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BACKGROUND: Early access program (formerly cohort Temporary Authorization for Use) was granted for trastuzumab deruxtecan (T-DXd) in France based on DESTINY-Breast01 trial which demonstrated its efficacy and safety in HER2-positive metastatic/unresectable breast cancer after ≥2 anti-HER2-based regimens received at metastatic stage. METHODS: This multicenter real-world early access program included HER2-positive metastatic/unresectable breast patients pretreated with at least two lines of anti-HER2 regimens who received T-DXd 5.4 mg/kg intravenously in monotherapy every 3 weeks. RESULTS: Four hundred and fifty-nine patients (median age, 58 years; hormone receptor-positive, 67%; brain metastases, 28.1%) received T-DXd. Before inclusion, 81.7% of patients had radiation therapy and 76.5% had undergone surgery. Median number of prior metastatic treatment lines was four (range, 2-22); 99.8% patients had received trastuzumab, 94.8% trastuzumab emtansine and 79.3% pertuzumab. Follow-up was performed from September 30, 2020 to March 30, 2021; when the early access program stopped, the median duration of T-DXd treatment was 3.4 (range, 0-7.8) months. In 160 patients with available tumor assessment, objective response rate was 56.7% and 12.1% had progression. In 57 patients with available brain tumor assessment, complete or partial intracranial response was reported for 35.7% patients and 5.4% had progression. A total of 17 (3.7%) patients with interstitial lung disease (ILD) was reported with no cases of ILD-related death. CONCLUSIONS: In this early access program in patients with heavily pretreated HER2-positive metastatic/unresectable breast cancer, T-DXd had antitumor activity with a similar response to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed.
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Neoplasias de la Mama , Receptor ErbB-2 , Trastuzumab , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Trastuzumab/uso terapéutico , Persona de Mediana Edad , Francia , Receptor ErbB-2/metabolismo , Anciano , Adulto , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Inmunoconjugados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Anciano de 80 o más Años , Resultado del TratamientoRESUMEN
Cancer-related thrombotic microangiopathy (TMA) is a rare entity whose clinical and biological characteristics have been described in various tumors. Here we describe the first case of cancer-related TMA revealing diffuse bone metastases from an ethmoid sinus carcinoma.
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BACKGROUND: Despite recent progress, investigating the impact of targeted therapies on Head and Neck Squamous Cell Carcinoma (HNSCC) remains a challenge. We investigated whether short-term culture of tumour fragments would permit the evaluation of tumour sensitivity to targeted therapies at the individual level. METHODS: We cultivated tumour slices prepared from 18 HNSCC tumour samples obtained during surgical resection. The samples were treated for 48 h with a panel of 8 targeted therapies directed against selected oncogenic transduction pathways. We analysed the cell proliferation index (CPI) of tumour cells using Ki67 labelling and the activation status of the RAF-MEK-ERK cascade through ERK phosphorylation analysis. RESULTS: Fourteen tumours were successfully analysed after short-term culture of tumour samples, revealing a striking individual heterogeneity of HNSCC in terms of tumour cell sensitivity to targeted therapies. Using 50% inhibition of CPI as threshold, sorafenib was shown to be active in 5/14 tumours. Cetuximab, the only approved targeted drug against HNSCC, was active in only 2/14 tumours. A more than 50% inhibition was observed with at least one drug out of the eight tested in 10/14 tumours. Cluster analysis was carried out in order to examine the effect of the drugs on cell proliferation and the RAF-MEK-ERK cascade. CONCLUSIONS: In vitro culture of tumour fragments allows for the evaluation of the effects of targeted therapies on freshly resected human tumours, and might be of value as a possible guide for the design of clinical trials and for the personalization of the medical treatment of HNSCC.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Técnicas de Cultivo de Célula , Proliferación Celular/efectos de los fármacos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Terapia Molecular Dirigida , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Cetuximab/administración & dosificación , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Antígeno Ki-67/biosíntesis , MAP Quinasa Quinasa 1/biosíntesis , MAP Quinasa Quinasa Quinasa 3/biosíntesis , Fosforilación , Medicina de Precisión , Proteínas Proto-Oncogénicas c-raf/biosíntesis , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Improving the pre-clinical characterization of therapeutic approaches and developing new biological assays that will enable treatment personalization for individual patients are promising developments in oncology. Here we describe a new approach consisting of culturing human tumour explants. This approach involves the preparation of slices from freshly-obtained, surgically-resected material that can be maintained ex vivo for several days. Recent studies have provided proof of principle that this approach can be easily implemented in order to explore the mode of action of various anticancer drugs and the responses of 'real' tumours at the individual patient level. We present the practical aspects and highlight the versatility of this approach, which allows for the analysis of the susceptibility of any individual tumour to multiple anticancer drugs in parallel. We discuss its potential as a companion assay in the design of optimal clinical trials and as a guide for the prescription of medical treatment. We discuss which future clinical and biological studies are needed to validate the information gathered from cultured tumour explants, and to integrate this information with that gathered from other assays in order to optimize the medical treatment of cancer.
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Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Técnicas de Cultivo de Tejidos , Animales , Antineoplásicos/uso terapéutico , Humanos , Ratones , Trasplante de Neoplasias , Medicina de Precisión/métodosRESUMEN
Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour. The loss of function of the retinoblastoma (Rb) protein is an important event during liver carcinogenesis, but it is unclear whether the Rb status modulates the response of HCC cells to sorafenib. Here, we examined this question in HCC cells with reduced levels of Rb achieved through stable RNA interference. We show that HCC cells with reduced levels of Rb exhibit a two- to threefold increase in cell death induction upon exposure to sorafenib compared with controls. Sorafenib treatment of Balb/c nude mice that received tumour xenografts derived from HCC cells with reduced Rb levels resulted in complete tumour regression in 50% of the animals treated, compared with tumour stabilization in mice that received control cells. We show that, upon exposure to sorafenib, the Rb-negative status of HCC cells promotes the occurrence of ferroptosis, a form of oxidative necrosis. The findings highlight the role of Rb in the response of HCC cells to sorafenib and the regulation of ferroptosis.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Necrosis , Niacinamida/análogos & derivados , Estrés Oxidativo/efectos de los fármacos , Compuestos de Fenilurea/farmacología , Proteína de Retinoblastoma/metabolismo , Animales , Western Blotting , Carcinoma Hepatocelular/metabolismo , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Niacinamida/farmacología , Especies Reactivas de Oxígeno/metabolismo , Sorafenib , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND/AIM: Ferroptosis is a recently identified form of regulated necrosis that can be experimentally induced in cancer cells with the chemical inducer erastin. Recently, we identified sorafenib, an inhibitor of oncogenic kinases, as an inducer of ferroptosis in hepatocellular carcinoma cells. Whether sorafenib is able to exert its ferroptotic activity in cancer cells originating from other tissues is presently unclear. MATERIALS AND METHODS: We compared the levels of ferroptosis induced by sorafenib with those induced by the reference compound erastin in a panel of ten human cell lines originating from various tissues. RESULTS: Sorafenib induced ferroptosis in different cancer cell lines. We found a positive correlation between the ferroptotic potency of sorafenib and erastin. Compared to other kinase inhibitors, sorafenib is the only drug that displays ferroptotic efficacy. CONCLUSION: The findings establish sorafenib as the first clinically-approved anticancer drug that can induce ferroptosis.
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Apoptosis/efectos de los fármacos , Necrosis , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacología , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Biomarcadores de Tumor/metabolismo , Western Blotting , Proliferación Celular/efectos de los fármacos , Humanos , L-Lactato Deshidrogenasa/metabolismo , Neoplasias/metabolismo , Niacinamida/farmacología , Sorafenib , Células Tumorales CultivadasRESUMEN
Ferroptosis is a form of cell death that has recently been reported during exposure to erastin, a chemical compound identified in a screen for molecules able to kill cancer cells carrying an active Ras oncogene. In cells exposed to inducers of ferroptosis, a catastrophic alteration of the cellular redox metabolism occurs, resulting in massive lipid peroxidation in the plasma membrane and loss of cell viability. We present our recent observations suggesting that sorafenib, the only medical treatment with proven efficacy against hepatocellular carcinoma, induces ferroptosis, a new anti-oncogenic mode of action of this drug. The discovery of ferroptosis sheds light on the critical adaptations of the redox metabolism in cancer cells. It might also foster the discovery of new biomarkers and innovative approaches for the treatment of cancer.