RESUMO
Blockade of the inhibitory receptor TIM-3 shows efficacy in cancer immunotherapy clinical trials. TIM-3 inhibits production of the chemokine CXCL9 by XCR1+ classical dendritic cells (cDC1), thereby limiting antitumor immunity in mammary carcinomas. We found that increased CXCL9 expression by splenic cDC1s upon TIM-3 blockade required type I interferons and extracellular DNA. Chemokine expression as well as combinatorial efficacy of TIM-3 blockade and paclitaxel chemotherapy were impaired by deletion of Cgas and Sting. TIM-3 blockade increased uptake of extracellular DNA by cDC1 through an endocytic process that resulted in cytoplasmic localization. DNA uptake and efficacy of TIM-3 blockade required DNA binding by HMGB1, while galectin-9-induced cell surface clustering of TIM-3 was necessary for its suppressive function. Human peripheral blood cDC1s also took up extracellular DNA upon TIM-3 blockade. Thus, TIM-3 regulates endocytosis of extracellular DNA and activation of the cytoplasmic DNA sensing cGAS-STING pathway in cDC1s, with implications for understanding the mechanisms underlying TIM-3 immunotherapy.
Assuntos
DNA/metabolismo , Células Dendríticas/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Transdução de Sinais/fisiologia , Animais , Transporte Biológico/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Citoplasma/metabolismo , Endocitose/fisiologia , Feminino , Células HEK293 , Humanos , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.
Assuntos
Neoplasias da Mama , Humanos , Neoplasias da Mama/terapia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Feminino , Oncologia/normas , Oncologia/métodos , Terapia Combinada/normasRESUMO
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer address all aspects of management for breast cancer. The treatment landscape of metastatic breast cancer is evolving constantly. The therapeutic strategy takes into consideration tumor biology, biomarkers, and other clinical factors. Due to the growing number of treatment options, if one option fails, there is usually another line of therapy available, providing meaningful improvements in survival. This NCCN Guidelines Insights report focuses on recent updates specific to systemic therapy recommendations for patients with stage IV (M1) disease.
Assuntos
Neoplasias da Mama , Humanos , Feminino , OncologiaRESUMO
PURPOSE: HER2-positive breast cancer has a high risk of brain metastasis. Stereotactic radiosurgery (SRS) is standard of care for limited brain metastases. Tucatinib, a HER2-targeted tyrosine kinase inhibitor, has demonstrated intracranial efficacy in the HER2-CLIMB Trial. However, it is unknown whether tucatinib with SRS is safe or effective. METHODS: A retrospective analysis of HER2-positive breast cancer treated with SRS and tucatinib for brain metastases management was performed. All patients received tucatinib and SRS for the management of active brain metastases. The primary endpoint was local and distant brain tumor control. Secondary endpoints were intracranial progression free survival (CNS-PFS), systemic PFS, overall survival (OS), and neurotoxicity. RESULTS: A total of 135 lesions treated with SRS over 39 treatment sessions in 22 patients were identified. Median follow-up from tucatinib initiation was 20.8 months. Local brain control was 94% at 12-months and 81% at 24-months. Distant brain control was 39% at 12-months and 26% at 24-months. Median survival was 21.2 months, with 12- and 24-month OS rates of 84% and 50%, respectively. Median CNS-PFS was 11.3 months, with 12- and 24-month CNS-PFS rates of 44.9% at both time points. Median systemic PFS was not reached, with 12- and 24-month systemic PFS rates of 86% and 57%, respectively. Symptomatic radiation necrosis occurred in 6 (4%) lesions. No additional unexpected toxicities were noted. CONCLUSIONS: SRS in combination with tucatinib, capecitabine, and trastuzumab appears to be a safe and feasible treatment for HER2 + brain metastases. Further prospective evaluation of potential synergistic effects is warranted.
Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Radiocirurgia , Feminino , Humanos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Neoplasias da Mama/patologia , Radiocirurgia/efeitos adversos , Estudos RetrospectivosRESUMO
The treatment of metastatic breast cancer (mBC) has evolved significantly in the past several years with the approval of new targeted agents. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate with a topoisomerase I inhibitor payload, is a new addition to the class of therapies that target the human epidermal growth factor 2 (HER2) receptor. T-DXd was approved in the US in December 2019 for patients with HER2-positive metastatic or unresectable breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting. In the DESTINY-Breast01 phase II trial (NCT03248492), T-DXd demonstrated high rates of durable responses in heavily pretreated patients with HER2-positive mBC, with a confirmed objective response rate of 62%, median duration of response of 18.2 months, and median progression-free survival of 19.4 months. In addition to efficacy, successful implementation of any new anticancer therapy includes learning how to prevent, monitor, and manage treatment-related adverse events. As T-DXd becomes more widely used, information can be gained from real-world clinical practices, institutional approaches, and the collaboration of multidisciplinary oncology teams who treat patients with T-DXd. This article reviews practical insights and management of nausea and vomiting, neutropenia, interstitial lung disease, risk of cardiotoxicity, and other adverse events associated with T-DXd administration from the perspective of health care providers who have experience utilizing T-DXd.
Assuntos
Neoplasias da Mama , Imunoconjugados , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/patologia , Camptotecina/análogos & derivados , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Receptor ErbB-2/metabolismo , Literatura de Revisão como Assunto , Trastuzumab/efeitos adversosRESUMO
Immunotherapy has resulted in unprecedented gains in long-term outcomes for many cancer types and has revolutionized the treatment landscape of solid tumor oncology. Checkpoint inhibition in combination with chemotherapy has proven to be effective for the treatment of a subset of advanced triple-negative breast cancer in the first-line setting. This initial success is likely just the tip of the iceberg as there is much that remains unknown about how to best harness the immune system as a therapeutic strategy in all breast cancer subtypes. Therefore, numerous ongoing studies are currently underway to evaluate the safety and efficacy of immunotherapy in breast cancer. In this review, we will discuss emerging immunotherapeutic strategies for breast cancer treatment including the following: (1) Intratumoral therapies, (2) Anti-tumor vaccines, (3) B-specific T-cell engagers, and (4) Chimeric antigen receptor T-cell therapy, and (5) Emerging systemic immunotherapy strategies. For each topic, we will review the existing preclinical and clinical literature, discuss ongoing clinical trials, and highlight future directions in the field.
Assuntos
Neoplasias da Mama , Vacinas Anticâncer , Neoplasias de Mama Triplo Negativas , Neoplasias da Mama/terapia , Terapia Combinada , Feminino , Humanos , Imunoterapia , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
PURPOSE: This study assessed the presentation and institutional outcomes treating brain metastases (BM) of breast cancer (BC), non-small cell lung cancer (NSCLC), and melanoma origin. METHODS: Patients with brain metastases treated between 2014 and 2019 with primary melanoma, NSCLC, and BC were identified. Overall survival (OS) was calculated from dates of initial BM diagnosis using the Kaplan-Meier method. RESULTS: A total of 959 patients were identified including melanoma (31%), NSCLC (51%), and BC (18%). Patients with BC were younger at BM diagnosis (median age: 57) than NSCLC (65) and melanoma patients (62, p < 0.0001). Breast cancer patients were more likely to present with at least 5 BM (27%) than NSCLC (14%) and melanoma (13%), leptomeningeal disease (23%, 6%, and 6%, p = 0.0004) and receive whole brain radiation therapy (WBRT) (58%, 37%, and 22%, p < 0.0001). There were no differences in surgical resection (24%, 24%, and 29%, p = 0.166). Median OS was shorter for BC patients (9.9, 10.3, and 13.7 months, p = 0.0006). CONCLUSION: Breast cancer patients were more likely to be younger, present with advanced disease, require WBRT, and have poorer OS than NSCLC and melanoma patients. Further investigation is needed to determine which BC patients are at sufficient risk for brain MRI screening.
Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Melanoma , Encéfalo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/epidemiologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Detecção Precoce de Câncer , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Melanoma/diagnóstico por imagem , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.
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Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Carcinoma Intraductal não Infiltrante/terapia , Feminino , Humanos , OncologiaRESUMO
Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at a particularly high risk of breast cancer brain metastasis (BCBM) and leptomeningeal disease (LMD). Improvements in systemic therapy have translated to improved survival for patients with HER2-positive BCBM and LMD. However, the optimal management of these cases is rapidly evolving and requires a multidisciplinary approach. Herein, a team of radiation oncologists, medical oncologists, neuro-oncologists, and breast surgeon created a review of the evolving management of HER2-positive BCBM and LMD. We assess the epidemiology, diagnosis, and evolving treatment options for patients with HER2-positive BCBM and LMD, as well as the ongoing prospective clinical trials enrolling these patients. The management of HER2-positive BCBM and LMD represents an increasingly common challenge that involves the coordination of local and systemic therapy. Advances in systemic therapy have resulted in an improved prognosis, and promising targeted therapies currently under prospective investigation have the potential to further benefit these patients.
Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Neoplasias Meníngeas , Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Neoplasias Meníngeas/terapia , Prognóstico , Estudos Prospectivos , Receptor ErbB-2/metabolismoRESUMO
HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Proteínas Culina/genética , Interferon gama/genética , Receptor ErbB-2/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Senescência Celular/genética , Senescência Celular/imunologia , Chaperoninas/genética , Proteínas Culina/imunologia , Citocinas/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Interferon gama/imunologia , Proteólise , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , VacinaçãoRESUMO
BACKGROUND: Little is known about the safety and efficacy of concurrent capecitabine and stereotactic radiotherapy in the setting of breast cancer brain metastases (BCBM). METHODS: Twenty-three patients with BCBM underwent 31 stereotactic sessions to 90 lesions from 2005 to 2019 with receipt of capecitabine. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of stereotactic radiation. Imaging was independently reviewed by a neuro-radiologist. RESULTS: Median follow-up from stereotactic radiation was 9.2 months. Receptor types of patients treated included triple negative (n = 7), hormone receptor (HR)+/HER2- (n = 7), HR+/HER2+ (n = 6), and HR-/HER2+ (n = 3). Fourteen patients had stage IV disease prior to BCBM diagnosis. The median number of brain metastases treated per patient was 3 (1 to 12). The median dose of stereotactic radiosurgery (SRS) was 21 Gy (range: 15-24 Gy) treated in a single fraction and for lesions treated with fractionated stereotactic radiation therapy (FSRT) 25 Gy (24-30 Gy) in a median of 5 fractions (range: 3-5). Of the 31 stereotactic sessions, 71% occurred within 1 month of capecitabine. No increased toxicity was noted in our series with no cases of radionecrosis. The 1-year OS, LC, and DIC were 46, 88, and 30%, respectively. CONCLUSIONS: In our single institution experience, we demonstrate stereotactic radiation and capecitabine to be a safe treatment for patients with BCBM with adequate LC. Further study is needed to determine the potential synergy between stereotactic radiation and capecitabine in the management of BCBM.
Assuntos
Neoplasias Encefálicas/terapia , Neoplasias da Mama/patologia , Capecitabina/efeitos adversos , Quimiorradioterapia/métodos , Radiocirurgia/efeitos adversos , Adulto , Idoso , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/efeitos da radiação , Neoplasias Encefálicas/mortalidade , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Capecitabina/administração & dosagem , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Necrose/diagnóstico , Necrose/etiologia , Estadiamento de Neoplasias , Lesões por Radiação/diagnóstico , Lesões por Radiação/etiologia , Radiocirurgia/estatística & dados numéricos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Due to recent concerns about the toxicity of trastuzumab emtansine (T-DM1) with stereotactic radiation, we assessed our institutional outcomes treating HER2-positive breast cancer brain metastases (BCBM) with T-DM1 and stereotactic radiation. METHODS: This is a single institution series of 16 patients with HER2-positive breast cancer who underwent 18 stereotactic sessions to 40 BCBM from 2013 to 2019 with T-DM1 delivered within 6 months. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), distant intracranial control (DIC), and systemic progression-free survival (sPFS) from the date of SRS. A neuro-radiologist independently reviewed follow-up imaging. RESULTS: One patient had invasive lobular carcinoma, and 15 patients had invasive ductal carcinoma. All cases were HER2-positive, while 10 were hormone receptor (HR) positive. Twenty-four lesions were treated with stereotactic radiosurgery (SRS) to a median dose of 21 Gy (14-24 Gy). Sixteen lesions were treated with fractionated stereotactic radiation (FSRT) with a median dose of 25 Gy (20-30Gy) delivered in 3 to 5 fractions. Stereotactic radiation was delivered concurrently with T-DM1 in 19 lesions (48%). Median follow up time was 13.2 months from stereotactic radiation. The 1-year LC, DIC, sPFS, and OS were 75, 50, 30, and 67%, respectively. There was 1 case of leptomeningeal progression and 1 case (3%) of symptomatic radionecrosis. CONCLUSIONS: We demonstrate that stereotactic radiation and T-DM1 is well-tolerated and effective for patients with HER2-positive BCBM. An increased risk for symptomatic radiation necrosis was not noted in our series.
Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/terapia , Radiocirurgia , Receptor ErbB-2/análise , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Necrose , Radiocirurgia/efeitos adversos , Dosagem RadioterapêuticaRESUMO
The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.
Assuntos
Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Terapia Combinada , Humanos , Masculino , OncologiaRESUMO
PURPOSE: We investigated the prognostic ability of tumor subtype for patients with breast cancer brain metastases (BCBM) treated with stereotactic radiation (SRT). METHODS: This is a retrospective review of 181 patients who underwent SRT to 664 BCBM from 2004 to 2019. Patients were stratified by subtype: hormone receptor (HR)-positive, HER2-negative (HR+/HER2-), HR-positive, HER2-positive (HR+/HER2+), HR-negative, HER2-positive (HR-/HER2+), and triple negative (TN). The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of SRT. Multivariate analysis (MVA) was conducted using the Cox proportional hazards model. RESULTS: Median follow up from SRT was 11.4 months. Of the 181 patients, 47 (26%) were HR+/HER2+, 30 (17%) were HR-/HER2+, 60 (33%) were HR+/HER2-, and 44 (24%) were TN. Of the 664 BCBMs, 534 (80%) received single fraction stereotactic radiosurgery (SRS) with a median dose of 21 Gy (range 12-24 Gy), and 130 (20%) received fractionated stereotactic radiation therapy (FSRT), with a median dose of 25 Gy (range 12.5-35 Gy) delivered in 3 to 5 fractions. One-year LC was 90%. Two-year DIC was 35%, 23%, 27%, and 16% (log rank, p = 0.0003) and 2-year OS was 54%, 47%, 24%, and 12% (log rank, p < 0.0001) for HR+/HER2+, HR-/HER2+, HR+/HER2-, and TN subtypes, respectively. On MVA, the TN subtype predicted for inferior DIC (HR 1.62, 95% CI 1.00-2.60, p = 0.049). The modified breast-Graded Prognostic Assessment (GPA) significantly predicted DIC and OS (both p < 0.001). CONCLUSIONS: Subtype is prognostic for OS and DIC for patients with BCBM treated with SRT.
Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Radiocirurgia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Neoplasias da Mama/radioterapia , Feminino , Humanos , Estudos RetrospectivosRESUMO
Latinas are less likely to participate in genetic counseling (GC) and genetic testing (GT) than non-Hispanic Whites. A multisite, randomized pilot study tested a culturally targeted educational intervention to increase uptake of GC/GT among Latina breast cancer (BC) survivors (N = 52). Participants were recruited in Tampa, FL and Ponce, PR and randomized to: (a) fact sheet about BC survivorship (control) or (b) a culturally targeted educational booklet about GC/GT (intervention). Participants in the intervention condition were also offered no-cost telephone GC followed by free GT with mail-based saliva sample collection. Participants self-reported hereditary breast and ovarian cancer (HBOC) knowledge and emotional distress at baseline and 1- and 3-month follow-ups. We used logistic regression to examine differences in GC/GT uptake by study arm (primary outcome) and repeated measures ANOVA to examine the effects of study arm and time on HBOC knowledge and emotional distress (secondary outcomes). Compared to the control arm, intervention participants were more likely to complete GC (ORIntervention = 13.92, 95% CI = 3.06-63.25, p < .01) and GT (ORIntervention = 12.93, 95% CI = 2.82-59.20, p < .01). Study site did not predict uptake of GC (p = .08) but Ponce participants were more likely to complete GT (ORPonce = 4.53, 95% CI = 1.04-19.72, p = .04). ANOVAs demonstrated an increase in HBOC knowledge over time across both groups (F(2,88) = 12.24, p < .01, ηp2 = 0.22). We also found a significant interaction of study arm and time, such that intervention participants demonstrated a greater and sustained (to the 3-month follow-up) increase in knowledge than control participants (F(2,88) = 3.66, p = .03, ηp2 = 0.08). No other main or interaction effects were significant (all p's> .15). Study findings demonstrate the potential of our culturally targeted print intervention. Lessons learned from this multisite pilot study for enhancing GC/GT in Latinas include the need to attend to both access to GC/GT and individual factors such as attitudes and knowledge.
Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Neoplasias da Mama/genética , Feminino , Aconselhamento Genético , Testes Genéticos , Hispânico ou Latino , Humanos , Projetos Piloto , SobreviventesRESUMO
T-helper cells express CD4 as a co-receptor that binds to major histocompatibility complex class II to synchronize the immune response against upcoming threats via mediating several cytokines. We have previously reported the presence of CD4 homologues in brown trout. The study of cellular immune responses in brown trout is limited by the availability of specific antibodies. We here describe the generation of a polyclonal antibody against CD4-1 that allows for the investigation of CD4+ cells. We used this novel tool to study CD4+ cells in different tissues during viral haemorrhagic septicaemia infection (VHSV) using flow cytometric technique. Flow cytometric analyses revealed an enhanced level of surface CD4-1 expression in the infected group in major lymphoid organs and in the intestine. These results suggest an important role for the T-helper cells within the immune response against viruses, comparable to the immune response in higher vertebrates.
Assuntos
Linfócitos T CD4-Positivos/fisiologia , Doenças dos Peixes/imunologia , Septicemia Hemorrágica Viral/imunologia , Novirhabdovirus/fisiologia , Truta , Animais , Fenômenos Biomecânicos , Linfócitos T CD4-Positivos/virologia , Doenças dos Peixes/virologia , Septicemia Hemorrágica Viral/virologia , CinéticaRESUMO
PURPOSE: Breast cancer brain metastases (BCBM) are becoming an increasingly common diagnosis due to improved systemic control and more routine surveillance imaging. Treatment continues to require a multidisciplinary approach managing systemic and intracranial disease burden. Although, improvements have been made in the diagnosis and management of BCBM, brain metastasis patients continue to pose a challenge for practitioners. METHODS: In this review, a group of medical oncologists, radiation oncologists, radiologists, breast surgeons, and neurosurgeons specializing in the treatment of breast cancer reviewed the available published literature and compiled a comprehensive review on the current state of BCBM. RESULTS: We discuss the pathogenesis, epidemiology, diagnosis, treatment options (including systemic, surgical, and radiotherapy treatment modalities), and treatment response evaluation for BCBM. Furthermore, we discuss the ongoing prospective trials enrolling BCBM patients and their biologic rationale. CONCLUSIONS: BCBM management is an increasing clinical concern. Multidisciplinary management combining the strengths of surgical, systemic, and radiation treatment modalities with prospective trials incorporating knowledge from the basic and translational sciences will ultimately lead to improved clinical outcomes for BCBM patients.
Assuntos
Neoplasias Encefálicas/terapia , Neoplasias da Mama/terapia , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Padrões de Prática Médica/estatística & dados numéricos , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Feminino , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: Neo-adjuvant chemotherapy (NaCT) facilitates complete surgical resection in locally advanced breast cancer. Due to its association with improved outcome, complete pathologic response (pCR) to neo-adjuvant treatment has been accepted as a surrogate for long-term outcome in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive, triple-negative, or luminal B breast cancer patients. In contrast, NaCT is effective in only ~ 7-10% of estrogen receptor (ER)-positive, HER2-negative disease. Response biomarkers would enable such patients to be selected for NaCT. METHODS: Two commercially available breast cancer prognostic signatures [12-gene molecular score (MS) and the 21-gene Recurrence Score (RS)] were compared in their ability to predict pCR to NaCT in ER-positive, HER2-negative breast cancer in six public RNA expression microarray data sets. Scores were approximated according to published algorithms and analyzed by logistic regression. RESULTS: Expression data were available for 764 ER-positive, HER2-negative breast cancer samples, including 59 patients with pCR. The two scores were well correlated. Either score was a significant predictor of pCR (12-gene MS p = 9.4 × 10-5; 21-gene RS p = 0.0041). However, in a model containing both scores, the 12-gene MS remained significant (p = 0.0079), while the 21-gene RS did not (p = 0.79). CONCLUSIONS: In this microarray study, two commercial breast cancer prognostic scores were significant predictors of response to NaCT. In direct comparison, the 12-gene MS outperformed the 21-gene RS as a predictive marker for NaCT. Considering pCR as surrogate for improved survival, these results support the ability of both scores to predict chemotherapy sensitivity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/diagnóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Seguimentos , Humanos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Prognóstico , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Increased usage of genomic risk assessment assays suggests increased reliance on data provided by these assays to guide therapy decisions. The current study aimed to assess the change in treatment decision and physician confidence based on the 70-gene risk of recurrence signature (70-GS, MammaPrint) and the 80-gene molecular subtype signature (80-GS, BluePrint) in early stage breast cancer patients. METHODS: IMPACt, a prospective, case-only study, enrolled 452 patients between November 2015 and August 2017. The primary objective population included 358 patients with stage I-II, hormone receptor-positive, HER2-negative breast cancer. The recommended treatment plan and physician confidence were captured before and after receiving results for 70-GS and 80-GS. Treatment was started after obtaining results. The distribution of 70-GS High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to the distribution of 80-GS compared to IHC status. RESULTS: The 70-GS classified 62.5% (n = 224/358) of patients as LR and 37.5% (n = 134/358) as HR. Treatment decisions were changed for 24.0% (n = 86/358) of patients after receiving 70-GS and 80-GS results. Of the LR patients initially prescribed CT, 71.0% (44/62) had CT removed from their treatment recommendation. Of the HR patients not initially prescribed CT, 65.1% (41/63) had CT added. After receiving 70-GS results, CT was included in 83.6% (n = 112/134) of 70-GS HR patient treatment plans, and 91.5% (n = 205/224) of 70-GS LR patient treatment plans did not include CT. For patients who disagreed with the treatment recommended by their physicians, most (94.1%, n = 16/17) elected not to receive CT when it was recommended. For patients whose physician-recommended treatment plan was discordant with 70-GS results, discordance was significantly associated with age and lymph node status. CONCLUSIONS: The IMPACt trial showed that treatment plans were 88.5% (n = 317/358) in agreement with 70-GS results, indicating that physicians make treatment decisions in clinical practice based on the 70-GS result. In clinically high risk, 70-GS Low Risk patients, there was a 60.0% reduction in treatment recommendations that include CT. Additionally, physicians reported having greater confidence in treatment decisions for their patients in 72% (n = 258/358) of cases after receiving 70-GS results. TRIAL REGISTRATION: "Measuring the Impact of MammaPrint on Adjuvant and Neoadjuvant Treatment in Breast Cancer Patients: A Prospective Registry" (NCT02670577) retrospectively registered on Jan 27, 2016.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Tomada de Decisão Clínica/métodos , Técnicas de Genotipagem/métodos , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Competência Clínica , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Medicina de Precisão , Estudos ProspectivosRESUMO
Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.