF-ß1 levels. TGF-ß1 did not stimulate CAF-D migration but enhanced invasion and expression of epithelial-mesenchymal transition (EMT) markers in malignant keratinocytes. Inhibiting TGF-ß1 in three-dimensional cultures containing CAF-D impaired keratinocyte invasion, suggesting TGF-ß1-induced EMT mediates CAF-D-induced carcinoma cell invasion. TGF-ß1-pretreated normal fibroblasts also induced invasive properties in transformed oral keratinocytes, indicating that TGF-ß1-synthesizing fibroblasts, as well as hyaluronan-synthesizing fibroblasts, are critical for carcinoma invasion. Taken together, these results discern two subtypes of CAF that promote OSCC cell invasion via different mechanisms.
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Carcinoma de Células Escamosas/patología , Fibroblastos/metabolismo , Neoplasias de la Boca/patología , Animales , Benzamidas/farmacología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidad , Movimiento Celular , Dioxoles/farmacología , Transición Epitelial-Mesenquimal , Fibroblastos/clasificación , Fibroblastos/fisiología , Expresión Génica , Ácido Hialurónico/metabolismo , Estimación de Kaplan-Meier , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/mortalidad , Invasividad Neoplásica , Trasplante de Neoplasias , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transcriptoma , Factor de Crecimiento Transformador beta1/fisiología , Células Tumorales CultivadasRESUMEN
PURPOSE: To identify functionally related prognostic gene sets for head and neck squamous cell carcinoma (HNSCC) by unsupervised statistical analysis of microarray data. PATIENTS AND METHODS: Microarray analysis was performed on 14 normal oral epithelium and 71 HNSCCs from patients with outcome data. Spectral clustering (SC) analysis of the data set identified multiple vectors representing distinct aspects of gene expression heterogeneity between samples. Gene ontology (GO) analysis of vector gene lists identified gene sets significantly enriched within defined biologic pathways. The prognostic significance of these was established by Cox survival analysis. RESULTS: The most influential SC vectors were V2 and V3. V2 separated normal from tumor samples. GO analysis of V2 gene lists identified pathways with heterogeneous expression between HNSCCs, notably focal adhesion (FA)/extracellular matrix remodeling and cytokine-cytokine receptor (CR) interactions. Similar analysis of V3 gene lists identified further heterogeneity in CR pathways. V2CR genes represent an innate immune response, whereas high expression of V3CR genes represented an adaptive immune response that was not dependent on human papillomavirus status. Survival analysis demonstrated that the FA gene set was prognostic of poor outcome, whereas classification for adaptive immune response by the CR gene set was prognostic of good outcome. A combined FA&CR model dramatically exceeded the performance of current clinical classifiers (P < .001 in our cohort and, importantly, P = .007 in an independent cohort of 60 HNSCCs). CONCLUSION: The application of SC and GO algorithms to HNSCC microarray data identified gene sets highly significant for predicting patient outcome. Further large-scale studies will establish the usefulness of these gene sets in the clinical management of HNSCC.