RESUMO
Cancer patients, due to their immunocompromised status, are at an increased risk for severe SARS-CoV-2 infection. Since severe SARS-CoV-2 infection causes multiple organ damage through IL-6-mediated inflammation while stimulating hypoxia, and malignancy promotes hypoxia-induced cellular metabolic alterations leading to cell death, we propose a mechanistic interplay between both conditions that results in an upregulation of IL-6 secretion resulting in enhanced cytokine production and systemic injury. Hypoxia mediated by both conditions results in cell necrosis, dysregulation of oxidative phosphorylation, and mitochondrial dysfunction. This produces free radicals and cytokines that result in systemic inflammatory injury. Hypoxia also catalyzes the breakdown of COX-1 and 2 resulting in bronchoconstriction and pulmonary edema, which further exacerbates tissue hypoxia. Given this disease model, therapeutic options are currently being studied against severe SARS-COV-2. In this study, we review several promising therapies against severe disease supported by clinical trial evidence-including Allocetra, monoclonal antibodies (Tixagevimab-Cilgavimab), peginterferon lambda, Baricitinib, Remdesivir, Sarilumab, Tocilizumab, Anakinra, Bevacizumab, exosomes, and mesenchymal stem cells. Due to the virus's rapid adaptive evolution and diverse symptomatic manifestation, the use of combination therapies offers a promising approach to decrease systemic injury. By investing in such targeted interventions, cases of severe SARS-CoV-2 should decrease along with its associated long-term sequelae and thereby allow cancer patients to resume their treatments.
Assuntos
COVID-19 , Neoplasias , Humanos , SARS-CoV-2 , Interleucina-6 , Neoplasias/complicações , Neoplasias/terapia , HipóxiaRESUMO
BACKGROUND: HER2)-low expression is a predictive biomarker for novel anti-HER2 antibody-drug conjugates. However, little is known about its clinical significance in inflammatory breast cancer (IBC). METHODS: Patients diagnosed with HER2-negative IBC between December 1999 and December 2020 were identified from the Dana-Farber Cancer Institute IBC registry. Patients were divided into HER2-low (IHC 1+ or 2+/ISH-) and HER2-zero (IHC 0), comparing clinicopathologic features and disease outcomes between the two subgroups. RESULTS: The study included 276 patients. Among patients with stage III (n = 209) and stage IV (n = 67) IBC, 54% and 39% had HER2-low tumours, respectively. Oestrogen receptor (ER)-expressing tumours were more common in patients with HER2-low versus HER2-zero stage III IBC (65% versus 38%, p < 0.01). Among stage III patients undergoing surgery (n = 182), pathologic complete response (pCR) rates were higher for HER2-zero versus HER2-low IBC (11% versus 6%, OR: 1.8, 95%CI:0.6-5.3), but minimal differences persisted when separately analysing pCR by ER status. Similar invasive disease-free survival (iDFS) outcomes were observed among ER-positive HER2-zero versus HER2-low IBC (48-month iDFS: 63% versus 63%, HR: 1.10, 95%CI:0.57-2.13) and ER-negative HER2-zero versus HER2-low IBC (48-month iDFS: 28% versus 25%, HR: 1.19, 95%CI:0.69-2.04). Differences in overall survival (OS) were small, both among ER-positive HER2-zero versus HER2-low IBC (48-month OS: 80% versus 81%, HR: 0.82, 95%CI:0.39-1.73) and ER-negative HER2-zero versus HER2-low IBC (48-month OS: 34% versus 47%, HR: 1.34, 95%CI: 0.74-2.41). CONCLUSIONS: Marginal differences in clinicopathologic features and outcomes were observed in HER2-low versus HER2-zero IBC when controlling for ER status, not supporting the definition of HER2-low as a distinct subtype of IBC.
Assuntos
Neoplasias Inflamatórias Mamárias , Receptor ErbB-2 , Feminino , Humanos , Imunoconjugados , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/metabolismo , Neoplasias Inflamatórias Mamárias/patologia , Prognóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
PURPOSE: The antigenic targets of immunity and the role of vaccination in breast cancer are unknown. We performed a phase I study of an autologous GM-CSF-secreting breast cancer vaccine in patients with metastatic and stage II-III breast cancer. METHODS: Tumor cells from patients with metastatic (n = 15) and stage II-III (n = 7) disease were transduced with a replication-defective adenoviral vector encoding GM-CSF, and then irradiated. Twelve and seven patients with metastatic and stage II-III disease, respectively, received weekly vaccination for three weeks, followed by every other week until disease progression or vaccine supply was exhausted (metastatic) or until six total vaccine doses were administered (stage II-III). RESULTS: Among those patients with metastatic disease who received vaccinations, eight had progressive disease at two months, three had stable disease for 4-13 months, and one has had no evidence of disease for 13 years. Of the patients with stage II-III disease, five died of metastatic disease between 1.16 and 8.49 years after the start of vaccinations (median 6.24 years) and two are alive as of September 2021. Toxicities included injection site reactions, fatigue, fever, upper respiratory symptoms, joint pain, nausea, and edema. Four of five evaluable patients with metastatic disease developed a skin reaction with immune cell infiltration after the fifth injection of unmodified, irradiated tumor cells. CONCLUSION: We conclude that tumor cells can be harvested from patients with metastatic or stage II-III breast cancer to prepare autologous GM-CSF-secreting vaccines that induce coordinated immune responses with limited toxicity. TRIAL REGISTRATION AND DATE OF REGISTRATION: clinicaltrials.gov, NCT00317603 (April 25, 2006) and NCT00880464 (April 13, 2009).
Assuntos
Neoplasias da Mama , Vacinas Anticâncer , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Vacinas Anticâncer/toxicidade , Estudos de Viabilidade , Feminino , Vetores Genéticos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , HumanosRESUMO
PURPOSE: We sought to understand the attitudes of individuals with abnormal breast imaging findings prompting a diagnostic breast biopsy toward donation of blood, excised tissue, or percutaneous biospecimens for research, and to understand medical oncologists' attitudes toward research biospecimen collection in this population. METHODS: We included individuals who presented to a single academic medical center for a clinically indicated, image-guided, percutaneous breast biopsy. We administered a survey prior to knowledge of biopsy results to assess willingness to consider, entirely for research purposes, donating blood or excess excised breast tissue, or having additional biospecimens (AB) obtained during a clinically indicated percutaneous biopsy. We also surveyed breast medical oncologists from National Cancer Institute-designated cancer centers to assess attitudes toward approaching patients for biospecimen research. RESULTS: Overall, 53/63 patients responded to the survey; 70% would consider donating blood, 85% would consider donating excess excised breast tissue, and 32% would consider having AB obtained during a clinically indicated biopsy. Main motivating factors for considering AB included contributing to scientific knowledge and return of study or biopsy results, whereas anxiety and the potential discomfort were the main dissuading factors. Among 191 medical oncologists, most were very comfortable (59.2%), or somewhat comfortable (32.5%) asking patients to have AB obtained during a clinically indicated breast biopsy. Medical oncologists reported hesitancy to refer a patient for AB due to potential pain/discomfort, and other procedure risks. CONCLUSIONS: Only one-third of individuals with breast imaging findings would consider consenting to AB during a diagnostic biopsy, whereas most were open to donating blood or excess excised breast tissue. Most medical oncologists would be comfortable asking patients to have AB obtained during the biopsy. Understanding patients' and oncologists' baseline attitudes may inform the design and approach to breast biospecimen-based research.
Assuntos
Neoplasias da Mama , Oncologistas , Biópsia , Mama , Neoplasias da Mama/diagnóstico por imagem , Feminino , Humanos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The objective of this study was to describe the perspective of patients with early breast cancer toward research biopsies. The authors hypothesized that more patients at academic sites than at community-based sites would be willing to consider these procedures. METHODS: In total, 198 patients with early stage breast cancer were recruited from 3 academic centers (n = 102) and from 1 community oncology practice (n = 96). The primary objective was to compare the proportion of patients willing to consider donating excess tissue biospecimens from surgery, from a clinically indicated breast biopsy, or from a research purposes-only biopsy (RPOB) between practice types. RESULTS: Most patients (93% at academic sites, 94% at the community oncology site) said they would consider donating excess tissue from surgery for research. One-half of patients from academic or community sites would consider donating tissue from a clinically indicated breast biopsy. On univariate analysis, significantly fewer patients from academic sites would consider an RPOB (22% at academic sites, 42% at the community site; P = .003); however, this difference was no longer significant on multivariate analysis (P = .96). Longer transportation times and unfavorable prior experiences were associated with less willingness to consider an RPOB on multivariate analysis. Significantly fewer patients from academic sites (14%) than from the community site (35%) would consider a research biopsy in a clinical trial (P = .04). Contributing to scientific knowledge, return of results, and a personal request by their physician were the strongest factors influencing patients' willingness to undergo research biopsies. CONCLUSIONS: The current results rejected the hypothesis that more patients with early breast cancer at academic sites would be willing to donate tissue biospecimens for research compared with those at community oncology sites. These findings identify modifiable factors to consider in biobanking studies and clinical trials.
Assuntos
Atitude , Pesquisa Biomédica , Neoplasias da Mama/patologia , Mama/patologia , Doadores de Tecidos/psicologia , Academias e Institutos/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biópsia/psicologia , Doadores de Sangue/estatística & dados numéricos , Neoplasias da Mama/psicologia , Institutos de Câncer/estatística & dados numéricos , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fatores Socioeconômicos , Inquéritos e Questionários , Obtenção de Tecidos e ÓrgãosRESUMO
In recent years, vaccines against tumor antigens have shown potential for combating invasive cancers, including primary tumors and metastatic lesions. This is particularly pertinent for breast cancer, which is the second-leading cause of cancer-related death in women. MUC1 is a glycoprotein that is normally expressed on glandular epithelium, but is overexpressed and under-glycosylated in most human cancers, including the majority of breast cancers. This under-glycosylation exposes the MUC1 protein core on the tumor-associated form of the protein. We have previously shown that a vaccine consisting of MUC1 core peptides stimulates a tumor-specific immune response. However, this immune response is dampened by the immunosuppressive microenvironment within breast tumors. Thus, in the present study, we investigated the effectiveness of MUC1 vaccination in combination with four different drugs that inhibit different components of the COX pathway: indomethacin (COX-1 and COX-2 inhibitor), celecoxib (COX-2 inhibitor), 1-methyl tryptophan (indoleamine 2,3 dioxygenase inhibitor), and AH6809 (prostaglandin E2 receptor antagonist). These treatment regimens were explored for the treatment of orthotopic MUC1-expressing breast tumors in mice transgenic for human MUC1. We found that the combination of vaccine and indomethacin resulted in a significant reduction in tumor burden. Indomethacin did not increase tumor-specific immune responses over vaccine alone, but rather appeared to reduce the proliferation and increase apoptosis of tumor cells, thus rendering them susceptible to immune cell killing.
Assuntos
Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Inibidores de Ciclo-Oxigenase/administração & dosagem , Indometacina/administração & dosagem , Neoplasias Mamárias Experimentais/terapia , Mucina-1/imunologia , Animais , Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Terapia Combinada/métodos , Feminino , Humanos , Imunogenicidade da Vacina/efeitos dos fármacos , Imunogenicidade da Vacina/imunologia , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/imunologia , Camundongos , Camundongos Transgênicos , Mucina-1/genética , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
Immunotherapy is a promising approach to treating cancer. Mucin1 (MUC1), an epithelial glycoprotein, is hypo-glycosylated and overexpressed on epithelial cancers. This renders it a promising target for potential immunotherapeutic approaches. However, MUC1 has also been identified on T cells, which might complicate its potential as a target for immunotherapies.
Assuntos
Biomarcadores Tumorais/metabolismo , Imunoterapia/tendências , Mucina-1/metabolismo , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Regulação Neoplásica da Expressão Gênica , Humanos , Imunomodulação , Terapia de Alvo Molecular , Mucina-1/imunologia , Neoplasias/metabolismo , Neoplasias/terapiaRESUMO
Type I interferons (IFN) are unique cytokines transcribed from intronless genes. They have been extensively studied because of their anti-viral functions. The anti-viral effects of type I IFN are mediated in part by natural killer (NK) cells. However, the exact contribution of type I IFN on NK cell development, maturation and activation has been somewhat difficult to assess. In this study, we used a variety of approaches to define the consequences of the lack of type I interferon receptor (IFNAR) signaling on NK cells. Using IFNAR deficient mice, we found that type I IFN affect NK cell development at the pre-pro NK stage. We also found that systemic absence of IFNAR signaling impacts NK cell maturation with a significant increase in the CD27+CD11b+ double positive (DP) compartment in all organs. However, there is tissue specificity, and only in liver and bone marrow is the maturation defect strictly dependent on cell intrinsic IFNAR signaling. Finally, using adoptive transfer and mixed bone marrow approaches, we also show that cell intrinsic IFNAR signaling is not required for NK cell IFN-γ production in the context of MCMV infection. Taken together, our studies provide novel insights on how type I IFN receptor signaling regulates NK cell development and functions.