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INTRODUCTION/BACKGROUND: To assess racial/ethnic disparities in endocrine therapy (ET) adherence among women with breast cancer. MATERIALS AND METHODS: A retrospective cohort study of Arkansas All-Payer Claims Database (APCD) linked to Arkansas Cancer Registry (ACR). Women with stages 0-3 HR+ breast cancer diagnosed in 2013-2017 were followed from cancer diagnosis for a year to determine ET initiation. Among women who initiated ETs within 1 year of diagnosis, we assessed first-year compliance (proportion of days covered ≥ 0.8) and followed them for 5 years, censoring at death, end of data availability (December 21, 2019), or disenrollment from insurance coverage, whichever occurred first, to determine time to discontinuation. Regression analysis was conducted to determine racial/ethnic disparities in ET use adjusting for patients demographic, clinical, tumor characteristics and county-level socioeconomic factors. RESULTS: Among women with continuous insurance coverage, 81% initiated ET within 1 year of diagnosis; 80% were compliant in the first year of ET use and 27.4% discontinued ET by year 5 among those who initiated ET in the first year. There were no racial/ethnic differences in ET initiation or first-year compliance adjusting for covariates. NHB women were significantly less likely to discontinue ET within 5 years after ET initiation compared to NHW women after (HR, 95% CI, 0.76, 0.58-0.98; P = .035). CONCLUSION: After adjusting for patients' and tumor characteristics, there were no racial/ethnic differences in ET initiation within 1 year of diagnosis and ET compliance within first year of ET use. However, NHB women were less likely to discontinue ET within 5 years of initiation.
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PURPOSE: Arkansas is one of only four known states that have linked All-Payer Claims Database (APCD) to state's cancer registry (Arkansas Cancer Registry [ACR]). We evaluated the reporting consistency of radiation therapy (RT) between the two sources. METHODS: Women age ≥ 18 years diagnosed in 2013-2017 with early-stage hormone receptor-positive breast cancer who received breast-conserving surgery were identified. Patients must have continuous insurance coverage (any private plans, Medicaid, and Medicare) in the 13 months (month of diagnosis and 12 months after). Receipt of RT was identified independently from ACR and APCD. We calculated sensitivity, specificity, positive predictive value, and negative predictive value for receipt of RT coded by the registry compared with APCD billing claims as the gold standard. We assessed the degree of concordance between the data sources by Cohen's kappa statistics. RESULTS: The final sample included 2,695 patients who were in both databases and satisfied our inclusion/exclusion criteria. Using APCD as the gold standard, there were high sensitivity (88.1%) and positive predictive value (87.7%) and moderate specificity (71.1%) and negative predictive value (71.8%). The overall agreement between the two sources was 83.0%, with a kappa statistic of 0.59 (95% CI, 0.56 to 0.63). Consistency measures varied by age, stage, and insurance type with Medicare fee-for-service coverage only having the best and private insurance only the worse consistency. CONCLUSION: In patients with early-stage hormone receptor-positive breast cancer who received breast-conserving surgery, recording of RT receipt was moderately consistent between Arkansas APCD and ACR. Future studies are needed to identify factors affecting reporting consistency to better use this unique resource in addressing population health problems.
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Neoplasias de la Mama , Medicare , Humanos , Estados Unidos/epidemiología , Femenino , Anciano , Adolescente , Medicaid , Sistema de Registros , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Manejo de DatosRESUMEN
BACKGROUND: The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood. PATIENTS AND METHODS: E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034). RESULTS: Occurrence of grades 1-2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1-2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1-2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1-2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1-2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3-4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3-4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1-2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found. CONCLUSIONS: Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3-4 irAEs.
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Adyuvantes Inmunológicos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunosupresores/uso terapéutico , Ipilimumab/efectos adversos , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/inmunología , Femenino , Humanos , Inmunosupresores/efectos adversos , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Immune response to a given antigen, particularly in cancer patients, is complex and is controlled by various genetic and environmental factors. Identifying biomarkers that can predict robust response to immunization is an urgent need in clinical cancer vaccine development. Given the involvement of DNA methylation in the development of lymphocytes, tumorigenicity and tumor progression, we aimed to analyze pre-vaccination DNA methylation profiles of peripheral blood mononuclear cells (PBMCs) from breast cancer subjects vaccinated with a novel peptide-based vaccine referred to as P10s-PADRE. This pilot study was performed to evaluate whether signatures of differentially methylated (DM) loci can be developed as potential predictive biomarkers for prescreening subjects with cancer who will most likely generate an immune response to the vaccine. Genomic DNA was isolated from PBMCs of eight vaccinated subjects, and their DNA methylation profiles were determined using Infinium® MethylationEPIC BeadChip array from Illumina. A linear regression model was applied to identify loci that were differentially methylated with respect to anti-peptide antibody titers and with IFN-γ production. The data were summarized using unsupervised-learning methods: hierarchical clustering and principal-component analysis. Pathways and networks involved were predicted by Ingenuity Pathway Analysis. We observed that the profile of DM loci separated subjects in regards to the levels of immune responses. Canonical pathways and networks related to metabolic and immunological functions were found to be involved. The data suggest that it is feasible to correlate methylation signatures in pre-treatment PBMCs with immune responses post-treatment in cancer patients going through standard-of-care chemotherapy. Larger and prospective studies that focus on DM loci in PBMCs is warranted to develop pre-screening biomarkers before BC vaccination. Clinical Trial Registration: www.ClinicalTrials.gov, Identifier: NCT02229084.
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PURPOSE: Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI. PATIENTS AND METHODS: E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI. RESULTS: Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti-programmed death 1 use in the HDI arm versus ipi3 and ipi10 (P ≤ .001). CONCLUSION: Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.
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Antineoplásicos Inmunológicos/administración & dosificación , Ipilimumab/administración & dosificación , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Quimioterapia Adyuvante/métodos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Interferón alfa-2/uso terapéutico , Ipilimumab/efectos adversos , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , Neoplasias Cutáneas/mortalidad , Adulto Joven , Melanoma Cutáneo MalignoRESUMEN
Most cancer deaths arise from metastases as a result of circulating tumor cells (CTCs) spreading from the primary tumor to vital organs. Despite progress in cancer prognosis, the role of CTCs in early disease diagnosis is unclear because of the low sensitivity of CTC assays. We demonstrate the high sensitivity of the Cytophone technology using an in vivo photoacoustic flow cytometry platform with a high pulse rate laser and focused ultrasound transducers for label-free detection of melanin-bearing CTCs in patients with melanoma. The transcutaneous delivery of laser pulses via intact skin to a blood vessel results in the generation of acoustic waves from CTCs, which are amplified by vapor nanobubbles around intrinsic melanin nanoclusters. The time-resolved detection of acoustic waves using fast signal processing algorithms makes photoacoustic data tolerant to skin pigmentation and motion. No CTC-associated signals within established thresholds were identified in 19 healthy volunteers, but 27 of 28 patients with melanoma displayed signals consistent with single, clustered, and likely rolling CTCs. The detection limit ranged down to 1 CTC/liter of blood, which is ~1000 times better than in preexisting assays. The Cytophone could detect individual CTCs at a concentration of ≥1 CTC/ml in 20 s and could also identify clots and CTC-clot emboli. The in vivo results were verified with six ex vivo methods. These data suggest the potential of in vivo blood testing with the Cytophone for early melanoma screening, assessment of disease recurrence, and monitoring of the physical destruction of CTCs through real-time CTC counting.
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Biopsia Líquida/métodos , Melanoma/patología , Citometría de Flujo , Humanos , Melanoma/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologíaRESUMEN
INTRODUCTION: GATA3 is a critical transcription factor in maintaining the differentiated state of luminal mammary epithelial cells. We sought to determine the prognostic and predictive roles of GATA3 genotypes for breast cancer. PATIENTS AND METHODS: Twelve single nucleotide polymorphisms (SNPs) were genotyped in 2 breast cancer cohorts, including the SWOG S8897 trial where patients were treated with adjuvant chemotherapy (CAF [cyclophosphamide, doxorubicin, 5-fluorouracil] vs. CMF [cyclophosphamide, methotrexate, 5-fluorouracil]) or untreated, and the observational Pathways Study. RESULTS: In the S8897 trial, rs3802604 and rs568727 were associated with disease-free survival and overall survival in the treated group, regardless of chemotherapy regimen. The GG genotype of rs3802604 conferred poorer overall survival (adjusted hazard ratio, 2.45; 95% confidence interval, 1.48-4.05) and disease-free survival (adjusted hazard ratio, 1.95; 95% confidence interval, 1.27-2.99) compared with the AA genotype. Similar associations were found for rs568727. In contrast, no association with either SNP was found in the untreated group. Subgroup analyses indicated that these 2 SNPs more strongly influenced outcomes in the patients who also received tamoxifen. However, the associations in the subgroup with tamoxifen treatment were not replicated in the Pathways Study, possibly owing to substantial differences between the 2 patient cohorts, such as chemotherapy regimen and length of follow-up. Results from joint analyses across these 2 cohorts were marginally significant, driven by the results in S8897. Bioinformatic analyses support potential functional disruption of the GATA3 SNPs in breast tissue. CONCLUSIONS: The present study provides some evidence for the predictive value of GATA3 genotypes for breast cancer adjuvant therapies. Future replication studies in appropriate patient populations are warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/mortalidad , Factor de Transcripción GATA3/genética , Mutación de Línea Germinal , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Ciclofosfamida/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Metotrexato/administración & dosificación , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
PURPOSE: The extent to which patients feel prepared for end-of-life (EOL) may be associated with important clinical outcomes. Despite growing interest in the concept of "preparedness," however, there is insufficient information about what cancer patients actually need to feel prepared. Such information is foundational for patient-centered care, theory-building, and instrument development. DESIGN: This qualitative study examined patient perspectives regarding preparedness for EOL care. PARTICIPANTS AND METHODS: In-depth interviews were conducted with patients with advanced malignancies and limited life expectancies. Participants were drawn from a large academic cancer center and had a diverse range of malignancies. Thematic text analysis was used to analyze the data. FINDINGS: Six overarching themes emerged. These included readiness to manage concerns about: (1) EOL planning (e.g., goals of care, location of care); (2) interactions with healthcare providers (e.g., communication, symptom control); (3) interactions with family/friends (e.g., perceived burden, support); (4) emotional well-being (e.g., existential distress, fulfillment); (5) spiritual well-being (e.g., spiritual comfort, congregational support); and (6) financial well-being (e.g., medical expenses, estate planning). CONCLUSIONS: Findings highlight areas that patients themselves regard as critical for a sense of preparedness for EOL care. Participants emphasized broader concerns than those previously construed as facets of patient preparedness, and these domains offer modifiable targets for intervention.
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Actitud Frente a la Salud , Neoplasias/terapia , Pacientes/psicología , Cuidado Terminal/psicología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pacientes/estadística & datos numéricos , Investigación CualitativaRESUMEN
BACKGROUND: Myeloid sarcoma (MS) is characterized by extramedullary infiltration by immature myeloid cells. Owing to rarity of this disease, the clinical features and overall outcomes are yet to be clarified. OBJECTIVE: To define clinical characteristics, epidemiology, pathologic findings, treatment options and outcomes in MS. METHODS: We conducted a retrospective review of 23 patients diagnosed with MS at our institute over a period of 13 years (2002-2015). RESULTS: MS presented mostly as a manifestation of relapsed acute myeloid leukemia, seen in 39% of patients. Skin and subcutaneous soft tissues were the most common sites of anatomic involvement (69.5%). Ninety five percent (n = 19) were positive for classical myeloid markers with either cytochemical staining (chloracetate-esterase, MPO), flow-cytometry (CD33, CD34, CD13 and CD117), or immunohistochemistry (CD34, CD43, CD68 and lysozyme). Of these, 52% were positive for CD33 (n = 12), 35% for CD68 (n = 8), 30% for CD34 (n = 7), and 26% for lysozyme (n = 6). Cytogenetic abnormalities were seen in 63% (n = 12/19) patients on bone-marrow aspirate, with five patients displaying a complex (n = 3) or monosomal (n = 2) karyotype. Twenty seven percent patients with a normal karyotype had presence of deleterious mutations (FLT3, ASXL, STAG and JAK2) on further testing with myeloid mutation panel. The Median overall survival (OS) of the entire cohort was 15.9 months (95% CI, 7.4-24.4 months). The OS was significantly better for patients <65 years (24.6 vs. 3.4 months, p = 0.009) of age, and for those attaining a complete remission (CR) to induction therapy (25.7 vs. 0.8 months, p < 0.001). All patients who underwent allogeneic hematopoietic stem cell transplant attained long-term remissions, with a median follow-up of 54 (range 32-120) months. CONCLUSION: Failure to achieve CR with induction therapy, and age >65 years are associated with poor outcomes in MS. Allogeneic stem-cell transplant in first remission appears to be the most effective modality for achieving long-term remissions.
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Sarcoma Mieloide , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Tumor-associated carbohydrate antigens (TACAs) support cell survival that could be interrupted by anti-TACA antibodies. Among TACAs that mediate cell survival signals are the neolactoseries antigen Lewis Y (LeY) and the ganglioside GD2. To induce sustained immunity against both LeY and GD2, we developed a carbohydrate mimicking peptide (CMP) as a surrogate pan-immunogen that mimics both. This CMP, referred to as P10s, is the N-terminal half of a peptide vaccine named P10s-PADRE, the C-terminal half of which (PADRE) is a Pan-T-cell epitope. A Phase I dose-escalation trial of P10s-PADRE plus adjuvant MONTANIDE™ ISA 51 VG was conducted in subjects with metastatic breast cancer to test 300 and 500 µg/injection in two cohorts of 3 subjects each. Doses of the P10s-PADRE vaccine were administered to research participants subcutaneously on weeks 1, 2, 3, 7 and 19. Antibody responses to P10s, GD2, and LeY were measured by ELISA. The P10s-PADRE vaccine induced antibodies specifically reactive with P10s, LeY and GD2 in all 6 subjects. Serum antibodies displayed Caspase-3-dependent apoptotic functionality against LeY or GD2 expressing breast cancer cell lines. Immunization with the P10s-PADRE vaccine was well-tolerated and induced functional antibodies, and the data suggest potential clinical benefit.
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Pharmacologic inhibition of the cytotoxic T lymphocyte antigen 4 (CTLA4) and the programmed death receptor-1 (PD1) has resulted in unprecedented durable responses in metastatic melanoma. However, resistance to immunotherapy remains a major challenge. Effective immune surveillance against melanoma requires 4 essential steps: activation of the T lymphocytes, homing of the activated T lymphocytes to the melanoma microenvironment, identification and episode of melanoma cells by activated T lymphocytes, and the sensitivity of melanoma cells to apoptosis. At each of these steps, there are multiple factors that may interfere with the immune surveillance machinery, thus allowing melanoma cells to escape immune attack and develop resistance to immunotherapy. We provide a comprehensive review of the complex immune surveillance mechanisms at play in melanoma, and a detailed discussion of how these mechanisms may allow for the development of intrinsic or acquired resistance to immunotherapeutic modalities, and potential avenues for overcoming this resistance.
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Vigilancia Inmunológica , Melanoma/inmunología , Escape del Tumor/inmunología , Animales , Apoptosis/genética , Apoptosis/inmunología , Movimiento Celular , Humanos , Inmunomodulación , Inmunoterapia , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Melanoma/metabolismo , Melanoma/patología , Melanoma/terapia , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
BACKGROUND: As we move away from the traditional chemotherapy era to targeted therapy, the validity of old assessment paradigms associated with therapeutics are being raised in the context of immunotherapy. The old paradigm required elaborating on the toxicity assessment, with no expectation of efficacy in early phase trials. Safety data from Phase 1 and 2 studies with many immunotherapeutics show limited toxicities and draw attention to the need to demonstrate efficacy in the early evaluation of new agents. METHODS: Literature searches indicate that molecular oncology mechanistic-based agents are being linked with molecular disease status and clinical benefit. Biomarkers and other endpoints are being employed to accomplish this. Perspectives for a meaningful context of integrating biomarkers and clinical trial design are reviewed. RESULTS: The design and conduct of clinical trials have not been fully adjusted to the new era of personalized oncology, and so we are in transition. A part of this transition is the management of expectations and trial designs that need to be considered relative to preclinical experience in the development of therapeutics. For example, pathological complete response is now considered a surrogate marker for favorable prognosis in breast cancer patients who are treated in the neoadjuvant setting. This surrogate marker is tied to novel agents' mechanistic characteristics with no preclinical counterpart. CONCLUSION: The old paradigm considers patients equal with similar chances to respond to treatments, but the new paradigm considers patient's heterogeneity, a major fact that informs the design of clinical trials. By linking every treatment to a mechanism of action and to the presence of a specific biomarker, new trials are going to have more subjects who are likely to respond to the treatment.
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Antineoplásicos/uso terapéutico , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Medicina de Precisión/tendencias , Prueba de Estudio Conceptual , Antineoplásicos/farmacología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Femenino , Predicción , Humanos , Masculino , Neoplasias/patologíaRESUMEN
BACKGROUND: We previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS). METHODS: DNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization. RESULTS: After adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95% CI 1.90-37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes. CONCLUSION: Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00203502.
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Bevacizumab/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Angiopoyetina 1/genética , Angiopoyetina 2/genética , Neoplasias de la Mama/etnología , Ensayos Clínicos Fase II como Asunto , Etnicidad , Femenino , Factor 2 de Crecimiento de Fibroblastos/genética , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/genética , Persona de Mediana Edad , Terapia Neoadyuvante , Neovascularización Patológica/genética , Estudios Observacionales como Asunto , Estudios Prospectivos , Receptor TIE-2/genética , Análisis de Regresión , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Integrating additive or synergistic antitumor effects that focus on distinct elements of tumor biology are the most rational strategies for cancer treatment. Treatments for breast cancer have increased overall survival, but remain limited by lack of efficacy in a subset of breast cancer patients. The real challenge is to define what elements of tumor biology make the most sense to be integrated. An emerging strategy is to consider a systems biology approach to impact multiple interactions in networks as compare with hitting a specific protein-protein interaction target. In this review, we consider how targeting tumor associated carbohydrate antigens (TACA) that are fundamental to signal pathways might be tailored to harness benefit from combination therapy of sustained immunity with chemotherapy. An approach we are developing makes use of a carbohydrate mimetic peptide (CMP) to induce polyspecific antibodies, which by their nature have numerous on and off target effects. Linking multi-target TACA recognition with mechanisms affecting tumor growth in the context of network heterogeneity and concepts of immune surveillance to tumor cells and the type of breast cancer patients that would benefit from such an approach provides a novel integrative treatment.
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Anticuerpos Antineoplásicos/inmunología , Anticuerpos Antineoplásicos/uso terapéutico , Antígenos de Carbohidratos Asociados a Tumores/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/uso terapéutico , Terapia Combinada , HumanosRESUMEN
BACKGROUND: The effect of moderately elevated blood glucose levels among non-diabetic subjects on cancer prognosis is not well described. The goal of this study was to examine the association of elevated random blood glucose (RBG) levels in non-diabetic breast cancer patients with overall survival (OS) and time to tumor recurrence (TTR). RESULTS: Forty-nine deaths and 32 recurrences occurred among 148 eligible study subjects during 855.44 person-years of follow-up, with median follow-up of 5.97 years. We observed that patients with elevated RBG levels experienced significantly shorter OS (hazard ratio [HR], 3.01; 95 % confidence interval [CI] (1.70-5.33); P < 0.001) and shorter TTR (HR, 2.08; CI (1.04-4.16); P = 0.04) as compared to patients with non-elevated RBG levels. After controlling for tumor grade, tumor stage, race, and BMI, elevated RBG continued to display high and statistically significant association with shorter OS (HR, 3.50; CI (1.87-6.54); P < 0.001). Adjustment for age, race, and BMI strengthened HR of RBG for TTR. The association of RGB with TTR lost its borderline statistical significance upon controlling for both tumor grade and stage. CONCLUSIONS: The data suggest that elevated blood glucose is associated with poor prognosis of breast cancer patients. Given the potential clinical implication, these findings warrant further investigation.
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There is accumulating evidence that the histone methyltransferase enhancer of zeste homolog 2 (EZH2), the main component of the polycomb-repressive complex 2 (PRC2), is involved in melanoma progression and metastasis. Novel drugs that target and reverse such epigenetic changes may find a way into the management of patients with advanced melanoma. We provide a comprehensive up-to-date review of the role and biology of EZH2 on gene transcription, senescence/apoptosis, melanoma microenvironment, melanocyte stem cells, the immune system, and micro RNA. Furthermore, we discuss EZH2 inhibitors as potential anti-cancer therapy.
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Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Histonas/metabolismo , Melanoma/genética , Progresión de la Enfermedad , Epigenómica , Humanos , Metástasis de la NeoplasiaRESUMEN
In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500 µg per peptide dose, the 50 µg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50% at the 50 µg dose (7 of 14) and 100 µg dose (3 of 6), and 45 % overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected at entry, it became undetectable in three subjects after vaccination, and the viral loads significantly decreased in nine subjects in whom HPV 16 infection was detected at entry and exit (p = 0.008). Immune profiling revealed increased T-helper type 1 cells after vaccinations (p = 0.02 and 0.0004 after 2 and 4 vaccinations, respectively). T-helper type 2 cells initially increased after two vaccinations (p = 0.01), but decreased below the baseline level after four vaccinations although not significantly. Pre-vaccination regulatory T cell levels were significantly lower in histological responders compared to non-responders (p = 0.03). Feasibility of testing plasma for multiplex cytokine/chemokine analysis and of performing proteomic analysis of PBMCs was examined for potentially identifying biomarkers in the future. While these analyses are feasible to perform, attention needs to be given to how soon the blood samples would be processed after phlebotomy. As sufficient safety of PepCan has been demonstrated, enrollment for the Phase II clinical trial has been opened.
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Papillomavirus Humano 16/inmunología , Infecciones por Papillomavirus/inmunología , Neoplasias del Cuello Uterino/inmunología , Carga Viral/inmunología , Adulto , Cromatografía Liquida , Citocinas/sangre , Citocinas/inmunología , Relación Dosis-Respuesta a Droga , Femenino , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/inmunología , Papillomavirus Humano 16/efectos de los fármacos , Papillomavirus Humano 16/fisiología , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Persona de Mediana Edad , Infecciones por Papillomavirus/tratamiento farmacológico , Infecciones por Papillomavirus/virología , Proteoma/inmunología , Proteoma/metabolismo , Proteómica/métodos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Espectrometría de Masas en Tándem , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/virología , Vacunación/métodos , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/uso terapéutico , Carga Viral/efectos de los fármacos , Adulto JovenRESUMEN
Ipilimumab is a cytotoxic T-lymphocyte-associated antigen-4-blocking monoclonal antibody, which has shown a significant survival benefit in metastatic melanoma patients. Despite being a promising therapy for a disease with an otherwise rather dismal prognosis, it is associated with several immune-related adverse effects (IRAE) mainly targeted toward the digestive tract, skin, liver, and hypothalamic-pituitary axis. Ipilimumab-induced gastrointestinal toxicity (IGT) include diarrhea (~44 %), colitis (~18 %), bowel perforation (<1 %), and pancreatitis (<1.5 %). Early recognition of IRAE and treatment initiation are critical to decrease the risk of further complications. Management included steroids as initial therapy, followed by infliximab (anti-tumor necrosis factor alpha antibody) and/or surgical option for complications like bowel perforation. We present a series of three patients with metastatic melanoma, who received treatment with ipilimumab, and presented with varying gastrointestinal clinical manifestations and complications. Through this case series, our attempt is to make practicing gastroenterologists cognizant about the wide spectrum of gastrointestinal toxicity of this rather new clinical entity, as well as to discuss management algorithm for IGT.
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Anticuerpos Monoclonales/efectos adversos , Colitis/inducido químicamente , Enfermedades Gastrointestinales/inducido químicamente , Anciano de 80 o más Años , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Femenino , Fármacos Gastrointestinales/uso terapéutico , Humanos , Infliximab/uso terapéutico , Ipilimumab , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Prednisona/uso terapéuticoRESUMEN
INTRODUCTION: Vascular endothelial growth factor (VEGF) is a central mediator of angiogenesis in breast cancer. Research in antiangiogenic cancer treatment has been marked by the development of the monoclonal antibody bevacizumab, which targets VEGF in many solid tumors. As patients do not equally benefit from bevacizumab, it has become necessary to define the profile of patients who will benefit from the drug. MATERIALS AND METHODS: We have conducted a prospective phase II study in 39 patients using bevacizumab in breast cancer in the neoadjuvant setting, and found improved pathologic complete response (pCR) when bevacizumab was added to chemotherapy in patients with hormone receptor negative and invasive ductal carcinoma. Blood samples were collected at baseline and serially while patients were on treatment. Circulating angiogenesis-related proteins angiopoietin (ANG)1, ANG2, basic fibroblast growth factor, IL-1a, matrix metalloproteinase 9, platelet derived growth factor - BB, platelet endothelial cell adhesion molecule -1, Tie2, VEGF, and vascular endothelial growth factor receptor 2 were measured at baseline and during treatment. This correlative study was conducted to identify specific serum angiogenic factor profiles that might be associated with pCR in the neoadjuvant setting in breast cancer patients receiving bevacizumab and chemotherapy. RESULTS: Elevated baseline serum Tie2 and basic fibroblast growth factor were associated with pCR in response to this combination. Changes in serum levels of these proteins were seen during treatment but were not significantly different between the pCR and non-pCR groups. CONCLUSIONS: Baseline-circulating Tie2 levels may help distinguish patients who will have pCR from those who will not and may form the basis for future development of antiangiogenic therapy in breast cancer. Larger studies are needed to validate these findings. ClinicalTrials.gov Identifier: NCT00203502.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Receptor TIE-2/sangre , Angiopoyetina 1/sangre , Angiopoyetina 2/sangre , Becaplermina , Bevacizumab/administración & dosificación , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/química , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/cirugía , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Docetaxel , Doxorrubicina/administración & dosificación , Femenino , Factor 2 de Crecimiento de Fibroblastos/sangre , Humanos , Interleucina-1alfa/sangre , Metaloproteinasa 9 de la Matriz/sangre , Terapia Neoadyuvante , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/sangre , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Estudios Prospectivos , Proteínas Proto-Oncogénicas c-sis/sangre , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Taxoides/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
PURPOSE: Non-surgical treatments for cervical intraepithelial neoplasia 2/3 (CIN2/3) are needed as surgical treatments have been shown to double preterm delivery rate. The goal of this study was to demonstrate safety of a human papillomavirus (HPV) therapeutic vaccine called PepCan, which consists of four current good-manufacturing production-grade peptides covering the HPV type 16 E6 protein and Candida skin test reagent as a novel adjuvant. PATIENTS AND METHODS: The study was a single-arm, single-institution, dose-escalation phase I clinical trial, and the patients (n = 24) were women with biopsy-proven CIN2/3. Four injections were administered intradermally every 3 weeks in limbs. Loop electrical excision procedure (LEEP) was performed 12 weeks after the last injection for treatment and histological analysis. Six subjects each were enrolled (50, 100, 250, and 500 µg per peptide). RESULTS: The most common adverse events (AEs) were injection site reactions, and none of the patients experienced dose-limiting toxicities. The best histological response was seen at the 50 µg dose level with a regression rate of 83% (n = 6), and the overall rate was 52% (n = 23). Vaccine-induced immune responses to E6 were detected in 65% of recipients (significantly in 43%). Systemic T-helper type 1 (Th1) cells were significantly increased after four vaccinations (P = 0.02). CONCLUSION: This study demonstrated that PepCan is safe. A significantly increased systemic level of Th1 cells suggests that Candida, which induces interleukin-12 (IL-12) in vitro, may have a Th1 promoting effect. A phase II clinical trial to assess the full effect of this vaccine is warranted.