RESUMO
PURPOSE: Metronomic chemotherapy has the potential to offer tumor control with reduced toxicity when compared to standard dose chemotherapy in patients with metastatic breast cancer. As metronomic chemotherapy may target the tumor microvasculature, it has the potential for synergistic effects with antiangiogenic agents such as the VEGF-A inhibitor bevacizumab. METHODS: In this randomized phase II study, patients with metastatic breast cancer were randomized to receive metronomic oral cyclophosphamide and methotrexate (CM) combined with bevacizumab (Arm A) or CM alone (Arm B). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: A total of 55 patients were enrolled, with 34 patients treated on Arm A and 21 patients treated on Arm B. The ORR was modestly higher in Arm A (26%) than in Arm B (10%); neither met the 40% cutoff for further clinical evaluation. The median time to progression (TTP) was 5.52 months (3.22-13.6) on Arm A and 1.82 months (1.54-6.70) on Arm B (log-rank p = 0.008). The median OS was 29.6 months (17.2-NA) on Arm A and 16.2 months (15.7-NA) on Arm B (log-rank p = 0.7). Common all-grade adverse events in both arms included nausea, fatigue, and elevated AST. CONCLUSION: The combination of metronomic CM with bevacizumab significantly improved PFS over CM alone, although there was no significant difference in OS. Oral metronomic chemotherapy alone has limited activity in advanced breast cancer. CLINICALTRIALS: gov Identifier: NCT00083031. Date of Registration: May 17, 2004.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Ciclofosfamida , Bevacizumab/efeitos adversos , Metotrexato , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The effects of primary tumors on the host systemic environment and resulting contributions of the host to tumor growth are poorly understood. Here, we find that human breast carcinomas instigate the growth of otherwise-indolent tumor cells, micrometastases, and human tumor surgical specimens located at distant anatomical sites. This systemic instigation is accompanied by incorporation of bone-marrow cells (BMCs) into the stroma of the distant, once-indolent tumors. We find that BMCs of hosts bearing instigating tumors are functionally activated prior to their mobilization; hence, when coinjected with indolent cells, these activated BMCs mimic the systemic effects imparted by instigating tumors. Secretion of osteopontin by instigating tumors is necessary for BMC activation and the subsequent outgrowth of the distant otherwise-indolent tumors. These results reveal that outgrowth of indolent tumors can be governed on a systemic level by endocrine factors released by certain instigating tumors, and hold important experimental and therapeutic implications.
Assuntos
Adenocarcinoma/metabolismo , Células da Medula Óssea/citologia , Neoplasias da Mama/metabolismo , Metástase Neoplásica , Osteopontina/metabolismo , Animais , Células da Medula Óssea/metabolismo , Divisão Celular , Linhagem Celular Tumoral , Movimento Celular , Neoplasias do Colo/metabolismo , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Transplante HeterólogoRESUMO
Genome-wide analysis at the level of single cells has recently emerged as a powerful tool to dissect genome heterogeneity in cancer, neurobiology, and development. To be truly transformative, single-cell approaches must affordably accommodate large numbers of single cells. This is feasible in the case of copy number variation (CNV), because CNV determination requires only sparse sequence coverage. We have used a combination of bioinformatic and molecular approaches to optimize single-cell DNA amplification and library preparation for highly multiplexed sequencing, yielding a method that can produce genome-wide CNV profiles of up to a hundred individual cells on a single lane of an Illumina HiSeq instrument. We apply the method to human cancer cell lines and biopsied cancer tissue, thereby illustrating its efficiency, reproducibility, and power to reveal underlying genetic heterogeneity and clonal phylogeny. The capacity of the method to facilitate the rapid profiling of hundreds to thousands of single-cell genomes represents a key step in making single-cell profiling an easily accessible tool for studying cell lineage.
Assuntos
Variações do Número de Cópias de DNA , DNA de Neoplasias/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Análise de Sequência de DNA/métodos , Análise de Célula Única/métodos , Algoritmos , Sequência de Bases , Linhagem Celular Tumoral , Genoma Humano , Humanos , Dados de Sequência MolecularRESUMO
To best define biomarkers of response, and to shed insight on mechanism of action of certain clinically important agents for early breast cancer, we used a brief-exposure paradigm in the preoperative setting to study transcriptional changes in patient tumors that occur with one dose of therapy prior to combination chemotherapy. Tumor biopsies from breast cancer patients enrolled in two preoperative clinical trials were obtained at baseline and after one dose of bevacizumab (HER2-negative), trastuzumab (HER2-positive) or nab-paclitaxel, followed by treatment with combination chemo-biologic therapy. RNA-Sequencing based PAM50 subtyping at baseline of 46 HER2-negative patients revealed a strong association between the basal-like subtype and pathologic complete response (pCR) to chemotherapy plus bevacizumab (p ≤ 0.0027), but did not provide sufficient specificity to predict response. However, a single dose of bevacizumab resulted in down-regulation of a well-characterized TGF-ß activity signature in every single breast tumor that achieved pCR (p ≤ 0.004). The TGF-ß signature was confirmed to be a tumor-specific read-out of the canonical TGF-ß pathway using pSMAD2 (p ≤ 0.04), with predictive power unique to brief-exposure to bevacizumab (p ≤ 0.016), but not trastuzumab or nab-paclitaxel. Down-regulation of TGF-ß activity was associated with reduction in tumor hypoxia by transcription and protein levels, suggesting therapy-induced disruption of an autocrine-loop between tumor stroma and malignant cells. Modulation of the TGF-ß pathway upon brief-exposure to bevacizumab may provide an early functional readout of pCR to preoperative anti-angiogenic therapy in HER2-negative breast cancer, thus providing additional avenues for exploration in both preclinical and clinical settings with these agents.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/análise , Fator de Crescimento Transformador beta/fisiologia , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Hipóxia Celular , Feminino , Humanos , Análise de Sequência de RNA , Transdução de Sinais/fisiologiaRESUMO
Bone loss is a significant clinical problem for female cancer survivors (FCS) and increases fracture risk. The aim of the Yale Fitness Intervention Trial (Yale FIT) was to determine the effects of a 12-month aerobic-resistance exercise intervention compared to a home-based physical activity group on bone outcomes [bone mineral density (BMD)] and biomarkers bone turnover). Early postmenopausal FCS (N = 154) were randomized to the exercise intervention (3 times/week) or to a home-based physical activity group. Calcium (1200 mg) and Vitamin D (400 IU) supplements were provided to both groups. BMD was measured at baseline and 12 months. No significant difference in BMD was observed for the exercise vs home-based group. However, subjects on Tamoxifen or no endocrine therapy did not significantly lose BMD, with the exception of the femoral neck (FN). In contrast subjects on aromatase inhibitors (AIs) had significant BMD loss at all sites. The majority of subjects had sufficient serum levels of Vitamin D (>20 ng/mL) but there was significantly less bone loss in subjects in the 20-29 ng/mL range at the LS (p = 0.01), hip (p = 0.03), and GT (p = 0.008) compared to lower or higher levels. Exercise stimulates bone remodeling but the intervention was not superior for BMD outcomes at one year. The dose of the osteogenic stimulus in the intervention has been effective in preserving BMD in healthy postmenopausal women but it may be inadequate for survivors with chemotherapy-induced menopause and for those on adjuvant AI therapy.
Assuntos
Neoplasias da Mama/terapia , Terapia por Exercício , Osteoporose Pós-Menopausa/terapia , Adulto , Idoso , Inibidores da Aromatase/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Neoplasias da Mama/sangue , Neoplasias da Mama/complicações , Neoplasias da Mama/fisiopatologia , Cálcio/sangue , Suplementos Nutricionais , Feminino , Colo do Fêmur/fisiopatologia , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/fisiopatologia , Sobreviventes , Vitamina D/sangueRESUMO
PURPOSE: The triple negative breast cancer (TNBC) subtype, known to be aggressive with high recurrence and mortality rates, disproportionately affects African-Americans, young women, and BRCA1 carriers. TNBC does not respond to hormonal or biologic agents, limiting treatment options. The unique characteristics of the disease and the populations disproportionately affected indicate a need to examine the responses of this group. No known studies describe the psychosocial experiences of women with TNBC. The purpose of this study is to begin to fill that gap and to explore participants' psychosocial needs. METHOD: An interpretive descriptive qualitative approach was used with in-depth interviews. A purposive sample of adult women with TNBC was recruited. Dominant themes were extracted through iterative and constant comparative analysis. RESULTS: Of the 22 participants, nearly half were women of color, and the majority was under the age of 60 years and within 5 years of diagnosis. The central theme was a perception of TNBC as "an addendum" to breast cancer. There were four subthemes: TNBC is Different: "Bottom line, it's not good"; Feeling Insecure: "Flying without a net"; Decision-Making and Understanding: "A steep learning curve"; and Looking Back: "Coulda, shoulda, woulda." Participants expressed a need for support in managing intense uncertainty with a TNBC diagnosis and in decision-making. CONCLUSIONS: Women with all subtypes of breast cancer have typically been studied together. This is the first study on the psychosocial needs specifically of women with TNBC. The findings suggest that women with TNBC may have unique experiences and unmet psychosocial needs.
Assuntos
Neoplasias de Mama Triplo Negativas/fisiopatologia , Neoplasias de Mama Triplo Negativas/psicologia , Adaptação Psicológica , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Avaliação das Necessidades , Pesquisa Qualitativa , Neoplasias de Mama Triplo Negativas/mortalidadeRESUMO
The HER2 receptor is amplified or overexpressed in approximately 20% of all breast cancers, but despite significant efforts of the clinical research community and a growing number of anti-HER2 agents, a significant number of patients with HER2-positive breast cancer either progress or suffer disease relapse within 5-10 years. The development of robust biomarkers that predict response to anti-HER2 agents is therefore an important clinical need to prevent overtreatment and to enable earlier assignment of patients to more optimal therapies. Here we review some of the recent advances in the field by focusing on pathways mediating resistance to anti-HER2 therapies, and the role of the immune system and cancer stem cells in therapy response. We also review preoperative treatment strategies and research paradigms that show promise in identifying novel biomarkers of response while also enabling the delineation of the mechanisms underlying clinical benefit from anti-HER2 therapies.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Terapia de Alvo Molecular , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Seleção de Pacientes , Valor Preditivo dos Testes , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Medição de Risco , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
BACKGROUND: The optimal weekly oral dose of sirolimus and intravenous nanoparticle albumin-bound paclitaxel (nab-paclitaxel) were evaluated. METHODS: A phase 1b study was performed to evaluate escalating doses of oral sirolimus (5-60 mg) on days 2, 9, and 16 with intravenous nab-paclitaxel (100 mg/m(2) ) on days 1, 8, and 15 in a 28-day cycle. A run-in treatment of nab-paclitaxel (day -14) and sirolimus (day -7) was administered for pharmacokinetic and pharmacodynamic assessments. Clinical trial endpoints included dose-limiting toxicities (DLTs), maximum tolerated doses, and response rates. Pharmacodynamics included immunohistochemistry for phosphatase and tensin homolog, mammalian target of rapamycin (mTOR), AKT, phosphorylated AKT, S6K1, and phosphorylated S6K1; exploratory gene expression analysis; and [(18) F]fludeoxyglucose (FDG) positron emission tomography. RESULTS: Twenty-three patients with advanced solid tumors were treated. Fifteen patients had prior taxane therapy. Twenty-two patients were evaluable for responses. One patient had a complete response, and 5 patients had a partial response (3 confirmed). DLTs were seen in 1 patient each at 10 (grade 3 dyspnea/hypoxia) and 40 mg (grade 4 leukopenia/neutropenia) and in 2 patients at 60 mg (grade 3 fatigue and grade 4 pericardial effusion). Patients with higher expression of posttreatment AKT and a greater decline in FDG activity were more likely to have a treatment response or stable disease. CONCLUSIONS: Sirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nab-paclitaxel at 100 mg/m(2) on days 1, 8, and 15 every 28 days. The posttreatment AKT score and changes in FDG activity may have roles as early predictors of responses to mTOR inhibitors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Paclitaxel Ligado a Albumina , Albuminas/administração & dosagem , Albuminas/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Estudos de Coortes , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Nanopartículas/administração & dosagem , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Sirolimo/administração & dosagem , Sirolimo/farmacocinética , Resultado do TratamentoRESUMO
Breast cancer is a major health problem affecting millions of women worldwide. Over 200,000 new cases are diagnosed annually in the USA, with approximately 40,000 of these cases resulting in death. HER2-positive (HER2+) breast tumors, representing 20-30 % of early-stage breast cancer diagnoses, are characterized by the amplification of the HER2 gene. However, the critical genes and pathways that become affected by HER2 amplification in humans are yet to be specifically identified. Furthermore, it is yet to be determined if HER2 amplification also affects the expression of long intervening non-coding (linc)RNAs, which are involved in the epigenetic regulation of gene expression. We examined changes in gene expression by next generation RNA sequencing in human tumors pre- and post- HER2 inhibition by trastuzumab in vivo, and changes in gene expression in response to HER2 knock down in cell culture models. We integrated our results with gene expression analysis of HER2+ tumors vs matched normal tissue from The Cancer Genome Atlas. The integrative analyses of these datasets led to the identification of a small set of mRNAs, and the associated biological pathways that become deregulated by HER2 amplification. Furthermore, our analyses identified three lincRNAs that become deregulated in response to HER2 amplification both in vitro and in vivo. Our results should provide the foundation for functional studies of these candidate mRNAs and lincRNAs to further our understanding of how HER2 amplification results in tumorigenesis. Also, the identified lincRNAs could potentially open the door for future RNA-based biomarkers and therapeutics in HER2+ breast cancer.
Assuntos
Neoplasias da Mama/metabolismo , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Receptor ErbB-2/metabolismo , Transcriptoma , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Receptor ErbB-2/antagonistas & inibidores , Análise de Sequência de RNA , Transdução de Sinais , Trastuzumab/farmacologiaRESUMO
Constitutive activation of the PI3K/Akt/mTOR pathway has been suggested as a mechanism of resistance to trastuzumab therapy. This phase II trial was designed to evaluate the safety and clinical activity of daily oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in combination with trastuzumab in HER2-positive metastatic breast cancer following disease progression on prior trastuzumab therapy. Sirolimus 6 mg oral daily dose was administered with a standard dose and schedule of trastuzumab weekly or every 3 weeks. Pharmacodynamic studies included Western blot analysis of S6K1, phosphoS6K1, and mTOR in peripheral mononuclear cells, circulating tumor cells (CTC), and endothelial cells (CEC). Eleven patients were evaluable for safety; and nine were evaluable for response assessment. Subsequent enrollment was stopped due to slow accrual. Study treatment-related grade 3 toxicity included pneumonitis, myelosuppression (leukopenia/anemia), and dermatologic reactions (mucositis, nail changes and rash), with no grade 4 events. One patient received eight cycles (58 weeks) and achieved a partial response. Five patients treated for a total of 101 weeks (median 12 weeks, range 8-47 weeks) achieved stable disease as best response. Overall response rate was 1/9 (11 %) and clinical benefit rate was 4/9 (44 %). There was no statistically significant correlation between response and post-treatment change in levels of the mTOR pathway biomarkers, CTCs, HER2 CTCs, or CECs. Sirolimus 6 mg administered daily with trastuzumab appears to be well tolerated in patients with metastatic HER2-positive breast cancer following disease progression on prior trastuzumab therapy, with evidence of disease activity. mTOR inhibition may overcome resistance to trastuzumab in some HER2-positive tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Células Neoplásicas Circulantes/metabolismo , Retratamento , Sirolimo/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Trastuzumab/administração & dosagem , Resultado do TratamentoRESUMO
Cells with distinct phenotypes including stem-cell-like properties have been proposed to exist in normal human mammary epithelium and breast carcinomas, but their detailed molecular characteristics and clinical significance are unclear. We determined gene expression and genetic profiles of cells purified from cancerous and normal breast tissue using markers previously associated with stem-cell-like properties. CD24+ and CD44+ cells from individual tumors were clonally related but not always identical. CD44+ cell-specific genes included many known stem-cell markers and correlated with decreased patient survival. The TGF-beta pathway was specifically active in CD44+ cancer cells, where its inhibition induced a more epithelial phenotype. Our data suggest prognostic relevance of CD44+ cells and therapeutic targeting of distinct tumor cell populations.
Assuntos
Neoplasias da Mama/metabolismo , Células-Tronco/metabolismo , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Antígeno CD24/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Linhagem da Célula , Células Cultivadas , Receptor de Proteína C Endotelial , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Gravidez , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Células-Tronco/patologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
We developed a computational method to characterize aneuploidy in tumor samples based on coordinated aberrations in expression of genes localized to each chromosomal region. We summarized the total level of chromosomal aberration in a given tumor in a univariate measure termed total functional aneuploidy. We identified a signature of chromosomal instability from specific genes whose expression was consistently correlated with total functional aneuploidy in several cancer types. Net overexpression of this signature was predictive of poor clinical outcome in 12 cancer data sets representing six cancer types. Also, the signature of chromosomal instability was higher in metastasis samples than in primary tumors and was able to stratify grade 1 and grade 2 breast tumors according to clinical outcome. These results provide a means to assess the potential role of chromosomal instability in determining malignant potential over a broad range of tumors.
Assuntos
Neoplasias da Mama/diagnóstico , Instabilidade Cromossômica , Perfilação da Expressão Gênica , Neoplasias/diagnóstico , Aneuploidia , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Humanos , Metástase Neoplásica , Neoplasias/genética , Neoplasias/patologia , PrognósticoRESUMO
BACKGROUND: Preoperative therapy with chemotherapy and the HER2-targeted monoclonal antibody trastuzumab is valuable for patients with large or locally advanced HER2-positive (HER2+) breast cancers but traditional methods of measuring HER2 expression do not accurately stratify patients for likelihood of response. Quantitative immunofluorescent approaches have the potential to provide a mathematically continuous measure of HER2. Here we seek to determine whether quantitative measurement of HER2 or phospho-HER2 correlates with likelihood of response to trastuzumab- containing neoadjuvant therapy. METHODS: We evaluated core biopsy samples from 27 HER2+ breast cancer patients enrolled in a preoperative clinical trial using trastuzumab, nab-paclitaxel and carboplatin combination therapy (BrUOG BR-211B (NCT00617942)). Tumor core biopsies were taken before initiation of treatment and 9-13 days after patients received "run-in" doses of either single agent trastuzumab or nab-paclitaxel. The AQUA method of quantitative immunofluorescence was used for analysis of in situ protein expression. Patients then received 18 weeks of treatment, followed by surgery to assess pathologic response to the neoadjuvant regimen. RESULTS: A HER2 score of 2111 by AQUA analysis has been shown to be equivalent to HER2 3+ by immunohistochemical staining in previous studies. Of 20 evaluable patients, 10 cases who achieved a pathologic complete response (pathCR) with neoadjuvant treatment had a mean HER2 level of 10251 compared with 4766 in the patients without pathCR (p = 0.0021). Measurement of phospho-HER2 showed no difference in pathCR vs non-pathCR groups. In 9 patients who had HER2 levels repeated after a single treatment with trastuzumab there was no evidence of a reduction in the HER2 or phospho-HER2 levels following that exposure. CONCLUSIONS: High levels of HER2 are associated with achievement of a pathCR in the preoperative setting, while levels of Phospho-HER2 were not predictive of response. This data suggests that accurate measurement of HER2 may help determine the likelihood of response in the pre-surgical setting. Further validation in larger cohorts is required, but this pilot data shows the feasibility of this approach.
Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Receptor ErbB-2/antagonistas & inibidores , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Albuminas/administração & dosagem , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carboplatina/administração & dosagem , Quimioterapia Adjuvante , Connecticut , Feminino , Imunofluorescência , Humanos , Paclitaxel/administração & dosagem , Fosforilação , Proteômica/métodos , Receptor ErbB-2/metabolismo , Rhode Island , Fatores de Tempo , Trastuzumab , Resultado do TratamentoRESUMO
BACKGROUND: A germline, variant in the BRCA1 3'UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3'UTR mutations in cancer. METHODS: The impact of the BRCA1-3'UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3'UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont. RESULTS: Luciferase reporters with the BRCA1-3'UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3'UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3'UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR=1.4, 95% CI 1.1-1.8, p=0.033). More importantly, patients with the BRCA1-3'UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p=0.018, OR=3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3'UTR-variant had significantly less dense breasts (p=0.0398) in the Vermont cohort. CONCLUSION: A variant in the 3'UTR of BRCA1 is functional, leading to decreased BRCA1 expression, modest increased breast cancer risk, and most importantly, presentation with stage IV breast cancer, likely due to aggressive tumor biology.
Assuntos
Proteína BRCA1/genética , Mutação em Linhagem Germinativa , Neoplasias de Mama Triplo Negativas/genética , Regiões 3' não Traduzidas , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Cyclin D1 is overexpressed in the majority of human breast cancers. We previously found that mice lacking cyclin D1 are resistant to mammary carcinomas triggered by the ErbB-2 oncogene. In this study, we investigated which function of cyclin D1 is required for ErbB-2-driven mammary oncogenesis. We report that the ability of cyclin D1 to activate cyclin-dependent kinase CDK4 underlies the critical role for cyclin D1 in breast cancer formation. We also found that the continued presence of CDK4-associated kinase activity is required to maintain breast tumorigenesis. We analyzed primary human breast cancers and found high cyclin D1 levels in a subset (approximately 25%) of ErbB-2-overexpressing tumors. We propose that this subset of breast cancer patients might benefit from inhibiting CDK4 kinase.
Assuntos
Neoplasias da Mama/enzimologia , Proliferação de Células , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Neoplasias Mamárias Experimentais/enzimologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ciclina D1/genética , Quinase 4 Dependente de Ciclina/genética , Ativação Enzimática , Feminino , Genes erbB-2 , Humanos , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Knockout , Ligação ProteicaRESUMO
PURPOSE OF REVIEW: Endocrine therapy for breast cancer has been the cornerstone of treatment for over a century since the discovery of the regressive effect of oophorectomy on 'cancer of the mamma' in 1896 by Beatson. Studies in the prevention and treatment of both early and metastatic breast cancer will be reviewed with a focus on recent large randomized clinical trials that may be practice changing. RECENT FINDINGS: Data from pivotal clinical trials that looked at the duration of adjuvant tamoxifen therapy in premenopausal women will be discussed. In addition, several recent clinical trials that address the optimal sequence of endocrine therapy and advances in the treatment of endocrine-resistant metastatic disease will be reviewed. New findings from molecular studies that demonstrate targets in the endocrine axis and the role of aromatase inhibitors in the prevention setting will be highlighted. SUMMARY: Overall, these clinical trials show the benefit of aromatase inhibitors in the prevention setting, longer duration of tamoxifen in the adjuvant setting for premenopausal women, and new biologic agents with hormonal therapies.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Adulto , Androstadienos/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Esquema de Medicação , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Feminino , Fulvestranto , Humanos , Pessoa de Meia-Idade , Ovariectomia , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamoxifeno/administração & dosagem , Resultado do TratamentoRESUMO
Detection of cell-free circulating tumor DNA (ctDNA) from solid tumors is a fast-evolving field with significant potential for improving patient treatment outcomes. The spectrum of applications for ctDNA assays is broad and includes very diverse intended uses that will require different strategies to demonstrate utility. On September 14-15, 2023, the National Cancer Institute held an in-person workshop in Rockville, MD entitled "ctDNA in Cancer Treatment and Clinical Care". The goal of the workshop was to examine what is currently known and what needs to be determined for various ctDNA liquid biopsy use cases related to treatment and management of patients with solid tumors and to explore how the community can best assess the value of ctDNA assays and technology. Additionally, new approaches were presented that may show promise in the future. The information exchanged in this workshop will provide the community with a better understanding of this field and its potential to affect and benefit decision-making in the treatment of patients with solid tumors.
RESUMO
The National Institutes of Health (NIH)/U.S. Food and Drug Administration (FDA) Joint Leadership Council Next-Generation Sequencing (NGS) and Radiomics Working Group (NGS&R WG) was formed by the NIH/FDA Joint Leadership Council to promote the development and validation of innovative NGS tests, radiomic tools, and associated data analysis and interpretation enhanced by artificial intelligence (AI) and machine-learning (ML) technologies. A two-day workshop was held on September 29-30, 2021 to convene members of the scientific community to discuss how to overcome the "ground truth" gap that has frequently been acknowledged as one of the limiting factors impeding high-quality research, development, validation, and regulatory science in these fields. This report provides a summary of the resource gaps identified by the WG and attendees, highlights existing resources and the ways they can potentially be leveraged to accelerate growth in these fields, and presents opportunities to support NGS and radiomic tool development and validation using technologies such as AI and ML.
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PURPOSE: Subprotocol K2 (EAY131-K2) of the NCI-MATCH platform trial was an open-label, single-arm, phase II study designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 mutations or fusions. METHODS: Central confirmation of tumor FGFR1-4 mutations or fusions was required for outcome analysis. Patients with urothelial carcinoma were excluded. Enrolled subjects received oral erdafitinib at a starting dose of 8 mg daily continuously until intolerable toxicity or disease progression. The primary end point was objective response rate (ORR) with key secondary end points of safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. The median age was 61 years, and 52% of subjects had received ≥3 previous lines of therapy. The confirmed ORR was 16% (4 of 25 [90% CI, 5.7 to 33.0], P = .034 against the null rate of 5%). An additional seven patients experienced stable disease as best-confirmed response. Four patients had a prolonged PFS including two with recurrent WHO grade IV, IDH1-/2-wildtype glioblastoma. The median PFS and OS were 3.6 months and 11.0 months, respectively. Erdafitinib was manageable with no new safety signals. CONCLUSION: This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor-altered tumors outside of currently approved indications in a potentially tumor-agnostic manner.