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BACKGROUND: Vascular endothelial growth factor (VEGF) was initially known as vascular permeability factor and identified as a driver of tumour angiogenesis. Recently, its role in supporting an immunosuppressive tumour microenvironment was demonstrated, and anti-VEGF treatment combined with immune checkpoint blockade is currently investigated. Further, beta-adrenergic signalling as a modifier of cancer hallmarks like immune response, angiogenesis and metastasis gained increased attention during past years. METHODS: Focusing on the aspect of immunosuppression in upregulated beta-adrenergic signalling, we investigated predictive markers in patients with metastatic melanoma who received bevacizumab monotherapy, a specific VEGF-A binding antibody. We explored the expression of beta-2 adrenergic receptor (ß2-AR), interleukin 6-receptor (IL6-R), cyclooxygenase 2 (COX2) and VEGF-A by immunohistochemistry in melanoma to assess the correlation between these proteins in melanoma cells and response to treatment. RESULTS: Strong ß2-AR expression in metastases was associated with clinical benefit of bevacizumab. Furthermore, expression of the latter was positively linked to expression of VEGF-A and COX2. ß2-AR expression in melanoma metastasis appears to distinguish a subgroup of patients that might benefit from anti-VEGF treatment. CONCLUSION: Our results strengthen further exploration of anti-VEGF therapy in combination with immune checkpoint blockade in clinical studies and the investigation of ß2-AR as predictive marker.
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Melanoma , Factor A de Crecimiento Endotelial Vascular , Humanos , Bevacizumab/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptores Adrenérgicos beta 2 , Ciclooxigenasa 2 , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/patología , Adrenérgicos/uso terapéutico , Microambiente TumoralRESUMEN
Ipilimumab was the first treatment that improved survival in advanced melanoma. Efficacy and toxicity in a real-world setting may differ from clinical trials, due to more liberal eligibility criteria and less intensive monitoring. Moreover, high costs and lack of biomarkers have raised cost-benefit concerns about ipilimumab in national healthcare systems and limited its use. Here, we report the prospective, interventional study, Ipi4 (NCT02068196), which aimed to investigate the toxicity and efficacy of ipilimumab in a real-world population with advanced melanoma. This national, multicentre, phase IV trial included 151 patients. Patients received ipilimumab 3 mg/kg intravenously and were followed for at least 5 years or until death. Treatment interruption or cessation occurred in 38%, most frequently due to disease progression (19%). Treatment-associated grade 3 to 4 toxicity was observed in 28% of patients, and immune-related toxicity in 56%. The overall response rate was 9%. Median overall survival was 12.1 months (95% CI: 8.3-15.9); and progression-free survival 2.7 months (95% CI: 2.6-2.8). After 5 years, 20% of patients were alive. In a landmark analysis from 6 months, improved survival was associated with objective response (HR 0.16, P = .001) and stable disease (HR 0.49, P = .005) compared to progressive disease. Poor performance status, elevated lactate dehydrogenase and C-reactive protein were identified as biomarkers. This prospective trial represents the longest reported follow-up of a real-world melanoma population treated with ipilimumab. Results indicate safety and efficacy comparable to phase III trials and suggest that the use of ipilimumab can be based on current cost-benefit estimates.
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Antineoplásicos Inmunológicos/uso terapéutico , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Neoplasias Cutáneas/secundario , Tasa de SupervivenciaRESUMEN
A subset of breast cancer patients benefits from preoperative bevacizumab and chemotherapy, but validated predictive biomarkers are lacking. Here, we aimed to evaluate tissue-based angiogenesis markers for potential predictive value regarding response to neoadjuvant bevacizumab treatment in breast cancer. In this randomized 1:1 phase II clinical trial, 132 patients with large or locally advanced HER2-negative tumors received chemotherapy ± bevacizumab. Dual Factor VIII/Ki-67 immunohistochemical staining was performed on core needle biopsies at baseline and week 12. Microvessel density (MVD), proliferative microvessel density (pMVD; Factor VIII/Ki-67 co-expression), glomeruloid microvascular proliferation (GMP), and a gene expression angiogenesis signature score, were studied in relation to pathologic complete response (pCR), clinico-pathologic features and intrinsic molecular subtype. We found that high baseline MVD (by median) significantly predicted pCR in the bevacizumab-arm (odds ratio 4.9, P = 0.012). High pMVD, presence of GMP, and the angiogenesis signature score did not predict pCR, but were associated with basal-like (P ≤ 0.009) and triple negative phenotypes (P ≤ 0.041). pMVD and GMP did also associate with high-grade tumors (P ≤ 0.048). To conclude, high baseline MVD significantly predicted response to bevacizumab treatment. In contrast, pMVD, GMP, and the angiogenesis signature score, did not predict response, but associated with aggressive tumor features, including basal-like and triple-negative phenotypes.
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Bevacizumab/administración & dosificación , Neoplasias de la Mama , Densidad Microvascular , Terapia Neoadyuvante , Neovascularización Patológica , Adulto , Anciano , Biopsia con Aguja Gruesa , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patologíaRESUMEN
The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl + cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when co-opted, maintains acquired stemness in breast cancer cells.
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BACKGROUND: Despite the extensive use of bevacizumab in a range of oncology indications, the US FDA revoked its approval for breast cancers, and multiple negative trials in several solid malignancies have been reported, so the need for predictive biomarkers has increased. The development of predictive biomarkers for anti-angiogenic bevacizumab therapy has long been pursued but without success. INTRODUCTION: Heat shock protein (HSP)-27 expression has recently been identified as a predictive biomarker for bevacizumab in treating metastatic melanoma. This study aimed to evaluate the cost effectiveness of HSP27 biomarker testing before administration of bevacizumab. METHODS: A partitioned survival analysis model with three mutually exclusive health states (progression-free survival, progressed disease, and death) was developed using a Norwegian health system perspective. The proportion of patients in each state was calculated using the area under the Kaplan-Meier curve for progression-free and overall survival derived from trials of bevacizumab and dacarbazine. Three strategies were compared: (1) test-treat with HSP27 biomarker and bevacizumab, (2) treat-all with dacarbazine without HSP27 testing, (3) treat-all with bevacizumab without HSP27 testing. Quality-adjusted life-years (QALYs) and costs were calculated for each strategy and discounted at 4%. A lifetime horizon was applied. Uncertainty analyses were performed. Expected value of perfect information (EVPI) was estimated to assess the potential value of further research to generate more evidence. RESULTS: Although the test-treat strategy was cost effective compared with treat-all with dacarbazine, it was not cost effective compared with treat-all with bevacizumab without HSP27 testing. However, EVPI results showed very minimal or no value in conducting further research efforts to reduce uncertainties around current information. CONCLUSION: The results of this study suggested that testing for HSP27 expression before administering bevacizumab is not cost effective compared with treat-all with bevacizumab without testing. It indicates that HSP27 expression is not cost effective as a potential predictive biomarker for bevacizumab. This may not necessarily mean that HSP27 is a bad biomarker for bevacizumab, but it may mean that bevacizumab is much better than dacarbazine regardless of HSP27 expression, so patient stratification according to HSP27 status is meaningless. Or, indeed, it may imply that HSP27 is not sufficiently good at identifying the right patients for bevacizumab.
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Bevacizumab is included in an increasing number of clinical trials. To find biomarkers to predict and monitor treatment response, cancer and angiogenesis relevant mutations in tumour and circulating tumour DNA (ctDNA) were investigated in 26 metastatic melanoma patients treated with bevacizumab. Patients with >1% BRAF/NRAS ctDNA at treatment start had significantly decreased progression free survival (PFS) and overall survival (OS) (PFS: p = 0.019, median 54 vs 774 days, OS: p = 0.026, median 209 vs 1064 days). Patients with >1% BRAF/NRAS ctDNA during treatment showed similar results (PFS: p = 0.002, OS: p = 0.003). ≤1% BRAF/NRAS ctDNA and normal lactate dehydrogenase (LDH) levels both significantly predicted increased response to treatment, but BRAF/NRAS ctDNA was better at predicting response compared to LDH at treatment start (OR 16.94, p = 0.032 vs OR 4.57, p = 0.190), and at predicting PFS (HR 6.76, p = 0.002) and OS (HR 6.78, p = 0.002) during therapy. ctDNA BRAF p.V600D/E/K and NRAS p.G12V/p.Q61K/L/R were better biomarkers for response prediction than TERT promoter mutations (OR 1.50, p = 0.657). Next generation sequencing showed that all patients with ≥2 mutations in angiogenesis-relevant genes had progressive disease, but did not reveal other biomarkers identifying responders. To conclude, ctDNA and LDH are useful biomarkers for both monitoring and predicting response to bevacizumab.
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Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , ADN Tumoral Circulante/análisis , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Melanoma/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Inmunológicos/farmacología , Bevacizumab/farmacología , Femenino , GTP Fosfohidrolasas/genética , Humanos , L-Lactato Deshidrogenasa (Citocromo)/genética , Masculino , Melanoma/genética , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Análisis de Supervivencia , Telomerasa/genética , Resultado del TratamientoRESUMEN
Numerous publications have stated that metastases are responsible for 90% of cancer deaths, but data underlying this assertion has been lacking. Our objective was to determine what proportions of cancer deaths are caused by metastases. Population-based data from the Cancer Registry of Norway for the years 2005-2015 was analyzed. We compared all deaths in the Norwegian population where a cancer diagnosis was registered as cause of death. Deaths caused by cancer, with and without metastases, were analyzed, by sex and tumor group. For solid tumors, 66.7% of cancer deaths were registered with metastases as a contributing cause. Proportions varied substantially between tumor groups. Our data support the idea that the majority of deaths from solid tumors are caused by metastases. Thus, a better understanding of the biology of metastases and identification of druggable targets involved in growth at the metastatic site is a promising strategy to reduce cancer mortality.
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Neoplasias/mortalidad , Causas de Muerte , Femenino , Humanos , Masculino , Metástasis de la Neoplasia , Noruega/epidemiología , Sistema de RegistrosRESUMEN
BACKGROUND: The aim of the research was to separate the distant metastasis (DM) enhancing effect due to breast tumour removal from that due to surgical manoeuvre by itself. METHODS: DM dynamics following surgery for ipsilateral breast tumour recurrence (IBTR), contralateral breast cancer (CBC) and delayed reconstruction (REC), which was performed after the original breast cancer surgical removal, was analysed. A total of 338 patients with IBTR, 239 with CBC and 312 with REC were studied. RESULTS: The DM dynamics following IBTR, CBC and REC, when assessed with time origin at their surgical treatment, is similar to the analogous pattern following primary tumour removal, with a first major peak at about 18 months and a second lower one at about 5 years from surgery. The time span between primary tumour removal and the second surgery is influential on DM risk levels for IBTR and CBC patients, not for REC patients. CONCLUSIONS: The role of breast tumour removal is different from the role of surgery by itself. Our findings suggest that the major effect of reconstructive surgery is microscopic metastasis acceleration, while breast tumour surgical removal (either primary or IBTR or CBC) involves both tumour homeostasis interruption and microscopic metastasis growth acceleration. The removal of a breast tumour would eliminate its homeostatic restrains on metastatic foci, thus allowing metastasis development, which, in turn, would be supported by the forwarding action of the mechanisms triggered by the surgical wounding.
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Neoplasias de la Mama/patología , Adulto , Anciano , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/cirugía , Femenino , Humanos , Mastectomía/efectos adversos , Mastectomía/métodos , Persona de Mediana Edad , Metástasis de la Neoplasia , Periodo Posoperatorio , Carga Tumoral , Adulto JovenRESUMEN
Tumor dormancy is considered one of the major unsolved questions in cancer biology. Understanding the mechanisms responsible for maintaining and interrupting dormancy would be a major step towards preventing overt metastatic disease. Increasing evidence points to tissue trauma and subsequent wound healing as contributing events in escape from dormancy. In this review, we outline relevant aspects of the wound healing process, and relate this to mechanisms of tumor dormancy and metastatic progression. In addition to important findings in epidemiological and experimental studies, more direct evidence of such a link has recently been presented. These results can have major implications for treatment and prevention of cancer.
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Recurrencia Local de Neoplasia/fisiopatología , Neoplasias/fisiopatología , Microambiente Tumoral , Cicatrización de Heridas , Progresión de la Enfermedad , Humanos , Metástasis de la NeoplasiaRESUMEN
INTRODUCTION: Clear cell renal cell carcinoma (ccRCC) is the most common type among renal cell carcinomas, and anti-angiogenic treatment is currently first line therapy in metastatic ccRCC (mccRCC). Response rates and duration of response show considerable variation, and adverse events have major influence on patient's quality of life. The need for predictive biomarkers to select those patients most likely to respond to receptor tyrosine kinase inhibitors (rTKI) upfront is urgent. We investigated the predictive value of plasma interleukin-6 (pIL6), interleukin-6 receptor α (pIL6Rα) and interleukin 6 signal transducer (pIL6ST) in mccRCC patients treated with sunitinib. MATERIAL AND METHODS: Forty-six patients with metastatic or non-resectable ccRCC treated with sunitinib were included. Full blood samples were collected at baseline before start of sunitinib and after every second cycle of treatment during the study time. pIL6, pIL6R and pIL6ST at baseline and week 12 samples were analysed by ELISA. The predictive potential of the candidate markers was assessed by correlation with response rates (RECIST). In addition, progression free survival (PFS) and overall survival (OS) were analysed. RESULTS: Low pIL6 at baseline was significantly associated with improved response to sunitinib (Fisher's exact test, p < 0.01). Furthermore, low pIL6 at baseline was significantly associated with improved PFS (log rank, pâ¯=â¯0.04). In addition, patients with a decrease in concentration of pIL6R between baseline and week 12 showed significantly improved PFS (log rank, pâ¯=â¯0.04) and patients with high pIL6ST at baseline showed significantly improved OS (log rank, pâ¯=â¯0.03). CONCLUSION: Low pIL6 at baseline in mccRCC patients treated with sunitinib predicts improved treatment response, and might represent a candidate predictive marker.
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Biomarcadores de Tumor/sangre , Carcinoma de Células Renales/secundario , Receptor gp130 de Citocinas/sangre , Interleucina-6/sangre , Neoplasias Renales/patología , Receptores de Interleucina-6/sangre , Sunitinib/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/sangre , Neoplasias Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Calidad de Vida , Tasa de SupervivenciaRESUMEN
The incidence of malignant melanoma is rising worldwide and survival for metastatic disease is still poor. Recently, new treatment options have become available. Still, predictive biomarkers are needed to optimise treatment for this patient group. In this study, we investigated the predictive value of 60 angiogenic factors in patients with metastatic melanoma treated with the anti-vascular endothelial growth factor A antibody bevacizumab. Thirty-five patients were included in a clinical phase II trial and baseline serum samples were analysed by multiplex protein array. High-serum concentration of Activin A was significantly associated with objective response (OR) to treatment (p = 0.014). Candidate proteins that indicated a borderline association with treatment response were further investigated by immunohistochemistry. Strong expression of Activin A, interleukin-1ß, and urokinase-type plasminogen activator receptor in metastases was significantly associated with OR (p = 0.011, p = 0.003, and p = 0.007, respectively), as well as with markers of activated angiogenesis, such as higher number of proliferating vessels and the presence of glomeruloid microvascular proliferations. Our findings indicate that these proteins may be potential predictive markers for treatment with bevacizumab monotherapy.
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Bevacizumab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Biomarcadores de Tumor/metabolismo , Femenino , Humanos , Masculino , Melanoma/secundario , Neovascularización Patológica/tratamiento farmacológicoRESUMEN
Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, and anti-angiogenic treatment is currently first line therapy for metastatic ccRCC (mccRCC). Response rates and duration of response show considerable variation, and adverse events have a major influence on patient quality of life. The need for predictive biomarkers to select responders to receptor tyrosine kinase inhibitors upfront is urgent. We investigated the predictive value of immunohistochemical biomarkers associated with angiogenesis and systemic inflammation in mccRCC. Forty-six patients with metastatic or non-resectable ccRCC treated with sunitinib were included. Metastatic and/or primary tumour tissue was stained by immunohistochemistry for selected markers related to angiogenesis [vascular endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGFR2), platelet-derived growth factor receptor ß (PDGFRß), and heat shock protein 27 (HSP27)] and immune responses [Interleukin 6 receptor α (IL6Rα), interleukin-6 (IL6), and jagged1 (JAG1)]. The predictive potential of the candidate markers was assessed by correlations with response rates (RECIST). In addition, progression free survival (PFS) and overall survival (OS) were analysed. Low tumour cell expression of IL6Rα was significantly associated with improved response to sunitinib (Fisher's exact test, p = 0.03), but not with PFS or OS. Median/high expression of IL6Rα showed significant association with median/high expression of VEGF-A and HSP27. Furthermore, low expression of IL6 was significantly associated with improved PFS, but not OS or response rates. High expression of IL6 was significantly associated with high expression of JAG1, VEGF-A, VEGFR2, and PDGFRß. Loss of tumour cell expression of IL6Rα in mccRCC patients treated with sunitinib predicts improved treatment response, and might represent a candidate predictive marker.
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Inhibidores de la Angiogénesis/administración & dosificación , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Sunitinib/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/patología , Femenino , Humanos , Inmunohistoquímica , Interleucina-6/metabolismo , Neoplasias Renales/diagnóstico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Neovascularización Patológica , Pronóstico , Estudios Prospectivos , Receptores de Interleucina-6/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Importance: In cancer models, warfarin inhibits AXL receptor tyrosine kinase-dependent tumorigenesis and enhances antitumor immune responses at doses not reaching anticoagulation levels. This study investigates the association between warfarin use and cancer incidence in a large, unselected population-based cohort. Objective: To examine the association between warfarin use and cancer incidence. Design, Setting, and Participants: This population-based cohort study with subgroup analysis used the Norwegian National Registry coupled with the Norwegian Prescription Database and the Cancer Registry of Norway. The cohort comprised all persons (N = 1â¯256â¯725) born between January 1, 1924, and December 31, 1954, who were residing in Norway from January 1, 2006, through December 31, 2012. The cohort was divided into 2 groups-warfarin users and nonusers; persons taking warfarin for atrial fibrillation or atrial flutter were the subgroup. Data were collected from January 1, 2004, to December 31, 2012. Data analysis was conducted from October 15, 2016, to January 31, 2017. Exposures: Warfarin use was defined as taking at least 6 months of a prescription and at least 2 years from first prescription to any cancer diagnosis. If warfarin treatment started after January 1, 2006, each person contributed person-time in the nonuser group until the warfarin user criteria were fulfilled. Main Outcomes and Measures: Cancer diagnosis of any type during the 7-year observation period (January 1, 2006, through December 31, 2012). Results: Of the 1â¯256â¯725 persons in the cohort, 607â¯350 (48.3%) were male, 649â¯375 (51.7%) were female, 132â¯687 (10.6%) had cancer, 92â¯942 (7.4%) were classified as warfarin users, and 1â¯163â¯783 (92.6%) were classified as nonusers. Warfarin users were older, with a mean (SD) age of 70.2 (8.2) years, and were predominantly men (57 370 [61.7%]) as compared with nonusers, who had a mean (SD) age of 63.9 (8.6) years and were mostly women (613 803 [52.7%]). Among warfarin users and compared with nonusers, there was a significantly lower age- and sex-adjusted incidence rate ratio (IRR) in all cancer sites (IRR, 0.84; 95% CI, 0.82-0.86) and in prevalent organ-specific sites (lung, 0.80 [95% CI, 0.75-0.86]; prostate, 0.69 [95% CI, 0.65-0.72]; and breast, 0.90 [95% CI, 0.82-1.00]). There was no observed significant effect in colon cancer (IRR, 0.99; 95% CI, 0.93-1.06). In a subgroup analysis of patients with atrial fibrillation or atrial flutter, the IRR was lower in all cancer sites (IRR, 0.62; 95% CI, 0.59-0.65) and in prevalent sites (lung, 0.39 [95% CI, 0.33-0.46]; prostate, 0.60 [95% CI, 0.55-0.66]; breast, 0.72 [95% CI, 0.59-0.87]; and colon, 0.71 [95% CI, 0.63-0.81]). Conclusions and Relevance: Warfarin use may have broad anticancer potential in a large, population-based cohort of persons older than 50 years. This finding could have important implications for the selection of medications for patients needing anticoagulation.
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Anticoagulantes/uso terapéutico , Neoplasias/epidemiología , Warfarina/uso terapéutico , Anciano , Fibrilación Atrial/tratamiento farmacológico , Aleteo Atrial/tratamiento farmacológico , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Sistema de RegistrosRESUMEN
BACKGROUND: Sunitinib has become mainstay first line treatment for patients with metastatic renal clear cell carcinoma (mRCC). Still, useful predictive markers of response are lacking and urgently needed for clinical decision making. METHODS: In the present study we investigated the predictive value of standard serum markers as well as clinical markers, including C-reactive protein (CRP), Neutrophil to Lymphocyte ratio (NLR) and early hypertension (eHTN) in an unselected prospective patient population treated with sunitinib for mRCC. Forty-six patients were enrolled in a prospective single-arm study of predictive markers for sunitinib response. Response rates according to RECIST 1.1 were used as primary end-point. Secondary objectives were to evaluate prognostic value of the candidate markers with regard to progression free survival (PFS) and overall survival (OS). In addition, toxicity rates and quality of life was recorded. RESULTS: Median PFS and OS was 9.1 months and 15.0 months, respectively. Of 38 patients evaluable for response, 1 patient had complete response (CR), 7 had partial response (PR), 18 had stable disease (SD) and 12 had progressive disease (PD). Normal CRP at baseline was significantly associated with objective response (CR + PR) (p = 0.01). Normal CRP was also significantly associated with improved PFS and OS (Log rank, p = 0.05 and <0.01, respectively). Early hypertension, NLR and IMDC risk score were not significantly associated with response rates or survival. CONCLUSION: Baseline CRP was a significant predictive factor of sunitinib response and a prognostic factor of survival. Baseline CRP might be a useful biomarker in the treatment planning of mRCC. Due to the relatively small sample size, our results need to be confirmed in larger studies.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Proteína C-Reactiva/análisis , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/uso terapéutico , Neoplasias Renales/sangre , Neoplasias Renales/tratamiento farmacológico , Pirroles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/secundario , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , SunitinibRESUMEN
The purpose of this study was to characterize the recurrence dynamics in breast cancer patients after delayed reconstruction. We hypothesized that surgical reconstruction might stimulate dormant micrometastases and reduce time to recurrence. All mastectomy breast cancer patients with delayed surgical reconstruction at Haukeland University Hospital, between 1977 and 2007, n = 312, were studied. Our control group consisted of 1341 breast cancer patients without reconstruction. For each case, all patients in the control group with identical T and N stages and age ±2 years were considered. A paired control was randomly selected from this group. 10 years after primary surgery, 39 of the cases had relapsed, compared to 52 of the matched controls. The reconstructed group was analyzed for relapse dynamics after mastectomy; the first peak in relapses was similarly timed, but smaller than for the controls, while the second peak was similar in time and size. Second, the relapse pattern was analyzed with reconstruction as the starting point. A peak in recurrences was found after 18 months, and a lower peak at the 5th-6th year. The height of the peak correlated with the extent of surgery and initial T and N stages. Timing of the peak was not affected, neither was the cumulative effect. The relapse pattern, when time origin is placed both at mastectomy and at reconstruction, is bimodal with a peak position at the same time points, at 2 years and at 5-6 years. The timing of the transition from dormant micrometastases into clinically detectable macrometastases might be explained by an enhancing effect of surgery.
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Neoplasias de la Mama/epidemiología , Carcinoma Intraductal no Infiltrante/epidemiología , Mastectomía/métodos , Recurrencia Local de Neoplasia/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/cirugía , Carcinoma Intraductal no Infiltrante/cirugía , Progresión de la Enfermedad , Femenino , Humanos , Mamoplastia , Márgenes de Escisión , Persona de Mediana Edad , Micrometástasis de Neoplasia , Recurrencia Local de Neoplasia/cirugía , Países Bajos/epidemiología , Tiempo de Tratamiento , Adulto JovenRESUMEN
The aim of this study was to identify potential predictive biomarkers in 35 patients with metastatic melanoma treated with anti-angiogenic bevacizumab monotherapy in a clinical phase II study. The immunohistochemical expression of various angiogenic factors in tissues from primary melanomas and metastases as well as their concentration in blood samples were examined. Strong expression of Heat Shock Protein 27 (HSP27) in metastases correlated significantly with complete or partial response to bevacizumab (p = 0.044). Furthermore, clinical benefit, i.e., complete or partial response or stable disease for at least 6 months, was more frequent in patients with strong expression of HSP27 in primary tumors (p = 0.046). Tissue expression of vascular endothelial growth factor (VEGF-A), its splicing variant VEGF165b or basic fibroblast growth factor (bFGF) did not correlate with response, and the concentration of HSP27, VEGF-A or bFGF measured in blood samples before treatment did not show predictive value. Further, microvessel density, proliferating microvessel density and presence of glomeruloid microvascular proliferations were assessed in sections of primary tumors and metastases. Microvessel density in primary melanomas was significantly higher in patients with clinical benefit than in non-responders (p = 0.042). In conclusion, our findings suggest that strong HSP27 expression in melanoma metastases predicts response to bevacizumab treatment.
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Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Proteínas de Choque Térmico HSP27/genética , Melanoma/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Femenino , Factor 2 de Crecimiento de Fibroblastos/sangre , Factor 2 de Crecimiento de Fibroblastos/genética , Proteínas de Choque Térmico HSP27/sangre , Proteínas de Choque Térmico , Humanos , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Metástasis Linfática , Masculino , Melanoma/irrigación sanguínea , Melanoma/genética , Melanoma/secundario , Persona de Mediana Edad , Chaperonas Moleculares , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Pronóstico , Transducción de Señal , Neoplasias Cutáneas/irrigación sanguínea , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
BACKGROUND: Erdheim-Chester disease is a rare histiocytosis characterized by multi-systemic organ involvement. Immune-modulating agents such as interferon-alpha have limited success and the disorder is progressive and causes high morbidity and mortality. Treatment with the BRAF-inhibitor vemurafenib has recently produced substantial improvement in three patients with Erdheim-Chester disease expressing the p. V600E BRAF mutation. The disorder commonly affects the central nervous system and it is not yet known whether vemurafenib can reverse intra-axial infiltration and the resulting neurological impairment. CASE PRESENTATION: In this work, we report for the first time an excellent clinical response to vemurafenib in a Norwegian patient with debilitating progressive spastic paraparesis due to intra-axial infiltration of the thoracic spinal cord. The patient had been unresponsive to interferon-alpha. Low dose vemurafenib (720 mg daily) for a period of three months resulted in significant tumor shrinkage by >60% and regression of contrast enhancement and fluorodeoxyglucose uptake on positron-emission tomography. The patient's spastic paraparesis and gait function improved dramatically. She currently walks unaided and reports a substantially improved quality of life. CONCLUSION: Our findings show that vemurafenib therapy, even at low doses, can be effective for the treatment of intra-axial central nervous system involvement in BRAF-positive Erdheim-Chester disease.
Asunto(s)
Enfermedad de Erdheim-Chester/tratamiento farmacológico , Indoles/uso terapéutico , Columna Vertebral/patología , Sulfonamidas/uso terapéutico , Adulto , Femenino , Humanos , Resultado del Tratamiento , VemurafenibRESUMEN
A significant variation in the metastatic pattern among breast cancer patients exists. Clinical observations suggest that these differences are related to time to recurrence (TTR), thus suggesting a common systemic growth signal at the time of surgery. Our goal was to identify a marker for synchronized growth of micrometastases. To quantify the metastatic pattern at first relapse, 180 patients with metastatic breast cancer were studied. Standard deviation (SD) of lesions size and lesion number was calculated and served as a marker for variation. Patients with low SD (multiple/similar sized lesions) were assumed to have synchronized growth, whereas patients with high SD were assumed to have unsynchronized growth. Patients were grouped according to TTR; early (< 3 years-) or late (> 3 years- after surgery). In patients not receiving systemic adjuvant treatment, median SD was significantly lower in the early group (2.5 mm) compared with 6.4 mm in the late group (p = 0.005). In node negative patients, median SD was significantly lower in the early group (3.0 mm) when compared with the late group (5.7 mm, p = 0.02). An additional drop in SD was observed immediately after end of adjuvant endocrine therapy. Our results identify SD as a marker of synchronized metastatic growth in breast cancer. A metastatic phenotype characterized by multiple similar sized metastases, suggesting synchronized onset of growth of micrometastases was predominantly found in patients recurring early after surgery and was counteracted by adjuvant treatment. Systemic growth signals caused by surgery might be antagonized during the time window following surgery.
Asunto(s)
Neoplasias de la Mama/epidemiología , Micrometástasis de Neoplasia/patología , Recurrencia Local de Neoplasia/epidemiología , Adulto , Anciano , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Micrometástasis de Neoplasia/terapia , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Radioterapia AdyuvanteRESUMEN
UNLABELLED: The angiogenic switch, a rate-limiting step in tumor progression, has already occurred by the time most human tumors are detectable. However, despite significant study of the mechanisms controlling this switch, the kinetics and reversibility of the process have not been explored. The stability of the angiogenic phenotype was examined using an established human liposarcoma xenograft model. Nonangiogenic cells inoculated into immunocompromised mice formed microscopic tumors that remained dormant for approximately 125 days (vs. <40 days for angiogenic cells) whereupon the vast majority (>95%) initiated angiogenic growth with second-order kinetics. These original, clonally derived angiogenic tumor cells were passaged through four in vivo cycles. At each cycle, a new set of single-cell clones was established from the most angiogenic clone and characterized for in vivo for tumorigenic activity. A total of 132 single-cell clones were tested in the second, third, and fourth in vivo passage. Strikingly, at each passage, a portion of the single-cell clones formed microscopic, dormant tumors. Following dormancy, like the original cell line, these revertant tumors spontaneously switched to the angiogenic phenotype. Finally, revertant clones were transcriptionally profiled and their angiogenic output determined. Collectively, these data demonstrate that the angiogenic phenotype in tumors is malleable and can spontaneously revert to the nonangiogenic phenotype in a population of human tumor cells. IMPLICATIONS: Leveraging the rate of reversion to the nonangiogenic phenotype and tumor dormancy may be a novel anticancer strategy.