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B7-H4 (VTCN1), a member of the B7 family, is overexpressed in several types of cancer. Here we investigated the pattern of expression of B7-H4 in salivary gland carcinomas (SGC) and assessed its potential as a prognostic marker and therapeutic target. Immunohistochemistry (IHC) analyses were performed in a cohort of 340 patient tumors, composed of 124 adenoid cystic carcinomas (ACC), 107 salivary duct carcinomas (SDC), 64 acinic cell carcinomas, 36 mucoepidermoid carcinomas (MEC), 9 secretory carcinomas (SC), as well as 20 normal salivary glands (controls). B7-H4 expression was scored and categorized into negative (<5% expression of any intensity), low (5%-70% expression of any intensity or >70% with weak intensity), or high (>70% moderate or strong diffuse intensity). The associations between B7-H4 expression and clinicopathologic characteristics, as well as overall survival, were assessed. Among all tumors, B7-H4 expression was more prevalent in ACC (94%) compared with those of SC (67%), MEC (44%), SDC (32%), and acinic cell carcinomas (0%). Normal salivary gland tissue did not express B7-H4. High expression of B7-H4 was found exclusively in ACC (27%), SDC (11%), and MEC (8%). In SDC, B7-H4 expression was associated with female gender (P = .002) and lack of androgen receptor expression (P = .012). In ACC, B7-H4 expression was significantly associated with solid histology (P < .0001) and minor salivary gland primary (P = .02). High B7-H4 expression was associated with a poorer prognosis in ACC, regardless of clinical stage and histologic subtype. B7-H4 expression was not prognostic in the non-ACC SGC evaluated. Our comparative study revealed distinct patterns of B7-H4 expression according to SGC histology, which has potential therapeutic implications. B7-H4 expression was particularly high in solid ACC and was an independent prognostic marker in this disease but not in the other SGC assessed.
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Neoplasias da Mama , Carcinoma de Células Acinares , Carcinoma Adenoide Cístico , Carcinoma Mucoepidermoide , Carcinoma , Neoplasias das Glândulas Salivares , Humanos , Feminino , Carcinoma Adenoide Cístico/patologia , Prognóstico , Carcinoma de Células Acinares/patologia , Neoplasias das Glândulas Salivares/patologia , Carcinoma Mucoepidermoide/patologia , Carcinoma/patologia , Glândulas Salivares/química , Glândulas Salivares/metabolismo , Glândulas Salivares/patologia , Biomarcadores Tumorais/análiseRESUMO
[This corrects the article DOI: 10.3389/fonc.2020.580141.].
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BACKGROUND: Salivary duct carcinoma (SDC) is a rare and aggressive malignancy. Recently, biomarker studies found promising targetable alterations. In this study, we provide a descriptive analysis of tumor and immune biomarkers and survival associations. METHODS: We extracted clinical data and performed immunohistochemistry for AR, AR-V7, HER-2, PD-L1, LAG-3, and tumor-infiltrating immune cells. RESULTS: We included 17 patients. Age ranged from 42 to 85 years old; HER-2 was overexpressed or amplified in 65%. AR was positive in 88% of patients, while AR-V7 was positive in 13% by IHC. We found low scores of immune infiltration and a PD-L1 expression in 53%. We found no clinically significant association between biomarkers and survival outcomes. CONCLUSION: In this small series of SDC, biomarkers do not seem to correlate with disease biology, although they provide additional treatment options. SDC may harbor a different immune profile compared to other subtypes, with an indication of T-cell dysfunction.
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Carcinoma Ductal , Neoplasias das Glândulas Salivares , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Humanos , Pessoa de Meia-Idade , Receptores Androgênicos , Ductos SalivaresRESUMO
Salivary gland carcinomas (SGCs) account for <5% of head and neck malignant neoplasms, further subcategorized in over 20 histological subtypes. For the most part, treatment for advanced disease is guided by morphology. SGCs in general respond poorly to a wide array of standard chemotherapy, with short durability, and significant toxicity. More recently, next-generation sequencing provided significant input on the molecular characterization of each SGC subtype, not only improving diagnostic differentiation between morphologically similar tumor types but also identifying novel driver pathways that determine tumor biology and may be amenable to targeted therapy. Among the most common histological subtype is adenoid cystic carcinoma, which often harbors a chromosome translocation resulting in an MYB-NFIB oncogene, with various degrees of Myb surface expression. In a smaller subset, NOTCH1 mutations occur, conferring a more aggressive pattern and potential sensitivity to Notch inhibitors. Salivary duct carcinomas may overexpress Her-2 and androgen receptors, with promising clinical outcomes after exposure to targeted therapies approved for other indications. Secretory carcinoma, previously known as mammary analog secretory carcinoma, is distinguished by an ETV6-NTRK3 fusion that can both help differentiate it from its morphologically similar acinar cell carcinoma and make it susceptible to Trk inhibitors. In the present article, we discuss the molecular abnormalities, their impact on tumor biology, and therapeutic opportunities for the most common SGC subtypes and review published and ongoing clinical trials and future perspectives for this rare disease.
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Salivary gland cancers represent a rare group of tumors composed by over 20 histological subtypes. Initially treated as one single disease, its diagnosis, prognosis, and treatment are currently being stratified based on morphology. More recently, insight has been provided on the molecular characterization of each subtype, further improving diagnostic accuracy and paving the way for personalized therapy. In this article, we provide a comprehensive review of recent breakthroughs, preliminary results of novel therapy, and future directions on the treatment of these complex malignancies.
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Neoplasias das Glândulas Salivares , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/terapia , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Adenoide Cístico/genética , Carcinoma Adenoide Cístico/metabolismo , Carcinoma Adenoide Cístico/terapia , Carcinoma Ductal/genética , Carcinoma Ductal/metabolismo , Carcinoma Ductal/terapia , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/terapia , Análise Mutacional de DNA , Perfilação da Expressão Gênica , Humanos , Mutação , Ductos Salivares/patologia , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/terapiaRESUMO
The role of chemotherapy in well differentiated neuroendocrine tumors (NET) has been questioned. It was recently demonstrated that everolimus and sunitinib have activity in low and intermediate grade pancreatic NET. The aim of this study was to evaluate the activity of capecitabine and oxaliplatin (CapOx) combination in treating NET in an unselected population. In this regard, we retrospectively evaluated 24 patients diagnosed with metastatic NET treated with CapOx at two Brazilian institutes that are reference centers in cancer care. Tumor response was measured by RECIST criteria. Median age at diagnosis was 56 years, 71% had ECOG 0 or 1, the majority of tumors were primary from pancreas (67%) followed by lung (17%), and 29% were functional. According to WHO classification criteria, 25% were grade 1, 37.5% grade 2 and 37.5% grade 3. Most patients received CapOx as second-line therapy, with a median of 6 cycles. Twenty-nine percent of patients had partial response by RECIST criteria. No association was observed between response rate and tumor grade, primary site or line of CapOx. The median time to progression was 9.8 months and median time to treatment failure was 12.1 months. Seventy-five percent of patients are alive at the time of this analysis; therefore, median overall survival was not reached. The CapOx combination was shown to be active in an unselected population with metastatic NET and may be a good platform for the incorporation of the newer molecular targeted agents being investigated for the treatment of this entity.
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Angiogenesis is essential to cancer development and progression, and its inhibition has been shown to benefit patients with several different malignancies. A considerable number of antiangiogenic compounds have been evaluated for the treatment of colorectal cancer, but only bevacizumab and aflibercept were able to demonstrate a survival benefit in phase III trials. In this review, we discuss important aspects of the interrelationship between tumor cells and the microenvironment leading to tumor progression, with a focus on angiogenesis. Clinical data on antiangiogenic therapies for colorectal cancer in the metastatic and adjuvant settings, as well as the potential use of antiangiogenics beyond tumor progression are analyzed. The need to identify surrogate biomarkers towards a more personalized approach in oncology is emphasized as this is becoming increasingly important in drug development.
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Inibidores da Angiogênese/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Animais , Neoplasias Colorretais/irrigação sanguínea , HumanosRESUMO
BACKGROUND: A considerable number of metastatic colorectal cancer (mCRC) patients who progress on standard treatment with 5-fluorouracil (5FU), oxaliplatin, irinotecan and monoclonal antibodies, still have adequate performance status and desire further treatment. Mitomycin C (MMC) has been widely used in this context, and despite good tolerability, there are doubts regarding its true benefit. METHODS: In order to assess the activity of MMC in the refractory mCRC setting, we retrospectively evaluated 109 heavily pre-treated patients who received MMC as single agent or in combination for mCRC at three different institutions in two countries. RESULTS: Median patient's age was 54 years old, 57% were male and 94% had performance status ECOG 0 or 1. MMC was used in second line in 11%, third line in 38% and fourth line or beyond in 51% of patients. 58% received MMC combinations, mainly with capecitabine. Grade 3 or 4 toxicity was observed in 5% of patients and 6% required dose reductions. Median time to treatment failure (TTF) was 1.7 months with MMC and 3.6 months on the regimen prior to MMC, with a ratio between these TTF below 1 in 82% of patients. Median survival was only 4.5 months (95% confidence interval (CI) of 3.48-5.56). CONCLUSIONS: This retrospective data represent the largest reported series of unselected refractory mCRC patients treated with MMC. The median survival of 4.5 months is similar to the survival expected for best supportive care. This lack of activity strongly suggests that MMC should not be routinely used in refractory mCRC.
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Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Mitomicina/uso terapêutico , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de SobrevidaRESUMO
BACKGROUND/PURPOSE: The median survival for patients with metastatic colorectal cancer (mCRC) has progressively increased over the past decades. Since the introduction of 5-fluorouracil (5-FU)-based chemotherapy, followed by hepatic resection of metastases, and more recently the adoption of newer chemotherapeutic regimens associated with targeted therapy, the gains are getting more substantial. Despite the recognition of the potential for long-term survival after surgical resection of metastatic disease, long-term survival data to determine the potential curative role of chemotherapy alone is lacking. METHODS: We performed a retrospective review of 2751 patients who presented with mCRC at The MD Anderson Cancer Center from 1990 through 2003. Patients alive at 5 years who achieved complete response with chemotherapy and were not submitted to any surgical or interventional procedures directed to the metastatic sites were included in the analysis. RESULTS: The 5-year overall survival rate for all patients with mCRC during this period was 10.8%. Among these long-term survivors, 2.2% achieved a sustained complete response after chemotherapy (all 6 with fluoropyrimidines and 2 with irinotecan) as the only treatment modality and were without evidence of disease until the last follow-up visit (median of 10.3 years). This number corresponds to 0.24% (6 of 2541) of all patients with mCRC included in this review. CONCLUSION: Cure with chemotherapy alone is possible for a very small number of patients with metastatic colorectal cancer. Improved therapies are increasing complete response rates, but the impact of modern chemotherapy on durable complete responses will require additional follow up.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adenocarcinoma/secundário , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Estudos de Coortes , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Irinotecano , Neoplasias Hepáticas/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Venous thromboembolism (VTE) is a serious and potentially fatal disorder, which is often associated with a significant impact on the quality of life and on the clinical outcome of cancer patients. The pathophysiology of the association between thrombosis and cancer is complex: malignancy is associated with a baseline hypercoagulable state due to many factors including release of inflammatory cytokines, activation of the clotting system, expression of hemostatic proteins on tumor cells, inhibition of natural anticoagulants, and impaired fibrinolysis. Several risk factors, related to the patient, the disease, and the therapeutic interventions, have been identified as contributing to the occurrence of VTE. There is convincing evidence to recommend the use of heparins or fondaparinux for prevention of VTE in selected cancer patients, and, especially in some particular types of malignancies and cancer treatments. Management of VTE in patients with cancer is more challenging and bleeding complications associated with the use of anticoagulants are significantly higher in cancer patients than in those without malignancy. Important issues that need to be considered in all cases are interference with anticancer therapy, inconvenience of treatment, and impact on quality of life.
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Neoplasias/complicações , Tromboembolia Venosa/prevenção & controle , Fondaparinux , Heparina/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Polissacarídeos/uso terapêutico , Qualidade de Vida , Fatores de Risco , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/etiologiaRESUMO
Tromboembolismo venoso é um evento potencialmente fatal, que complica a evolução de 20 por cento dos pacientes com neoplasia, causando impacto significativo na qualidade de vida e nos desfechos clínicos desses pacientes. A fisiopatologia da associação entre trombose e câncer é complexa. As neoplasias estão associadas a estado de hipercoagulabilidade secundário à liberação de citocinas inflamatórias, ativação do sistema de coagulação, expressão de proteínas hemostáticas nas células tumorais, inibição de anticoagulantes naturais e alteração no processo fibrinolítico. Os fatores de risco associados ao tromboembolismo venoso podem ser relacionados ao paciente, à doença ou às intervenções terapêuticas. O uso profilático de heparinas e fondaparinux está indicado em pacientes selecionados de acordo com o tipo de neoplasia e da terapia utilizada. O tratamento dos pacientes oncológicos com tromboembolismo venoso é desafiador: as complicações associadas ao uso de anticoagulantes são significativamente maiores, podem interferir com o tratamento antineoplásico e têm impacto negativo na qualidade de vida.
Venous thromboembolism is a serious and potentially fatal disorder, which complicates the course of 20% of cancer patients, and has a significant impact on the quality of life and clinical outcomes of these patients. The pathophysiology of the association between thrombosis and cancer is complex. Malignancy is associated with a baseline hypercoagulable state secondary to the release of inflammatory cytokines, activation of the clotting system, expression of hemostatic proteins on tumor cells, inhibition of natural anticoagulants and impaired fibrinolysis. Several risk factors have been identified as contributing to venous thromboembolism and may be related to the patient characteristics, to the disease, and to the therapeutic interventions. The use of heparins and fondaparinux is indicated for selected cancer patients according to the types of malignancies and treatments. The treatment of venous thromboembolism in patients with cancer is challenging: the complications associated with the use of anticoagulants are significantly higher, may interfere with anticancer therapy and have a negative impact on quality of life.