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1.
J Clin Oncol ; 41(36): 5550-5560, 2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-37801674

RESUMO

PURPOSE: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in breast cancer; high expression is associated with an adverse prognosis. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted antibody-drug conjugate that is being evaluated as a novel treatment in HER3-expressing advanced breast cancer in the U31402-A-J101 study. METHODS: Adults with disease progression on previous therapies were eligible. Patients in the dose-escalation, dose-finding, and dose-expansion parts received HER3-DXd 1.6-8.0 mg/kg intravenously once every 3 weeks or one of two alternative dosing regimens. In the dose-escalation part, the primary objectives were to determine the maximum tolerated dose and recommended dose for expansion (RDE). The safety and efficacy of the RDE were assessed during dose expansion. RESULTS: One hundred eighty-two enrolled patients received ≥1 dose of HER3-DXd. Patients had a median of five previous therapies for advanced disease. Efficacy results are reported across clinical subtypes: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer (n = 113; objective response rate [ORR], 30.1%; median progression-free survival [mPFS], 7.4 months), triple-negative breast cancer (n = 53; ORR, 22.6%; mPFS, 5.5 months), and HER2-positive breast cancer (n = 14; ORR, 42.9%; mPFS, 11.0 months). Objective responses were observed in cancers with HER3-high and HER3-low membrane expression. Dose-limiting toxicities observed during dose selection were decreased platelet count and elevated aminotransferases. In dose expansion, GI and hematologic toxicities were the most common treatment-emergent adverse events (TEAEs) observed. Grade ≥3 TEAEs were observed in 71.4% of patients, and 9.9% discontinued treatment because of TEAEs. Three grade 3 and one grade 5 treatment-related interstitial lung disease events occurred. CONCLUSION: HER3-DXd demonstrated a manageable safety profile and durable efficacy in heavily pretreated patients across clinical subtypes. These data warrant further evaluation of HER3-DXd in patients with HER3-expressing metastatic breast cancer.


Assuntos
Neoplasias da Mama , Imunoconjugados , Adulto , Humanos , Feminino , Neoplasias da Mama/patologia , Imunoconjugados/efeitos adversos , Receptor ErbB-2 , Anticorpos Monoclonais Humanizados/efeitos adversos , Trastuzumab
2.
Target Oncol ; 15(6): 733-741, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33090333

RESUMO

BACKGROUND: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets. OBJECTIVE: With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations. PATIENTS AND METHODS: Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/m2 over 60 min). A Simon two-stage design, requiring ten patients in stage I, was employed per each disease-specific cohort. The primary endpoint was disease control (objective response or stable disease for at least 16 weeks). If two or more patients in stage I achieved disease control, the cohort would enroll 18 more patients in stage II. Power and alpha of the design are 85% and 10%, respectively. Secondary endpoints included progression-free survival, overall survival, and safety. RESULTS: Patients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab. CONCLUSIONS: Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations. CLINICAL TRIAL REGISTRATION: NCT02693535 (26 February, 2016).


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Cetuximab/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Antineoplásicos Imunológicos/farmacologia , Cetuximab/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Sistema de Registros
3.
Ther Adv Med Oncol ; 11: 1758835919866065, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31452692

RESUMO

BACKGROUND: We retrospectively evaluated the correlation between a baseline measurement of circulating tumor cells (CTCs) and inflammation-based scores in patients with metastatic breast cancer (MBC). METHODS: The optimal value of inflammation-based scores as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR) and systemic immune-inflammation index (SII) to predict survival was determined and compared with CTC <5 or ⩾5 per 7.5 ml of blood. RESULTS: In the overall population of 516 women with MBC, CTCs correlated with peripheral blood monocytes (p = 0.008) and neutrophils (p = 0.038). In triple-negative tumors, CTCs correlated with monocyte count (p = 0.009); in HER2+ tumors, CTCs correlated with neutrophil count (p = 0.009), with a trend versus monocyte count (p = 0.061), whereas no correlation was found in HER2- estrogen receptor-positive (ER+) tumors. In multivariate analysis only monocytes were associated with ⩾5 CTCs (OR = 2.72, 95% CI 1.09-6.80, p = 0.033). In multivariable analysis for predictors of overall survival, CTC (⩾5 versus <5), number of metastatic sites (>1 versus 1), tumor subtypes (triple-negative versus HER2- ER+ tumors) and MLR only remained significant. CONCLUSIONS: CTC and MLR are predictors of overall survival in MBC. CTC correlates with monocytes, in particular in triple-negative tumors.

4.
Breast Cancer Res Treat ; 176(3): 545-556, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31054033

RESUMO

PURPOSE: The carbohydrate sialyl LewisX (sLeX) mediates cell adhesion, is critical in the normal function of immune cells, and is frequently over-expressed on cancer cells. We assessed the association, differential levels, and prognostic value of sLeX and inflammatory cytokines/chemokines in breast cancer sera. METHODS: We retrospectively measured sLeX and a panel of cytokines/chemokines in the sera of 26 non-invasive ductal carcinoma in situ (DCIS), 154 invasive non-metastatic breast cancer (non-MBC), 63 metastatic breast cancer (MBC) patients, and 43 healthy controls. Differences in sLeX and inflammatory cytokines among and between patient groups and healthy controls were assessed with nonparametric tests and we performed survival analysis for the prognostic potential of sLeX using a cut-off of 8 U/mL as previously defined. RESULTS: Median serum sLeX was significantly higher than controls for invasive breast cancer patients (MBC and non-MBC) but not DCIS. In univariate analysis, we confirmed patients with serum sLeX > 8 U/mL have a significantly shorter progression-free survival (PFS) (P = 0.0074) and overall survival (OS (P = 0.0003). Similarly, patients with high serum MCP-1 and IP-10 had shorter OS (P = 0.001 and P < 0.001, respectively) and PFS (P = 0.010 and P < 0.001, respectively). sLeX, MCP-1 and IP-10 remained significant in multivariate survival analysis. CONCLUSION: Elevated serum sLeX was associated with invasive cancer but not DCIS. High serum sLeX levels were associated with inflammatory mediators and may play a role in facilitating local invasion of breast tumor. Furthermore, serum MCP-1, IP-10 and sLeX may have prognostic value in breast cancer.


Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Mediadores da Inflamação/sangue , Antígeno Sialil Lewis X/sangue , Biomarcadores , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Estudos de Casos e Controles , Análise por Conglomerados , Citocinas/sangue , Feminino , Humanos , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de Sobrevida
5.
JCO Precis Oncol ; 3: 1-8, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35100714

RESUMO

PURPOSE: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study identifies signals of antitumor activity of commercially available targeted agents in patients with advanced cancers that harbor genomic alterations known as drug targets. In this article, data from two cohorts of patients with pancreatic and biliary cancers with CDKN2A loss or mutation treated with palbociclib are reported. METHODS: Eligible patients age 12 years and older with advanced measurable or evaluable solid tumors are provided treatment according to protocol-specified genomic matching rules. The primary study end point is objective response or stable disease of at least 16 weeks duration. For each cohort, a Simon two-stage design was used with a futility evaluation after 10 patients. Secondary end points include safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Between July 2016 and November 2017, 12 and 10 patients with pancreatic and biliary cancer, respectively, with CDKN2A loss or mutation were treated with palbociclib. Twenty evaluable patients (10 per cohort) were included in the analysis. No patients had objective response or stable disease at 16 weeks, and both cohorts were closed. Two patients, neither with response, were determined to be ineligible. All patients were evaluated for safety, PFS, and OS. A median PFS of 7.2 weeks (90% CI, 4.0 to 8.0 weeks) and median OS of 12.4 weeks (90% CI, 4.7 to 23.1 weeks) were observed in the pancreatic cohort. A median PFS of 7.3 weeks (90% CI, 3.9 to 7.9 weeks) and median OS of 11.1 weeks (90% CI, 5.1 to 14.0 weeks) were observed in the biliary cohort. No unexpected toxicities were observed. CONCLUSION: Palbociclib monotherapy does not have clinical activity in patients with advanced pancreatic or biliary cancers with CDKN2A loss or mutation. Toxicity is similar to reported experience with palbociclib in other tumor types.

6.
PLoS One ; 13(9): e0204372, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30248155

RESUMO

BACKGROUND: To date, studies on inflammatory breast cancer (IBC) lack comprehensive epidemiological data. We analyzed detailed prospectively collected clinical and epidemiological data from the IBC Registry at The University of Texas MD Anderson Cancer Center. METHODS: Patients with IBC (n = 248) were consecutively diagnosed and prospectively enrolled between November 2006 and April 2013. All patients were newly diagnosed and at least 18 years old. Secondary IBC was excluded. Overall 160 variables were collected and evaluated including sociodemographics, anthropometrics, tobacco and alcohol consumption, reproductive variables, and family history data. RESULTS: Mean age at diagnosis was 51.6 (±11.5 SD) years, and the majority of patients were White (77.8%). A mean BMI ≥ 25 kg/m2, irrespective of menopausal status, was observed in 80.2% of all patients, with 82.6% of African Americans being obese. Approximately 42.2% of patients were ever smokers, and 91% reported ever being pregnant. A history of breastfeeding was reported in 54% of patients, with significant differences between ethnic groups in favor of White women (P<0.0001). Other reproductive factors such as use of birth control pills & hormone replacement therapy were also more frequently associated with White women compare to other ethnic groups (P < 0.05). In the multivariate Cox proportional hazard analysis, African American or Hispanic ethnicity, not having breastfed, higher clinical stage, and TNBC subtype were associated with shorter survival. CONCLUSION: Our data suggest that IBC is associated with distinct epidemiological profiles. This information could assist in targeting patients with specific preventive strategies based on their modifiable behavioral patterns.


Assuntos
Neoplasias Inflamatórias Mamárias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/patologia , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Análise de Sobrevida , Adulto Jovem
7.
JAMA Oncol ; 4(9): 1207-1213, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29879283

RESUMO

Importance: Combining conventional chemotherapy with targeted therapy has been proposed to improve the pathologic complete response (pCR) rate in patients with inflammatory breast cancer (IBC). Epidermal growth factor receptor (EGFR) expression is an independent predictor of low overall survival in patients with IBC. Objective: To evaluate the safety and efficacy of the anti-EGFR antibody panitumumab plus neoadjuvant chemotherapy in patients with primary human epidermal growth factor receptor 2 (HER2)-negative IBC. Design, Setting, and Participants: Women with primary HER2-negative IBC were enrolled from 2010 to 2015 and received panitumumab plus neoadjuvant chemotherapy. Median follow-up time was 19.3 months. Tumor tissues collected before and after the first dose of panitumumab were subjected to immunohistochemical staining and RNA sequencing analysis to identify biomarkers predictive of pCR. Intervention: Patients received 1 dose of panitumumab (2.5 mg/kg) followed by 4 cycles of panitumumab (2.5 mg/kg), nab-paclitaxel (100 mg/m2), and carboplatin weekly and then 4 cycles of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks. Main Outcomes and Measures: The primary end point was pCR rate; the secondary end point was safety. The exploratory objective was to identify biomarkers predictive of pCR. Results: Forty-seven patients were accrued; 7 were ineligible. The 40 enrolled women had a median age of 57 (range, 23-68) years; 29 (72%) were postmenopausal. Three patients did not complete therapy because of toxic effects (n = 2) or distant metastasis (n = 1). Nineteen patients had triple-negative and 21 had hormone receptor-positive IBC. The pCR and pCR rates were overall, 11 of 40 (28%; 95% CI, 15%-44%); triple-negative IBC, 8 of 19 (42%; 95% CI, 20%-66%); and hormone receptor-positive/HER2-negative IBC, 3 of 21 (14%; 95% CI, 3%-36%). During treatment with panitumumab, nab-paclitaxel, and carboplatin, 10 patients were hospitalized for treatment-related toxic effects, including 5 with neutropenia-related events. There were no treatment-related deaths. The most frequent nonhematologic adverse event was skin rash. Several potential predictors of pCR were identified, including pEGFR expression and COX-2 expression. Conclusions and Relevance: This combination of panitumumab and chemotherapy showed the highest pCR rate ever reported in triple-negative IBC. A randomized phase 2 study is ongoing to determine the role of panitumumab in patients with triple-negative IBC and to further validate predictive biomarkers. Trial Registration: ClinicalTrials.gov Identifier: NCT01036087.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Panitumumabe/uso terapêutico , Adulto , Idoso , Alopecia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Intervalo Livre de Doença , Quimioterapia Combinada , Fadiga/induzido quimicamente , Feminino , Humanos , Leucopenia/induzido quimicamente , Pessoa de Meia-Idade , Terapia Neoadjuvante , Panitumumabe/administração & dosagem , Panitumumabe/efeitos adversos , Receptor ErbB-2/metabolismo , Adulto Jovem
8.
Hum Pathol ; 77: 121-129, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29689244

RESUMO

Advanced-stage breast cancer patients comprise a smaller proportion of breast cancer patients than do early stage patients and are more likely to experience a poor outcome. Understanding the underlying molecular mechanisms and identifying new biomarkers for treatment in this subgroup of patients is paramount. With the aim of identifying microRNAs that are regulated in advanced-stage breast cancer, we found lower expression of miR-26b, a member of the miR-26 family, in inflammatory breast cancer and noninflammatory locally advanced breast cancer tissue than in normal breast tissue, by quantitative real-time polymerase chain reaction and in situ hybridization. Quantitative real-time polymerase chain reaction (but not in situ hybridization) also revealed lower miR-26b expression in inflammatory breast cancer than in noninflammatory locally advanced breast cancer. Furthermore, lower expression of miR-26b was correlated with shorter distant metastasis-free survival and overall survival in univariate analysis, and with shorter overall survival in multivariate analysis. The expression of miRNA-26b was inversely associated with EZH2 protein expression in several breast cancer cell lines, and overexpression and knockdown of miR-26b caused corresponding changes in EZH2 expression. Our study shows that miR-26b may regulate EZH2 expression in breast cancer and may be useful as a therapeutic target for inflammatory breast cancer and noninflammatory locally advanced breast cancer.


Assuntos
Neoplasias da Mama/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/metabolismo , MicroRNAs/genética , Adulto , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Progressão da Doença , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/mortalidade , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real/métodos
9.
Oncologist ; 23(6): 660-669, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29487226

RESUMO

Substantial improvements in the early detection and treatment of breast cancer have led to improvements in survival, but breast cancer remains a significant cause of morbidity and mortality in women. In 2012, the mammalian target of rapamycin (mTOR) inhibitor everolimus was approved by the U.S. Food and Drug Administration for the treatment of advanced breast cancer in patients resistant to endocrine therapy. Although everolimus is generally well tolerated, mTOR inhibitor-associated pneumonitis is one of the most common adverse drug events leading to treatment discontinuation. To date, the underlying pathophysiology of this toxicity is unclear, and this uncertainty may hinder the optimization of management strategies. However, experiences from breast cancer and renal cell carcinoma clinical trials indicate that mTOR inhibitor-associated pneumonitis can be effectively managed by early detection, accurate diagnosis, and prompt intervention that generally involves everolimus dose reductions, interruptions, or discontinuation. Management can be achieved by a multidisciplinary approach that involves the collaborative efforts of nurses, oncologists, radiologists, infectious disease specialists, pulmonologists, clinical pharmacists, and pathologists. Comprehensive education must be provided to all health care professionals involved in managing patients receiving everolimus therapy. Although general recommendations on the management of mTOR inhibitor-associated pneumonitis have been published, there is a lack of consensus on the optimal management of this potentially serious complication. This article provides an overview of mTOR inhibitor-associated pneumonitis, with a focus on the detection, accurate diagnosis, and optimal management of this class-related complication of mTOR inhibitor therapy. IMPLICATIONS FOR PRACTICE: This article summarizes the pathogenesis, clinical presentation, incidence, detection, and optimal management of everolimus-related noninfectious pneumonitis in breast cancer. In particular, this article provides a detailed overview of the important aspects of the detection, accurate diagnosis, and appropriate management of mammalian target of rapamycin inhibitor-associated pneumonitis. In addition, this article emphasizes that effective management of this adverse drug event in patients with breast cancer will require a multidisciplinary approach and collaboration among various health care professionals.


Assuntos
Neoplasias da Mama/complicações , Pneumonia/induzido quimicamente , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Mama/patologia , Feminino , Humanos
10.
Cancer ; 124(11): 2299-2305, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29579338

RESUMO

BACKGROUND: Inflammatory breast cancer (IBC) is associated with a poor prognosis and high risk of central nervous system (CNS) metastases. METHODS: We retrospectively reviewed stage III-IBC patients compared with noninflammatory invasive ductal carcinoma (NI-IDC) patients treated between January 1, 1984, and December 31, 2011, who began primary treatment within 1 year of diagnosis and had been followed up for at least 1 year before the development of CNS metastasis or death. Cumulative CNS metastasis incidence and post-CNS metastasis overall survival (OS) estimates were computed. Multivariable Cox proportional hazard models explored factors for post-CNS metastasis survival. RESULTS: A total of 2323 patients were identified (589-IBC/1734-NI-IDC). Eighty-one IBC patients developed CNS metastasis, versus 154 NI-IDC patients. The 2-, 5-, and 10-year cumulative CNS metastasis incidence rates in IBC and NI-IDC were 9.8%, 15.8%, 17.4% and 6.5%, 10.1%, and 12.7%, respectively. This was significantly different between IBC and NI-IDC patients (P = .0037). Multicovariate competing risk regression models in IBC and NI-IDC patients showed no statistically significant associations with the risk of developing CNS metastasis, except neoadjuvant taxane use in NI-IDC patients (hazard ratio, 0.45; 95% confidence interval, 0.24-0.83; P = .011). The median follow-up was 7.2 years, and the median post-CNS metastasis OS was not significantly different between IBC (7.6 months) and NI-IDC (5.6 months) patients. One hundred ninety patients with CNS metastasis died. HER2-positive patients had better OS, with a median 14.1 versus 4.3 months (P < .0001). Age >50 years (P = .012) but not IBC status was a significant predictor of post-CNS metastasis survival. CONCLUSION: IBC patients demonstrated higher CNS metastasis incidence rates but OS following CNS metastases is similar in both groups. HER2 status and age may play prognostic roles. Cancer 2018;124:2299-305. © 2018 American Cancer Society.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias Inflamatórias Mamárias/patologia , Receptor ErbB-2/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Mama/cirurgia , Neoplasias do Sistema Nervoso Central/prevenção & controle , Neoplasias do Sistema Nervoso Central/secundário , Quimioterapia Adjuvante/métodos , Feminino , Seguimentos , Humanos , Incidência , Neoplasias Inflamatórias Mamárias/mortalidade , Neoplasias Inflamatórias Mamárias/terapia , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Taxa de Sobrevida , Taxoides/uso terapêutico , Resultado do Tratamento , Adulto Jovem
11.
Breast Cancer Res Treat ; 163(2): 263-272, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28243898

RESUMO

PURPOSE: Inflammatory breast cancer is an aggressive form of breast cancer that shows distinct clinical features from non-inflammatory breast cancer. Genomic understanding of inflammatory breast cancer will shed light on biological targets for this disease. Our objective was to identify targeted hotspot mutations using multiplex genome sequencing in inflammatory breast cancer and compare the findings with those for patients with non-inflammatory breast cancer to further recognize novel targets. METHODS: We studied 400 patients with metastatic breast cancer who had somatic hotspot mutation testing using a 46- or 50-gene multiplex platform from March 2012 to December 2014. Among this population, 24 patients had inflammatory breast cancer and 376 patients had non-inflammatory breast cancer. We tested a total of 26 samples from 24 patients with inflammatory breast cancer. RESULTS: The average number of mutations per patient was higher in inflammatory breast cancer than in non-inflammatory breast cancer (1.23 vs. 0.65, respectively). Identified somatic mutations in inflammatory breast cancer were TP53 (n = 18, 75%), PIK3CA (n = 10, 41.7%), and ERBB2 (n = 4, 16.7%). TP53 and ERBB2 mutations were significantly more prevalent in inflammatory breast cancer than in non-inflammatory breast cancer (P < 0.01). All patients with ERBB2 mutations had hormone receptor (HR)+ primary tumors. CONCLUSIONS: TP53, PIK3CA, and ERBB2 were detected as three major somatic mutations in metastatic inflammatory breast cancer patients. While the inflammatory breast cancer TP53 and PIK3CA mutations mirrored previously reported data for metastatic non-inflammatory breast cancer, this is the first report of higher frequency of ERBB2 mutation in inflammatory breast cancer, especially in the HR+ subtype. Once validated in a larger cohort of inflammatory breast cancer patients, this novel finding could lead to development of treatments for HR+ inflammatory breast cancer.


Assuntos
Carcinoma Ductal de Mama/genética , Neoplasias Inflamatórias Mamárias/genética , Adulto , Idoso , Carcinoma Ductal de Mama/mortalidade , Classe I de Fosfatidilinositol 3-Quinases/genética , Análise Mutacional de DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Neoplasias Inflamatórias Mamárias/mortalidade , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas c-akt/genética , Receptor ErbB-2/genética , Proteína Supressora de Tumor p53/genética
12.
Oncotarget ; 8(9): 14897-14911, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28107181

RESUMO

Inflammatory breast cancer (IBC) is a virulent form of breast cancer, and novel treatment strategies are urgently needed. Immunohistochemical analysis of tumors from women with a clinical diagnosis of IBC (n = 147) and those with non-IBC breast cancer (n = 2510) revealed that, whereas in non-IBC cases cytoplasmic cyclin E was highly correlated with poor prognosis (P < 0.001), in IBC cases both nuclear and cytoplasmic cyclin E were indicative of poor prognosis. These results underscored the utility of the cyclin E/CDK2 complex as a novel target for treatment. Because IBC cell lines were highly sensitive to the CDK2 inhibitors dinaciclib and meriolin 5, we developed a high-throughput survival assay (HTSA) to design novel sequential combination strategies based on the presence of cyclin E and CDK2. Using a 14-cell-line panel, we found that dinaciclib potentiated the activity of DNA-damaging chemotherapies treated in a sequence of dinaciclib followed by chemotherapy, whereas this was not true for paclitaxel. We also identified a signature of DNA repair-related genes that are downregulated by dinaciclib, suggesting that global DNA repair is inhibited and that prolonged DNA damage leads to apoptosis. Taken together, our findings argue that CDK2-targeted combinations may be viable strategies in IBC worthy of future clinical investigation.


Assuntos
Biomarcadores Tumorais/metabolismo , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Inflamatórias Mamárias/patologia , Proteínas Oncogênicas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Ciclo Celular , Proliferação de Células , Terapia Combinada , Óxidos N-Cíclicos , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Feminino , Seguimentos , Humanos , Indolizinas , Neoplasias Inflamatórias Mamárias/metabolismo , Neoplasias Inflamatórias Mamárias/terapia , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Compostos de Piridínio/uso terapêutico , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto Jovem
13.
Oncotarget ; 8(22): 35656-35668, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-27374101

RESUMO

CTCs are involved in tumor dissemination and are an independent prognostic factor in primary and metastatic breast cancer patients. Dendritic cells (DCs) are the most efficient antigen presenting cells and are comprised of plasmacytoid-(pDC) and myeloid-(mDC) derived DC subsets. This study aimed to correlate CTC counts with the peripheral blood DC immunophenotypes and functions of inflammatory breast cancer (IBC) patients. This study included 65 IBC patients. Peripheral blood (PB) was obtained from patients prior to starting a new line of chemotherapy for CTCs enumeration by CellSearch® and DC phenotype and function by flow cytometry; the characteristics of DCs were then correlated with CTC counts and clinical outcome. Twenty-one (32.3%) patients with CTCs ≥5 had a significantly inferior overall survival (OS) compared to patients with <5 CTCs (p=0.045). In addition, patients with ≥5 CTCs had a lower percentage of mDCs capable of producing TNF-α before or after activation through the toll-like receptor (TLR), as well as a lower percentage of mDCs producing IL-12 after TLR-activation. There was a positive correlation between CTCs counts and expression of the activation (CCR7) and costimulatory (CD86) receptors on TLR-activated mDCs and pDCs, respectively. Moreover, presence of high percentage of mDC capable to produce increased levels of TNF-α was independently associated with inferior OS (p = 0.0006). An increase in the percentage of mDC producing TNF-α might induce a pro-inflammatory environment that could play a role in determining the poor clinical outcome in IBC patients and could add further prognostic value to CTCs.


Assuntos
Células Dendríticas/metabolismo , Neoplasias Inflamatórias Mamárias/imunologia , Neoplasias Inflamatórias Mamárias/patologia , Células Neoplásicas Circulantes/patologia , Imunidade Adaptativa , Adulto , Idoso , Contagem de Células , Citocinas/metabolismo , Células Dendríticas/patologia , Feminino , Humanos , Imunidade Inata , Neoplasias Inflamatórias Mamárias/mortalidade , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Receptores de Quimiocinas/metabolismo , Análise de Sobrevida
14.
Future Oncol ; 13(9): 833-841, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27875910

RESUMO

Cancer-related pain, reported by more than 70% of patients, is one of the most common and troublesome symptoms affecting patients with cancer. Despite the availability of effective treatments, cancer-related pain may be inadequately controlled in up to 50% of patients. With the growing focus on 'value' (healthcare outcomes achieved per dollar spent) in healthcare, the management of cancer-related pain has assumed novel significance in recent years. Data from initiatives that assess the quality of pain management in clinical practice have shown that effective management of cancer-related pain improves patient-perceived value of cancer treatment. As a result, assessment and effective management of cancer-related pain are now recognized as important measures of value in cancer care.


Assuntos
Dor do Câncer/epidemiologia , Dor do Câncer/etiologia , Neoplasias/complicações , Neoplasias/epidemiologia , Dor do Câncer/diagnóstico , Dor do Câncer/terapia , Efeitos Psicossociais da Doença , Humanos , Manejo da Dor , Medição da Dor , Satisfação do Paciente , Qualidade de Vida , Resultado do Tratamento
15.
Oncotarget ; 7(47): 76362-76373, 2016 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-27806348

RESUMO

BACKGROUND: Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS: Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene (N = 126) and/or 46 or 50 gene (N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected. RESULTS: Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients. CONCLUSIONS: Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Perfilação da Expressão Gênica , Família Multigênica , Alelos , Neoplasias da Mama/patologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genômica/métodos , Genótipo , Humanos , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico
16.
Oncology ; 91(6): 299-301, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27705967

RESUMO

It is increasingly recognized that cancer is a highly heterogeneous group of illnesses even within a particular organ site (e.g., breast, lung, colon, etc.). This observation presents a serious challenge to the traditional concept of phase 3 randomized trials designed to define therapeutic efficacy of a novel treatment strategy. For while 10% of the patients with a common malignancy (e.g., non-small-cell lung cancer) may be sufficient to consider such an effort, enrolling a sufficient number of patients into a clinical trial in a timely manner to define clinical utility would be extremely difficult if the population in question represented only 1% of this population, and essentially impossible if one wished to explore the benefits of treatment in a rarer neoplasm (e.g. ovarian cancer). Therefore, in the new era of precision cancer medicine, alternative research designs are imperative. One option would be to compare the time-to-disease progression of an individual cancer patient following treatment with a novel therapeutic to the time-to-disease progression for that specific patient on her/his immediately preceding treatment. The rationale for this strategy and early experience with this innovative approach to evaluating the efficacy of anticancer therapy is highlighted in this report.


Assuntos
Progressão da Doença , Neoplasias/tratamento farmacológico , Medicina de Precisão , Projetos de Pesquisa , Ensaios Clínicos Fase III como Assunto , Humanos , Terapia de Alvo Molecular , Neoplasias/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo
17.
Mod Pathol ; 29(4): 330-46, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26916073

RESUMO

Inflammatory breast cancer is the most aggressive form of breast cancer. Identifying new biomarkers to be used as therapeutic targets is in urgent need. Messenger RNA expression profiling studies have indicated that inflammatory breast cancer is a transcriptionally heterogeneous disease, and specific molecular targets for inflammatory breast cancer have not been well established. We performed microRNA expression profiling in inflammatory breast cancer in comparison with locally advanced noninflammatory breast cancer in this study. Although many microRNAs were differentially expressed between normal breast tissue and tumor tissue, most of them did not show differential expression between inflammatory and noninflammatory tumor samples. However, by microarray analysis, quantitative reverse transcription PCR, and in situ hybridization, we showed that microRNA-205 expression was decreased not only in tumor compared with normal breast tissue, but also in inflammatory breast cancer compared with noninflammatory breast cancer. Lower expression of microRNA-205 correlated with worse distant metastasis-free survival and overall survival in our cohort. A small-scale immunohistochemistry analysis showed coexistence of decreased microRNA-205 expression and decreased E-cadherin expression in some ductal tumors. MicroRNA-205 may serve as a therapeutic target in advanced breast cancer including inflammatory breast cancer.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Inflamatórias Mamárias/genética , MicroRNAs/biossíntese , Adulto , Idoso , Biomarcadores Tumorais/análise , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização In Situ , Neoplasias Inflamatórias Mamárias/mortalidade , Estimativa de Kaplan-Meier , MicroRNAs/análise , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Oncologist ; 21(1): 21-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26659222

RESUMO

BACKGROUND: The present study was performed to determine whether the human epidermal growth factor receptor-related 2 (HER2)/centromeric probe for chromosome 17 fluorescence in situ hybridization (FISH) ratio is a predictor of a pathologic complete response (pCR), recurrence-free survival (RFS), and/or overall survival (OS) in patients receiving neoadjuvant systemic treatment (NST) with trastuzumab (NST-T) for HER2+ locally advanced breast cancer (LABC). PATIENTS AND METHODS: The present retrospective study included 555 patients with HER2+ LABC who had undergone NST and definitive surgery (1999-2012); 373 had concurrently received trastuzumab. HER2-positivity was considered present with an immunohistochemical score of 3+ and/or HER2 FISH ratio of ≥2.0. We used logistic regression analysis and Cox proportional hazard modeling to determine whether a high HER2 FISH ratio, either as a continuous variable or with a cutoff of ≥7.0, would predict for pCR (no invasive disease in the breast and no tumor in the ipsilateral axillary lymph nodes), RFS, and/or OS. RESULTS: The pCR group's median HER2 FISH ratio was significantly higher than that of the non-pCR group (6.4 vs. 5.2; p = .003). The logistic regression model demonstrated that the independent predictors of pCR included a high HER2 FISH ratio as a continuous variable (p = .04). The multicovariate Cox proportional hazard model showed that a high HER2 FISH ratio (with a cutoff of ≥7.0 or as a continuous variable) was a significant prognostic indicator of longer RFS time (p = .047 and p = .04, respectively). Similarly, a high HER2 FISH ratio of ≥7.0 was associated with longer OS (p = .06). CONCLUSION: A high HER2 FISH ratio is a predictor of pCR in patients with HER2+ LABC who receive NST-T. IMPLICATIONS FOR PRACTICE: This study demonstrated the optimal predictive and prognostic value of a HER2/centromeric probe for chromosome 17 FISH ratio for primary HER2+ breast cancer treated with trastuzumab combined with neoadjuvant systemic treatment (NST-T). This suggests that a high HER2 FISH ratio is a potential indicator for a high pathologic complete response rate and a better prognosis when patients are treated with NST-T.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Centrômero/genética , Terapia Neoadjuvante , Receptor ErbB-2/biossíntese , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/patologia , Cromossomos Humanos Par 17 , Intervalo Livre de Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Prognóstico , Receptor ErbB-2/genética , Estudos Retrospectivos , Trastuzumab/administração & dosagem
19.
Onco Targets Ther ; 8: 3323-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26648736

RESUMO

BACKGROUND: ESR1 mutation has recently emerged as one of the important mechanisms involved in endocrine resistance. The incidence and clinical implication of ESR1 mutation has not been well evaluated in heavily pretreated breast cancer patients. METHODS: We conducted a retrospective review of advanced breast cancer patients with tumors who underwent next-generation sequencing genomic profiling using Foundation One test at Cancer Treatment Centers of America(®) regional hospitals between November 2012 and November 2014. RESULTS: We identified a total of 341 patients including 217 (59%) estrogen receptor (ER)+, 177 (48%) progesterone receptor (PR)+, 30 (8%) hormone receptor+/HER2 positive, and 119 (32%) triple negative patients. ESR1 mutation was noted in 27/222 (12.1%) ER+ or PR+ breast cancer patients. All ER+ patients received at least one line of an aromatase inhibitor. All 28 patients were found to harbor ESR1 mutations affecting ligand-binding domain with the most common mutations affecting Y537 (17/28, 60.7%) and D538 (9/28, 32.1%). In this cohort, 19 (67.9%) patients carried three or more, seven (25%) patients had one or two additional genomic alterations and one (3.6%) patient had an ESR1 mutation only. Of 28 patients, three patients were treated with fulvestrant immediately before and two patients were treated after next-generation sequencing testing; only one patient achieved stable disease for 8 months and the other four patients had progression of disease. In all, 3/3 (100%) patients before testing and 2/4 (50%) after testing treated with exemestane and everolimus achieved stable disease for at least 6 months. CONCLUSION: ESR1 mutation was found in 12.1% of a large cohort of advanced breast cancer patients. Exemestane in combination with everolimus might be a reasonable option. Prospective studies are warranted to validate these findings.

20.
Am J Clin Pathol ; 144(5): 713-21, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26486734

RESUMO

OBJECTIVES: The advent of next-generation sequencing (NGS) platforms in the realm of clinical molecular diagnostics provides multigene mutational profiling through massively parallel sequencing. METHODS: We analyzed 415 breast carcinoma samples from 354 patients using NGS in known hotspots of 46 commonly known cancer-causing genes. RESULTS: A total of 281 somatic nonsynonymous mutations were detected in 62.1% of patients. TP53 was most frequently mutated (38.8%), followed by PIK3CA (31.7%), AKT1 (6%), and ATM (3.9%), with other mutations detected at a lower frequency. When stratified into clinically relevant therapeutic groups (estrogen receptor [ER]/progesterone receptor [PR]+ human epidermal growth factor receptor 2 [HER2]-, ER/PR+HER2+, ER/PR-HER2+, ER/PR/HER2-), each group showed distinct mutational profiles. The ER/PR+HER2- tumors (n = 132) showed the highest frequency of PIK3CA mutations (38%), while the triple-negative tumors (n = 64) had a significantly higher number of TP53 mutations (62%). Of the 61 patients tested for both primary and metastatic tumors, concordant results were seen in 47 (77%) patients, while 13 patients showed additional mutations in the metastasis. CONCLUSIONS: Our results indicate that breast cancers may harbor potentially actionable mutations for targeted therapeutics. Therefore, NGS-based mutational profiling can provide useful information that can guide targeted cancer therapy.


Assuntos
Neoplasias da Mama/genética , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Adulto Jovem
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