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1.
Clin Cancer Res ; 29(24): 5021-5030, 2023 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-37363965

RESUMEN

PURPOSE: To overcome resistance to antihormonal and HER2-targeted agents mediated by cyclin D1-CDK4/6 complex, we proposed an oral combination of the HER2 inhibitor tucatinib, aromatase inhibitor letrozole, and CDK4/6 inhibitor palbociclib (TLP combination) for treatment of HR+/HER2+ metastatic breast cancer (MBC). PATIENTS AND METHODS: Phase Ib/II TLP trial (NCT03054363) enrolled patients with HR+/HER2+ MBC treated with ≥2 HER2-targeted agents. The phase Ib primary endpoint was safety of the regimen evaluated by NCI CTCAE version 4.3. The phase II primary endpoint was efficacy by median progression-free survival (mPFS). RESULTS: Forty-two women ages 22 to 81 years were enrolled. Patients received a median of two lines of therapy in the metastatic setting, 71.4% had visceral disease, 35.7% had CNS disease. The most common treatment-emergent adverse events (AE) of grade ≥3 were neutropenia (64.3%), leukopenia (23.8%), diarrhea (19.0%), and fatigue (14.3%). Tucatinib increased AUC10-19 hours of palbociclib 1.7-fold, requiring palbociclib dose reduction from 125 to 75 mg daily. In 40 response-evaluable patients, mPFS was 8.4 months, with similar mPFS in non-CNS and CNS cohorts (10.0 months vs. 8.2 months; P = 0.9). Overall response rate was 44.5%, median duration of response was 13.9 months, and clinical benefit rate was 70.4%; 60% of patients were on treatment for ≥6 months, 25% for ≥1 year, and 10% for ≥2 years. In the CNS cohort, 26.6% of patients remained on study for ≥1 year. CONCLUSIONS: TLP combination was safe and tolerable. AEs were expected and manageable with supportive therapy and dose reductions. TLP showed excellent efficacy for an all-oral chemotherapy-free regimen warranting further testing. See related commentary by Huppert and Rugo, p. 4993.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Humanos , Femenino , Letrozol , Neoplasias de la Mama/patología , Receptor ErbB-2/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antineoplásicos/uso terapéutico
2.
NPJ Breast Cancer ; 9(1): 41, 2023 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-37210417

RESUMEN

This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2- breast cancer (BC). Eligible patients were women with ECOG 0-2, ER+/HER2- measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46-87); PS 1 (0-1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2-52). Adverse events were as expected for hormonal therapy. Significant (p < 0.1) univariate relationships existed between PFS and ER%, AR%, and PIK3CA and/or PTEN mutations. Baseline levels of phospho-proteins in the mTOR pathway were more highly expressed in biopsies of patients with shorter PFS. Fulvestrant plus enzalutamide had manageable side effects. The primary endpoint of CBR24 was 25% in heavily pretreated metastatic ER+/HER2- BC. Short PFS was associated with activation of the mTOR pathway, and PIK3CA and/or PTEN mutations were associated with an increased hazard of progression. Thus, a combination of fulvestrant or other SERD plus AKT/PI3K/mTOR inhibitor with or without AR inhibition warrants investigation in second-line endocrine therapy of metastatic ER+ BC.

3.
Eur J Cancer ; 168: 119-127, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35525161

RESUMEN

BACKGROUND: Women diagnosed with breast cancer prior to age 45 years (<45y) and within the first 5 years postpartum (postpartum breast cancer, PPBC) have the greatest risk for distal metastatic recurrence. METHODS: Pooling data from the Colorado Young Women Breast Cancer cohort and the Breast Cancer Health Disparities Study (N = 2519 cases), we examined the association of parity, age, and clinical factors with overall survival (OS) of breast cancer over 15 years of follow-up. RESULTS: Women with PPBC diagnosed at <45y had the lowest OS (p < 0.0001), while OS of nulliparous cases diagnosed at <45y did not differ from OS of cases diagnosed at 45-65y regardless of parity status. After adjustment for study site, race/ethnicity, clinical stage, year of diagnosis and stratification for oestrogen receptor status, PPBC remained an independent factor associated with poor OS. Among cases diagnosed at <45y, nulliparous cases had 1.6 times better OS (hazard ratio (HR) = 0.61, 95%CI 0.42-0.87) compared to those with PPBC, with a more pronounced survival difference among stage I breast cancers (HR = 0.30, 95%CI 0.11-0.79). Among very young women diagnosed at age ≤35y, nulliparous cases had 2.3 times better OS (HR = 0.44, 95%CI 0.23-0.84) compared to PPBC. CONCLUSION: Our results suggest that postpartum status is the main driver of poor prognosis in young women with breast cancer, with the strongest association in patients diagnosed at age ≤35y and in those with stage I disease.


Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama/patología , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Paridad , Periodo Posparto , Embarazo , Pronóstico , Modelos de Riesgos Proporcionales
4.
JCO Precis Oncol ; 6: e2100370, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35357905

RESUMEN

The phosphatidylinositol 3-kinase (PI3K) pathway is an intracellular pathway activated in response to progrowth signaling, such as human epidermal growth factor receptor 2 (HER2) and other kinases. Abnormal activation of PI3K has long been recognized as one of the main oncogenic drivers in breast cancer, including HER2-positive (HER2+) subtype. Somatic activating mutations in the gene encoding PI3K alpha catalytic subunit (PIK3CA) are present in approximately 30% of early-stage HER2+ tumors and drive therapeutic resistance to multiple HER2-targeted agents. Here, we review currently available agents targeting PI3K, discuss their potential role in HER2+ breast cancer, and provide an overview of ongoing trials of PI3K inhibitors in HER2+ disease. Additionally, we review the landscape of PIK3CA mutational testing and highlight the gaps in knowledge that could present potential barriers in the effective application of PI3K inhibitors for treatment of HER2+ breast cancer.


Asunto(s)
Neoplasias de la Mama , Fosfatidilinositol 3-Quinasa Clase I , Resistencia a Antineoplásicos , Neoplasias de la Mama/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I/genética , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Mutación , Receptor ErbB-2
5.
Mol Cancer Ther ; 21(1): 48-57, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34728571

RESUMEN

Breast cancers that express hormonal receptors (HR) and HER2 display resistance to targeted therapy. Tumor-promotional signaling from the HER2 and estrogen receptor (ER) pathways converges at the cyclin D1 and cyclin-dependent kinases (CDK) 4 and 6 complex, which drives cell-cycle progression and development of therapeutic resistance. Therefore, we hypothesized that co-targeting of ER, HER2, and CDK4/6 may result in improved tumoricidal activity and suppress drug-resistant subclones that arise on therapy. We tested the activity of the triple targeted combination therapy with tucatinib (HER2 small-molecule inhibitor), palbociclib (CKD4/6 inhibitor), and fulvestrant (selective ER degrader) in HR+/HER2+ human breast tumor cell lines and xenograft models. In addition, we evaluated whether triple targeted combination prevents growth of tucatinib or palbociclib-resistant subclones in vitro and in vivo Triple targeted combination significantly reduced HR+/HER2+ tumor cell viability, clonogenic survival, and in vivo growth. Moreover, survival of HR+/HER2+ cells that were resistant to the third drug in the regimen was reduced by the other two drugs in combination. We propose that a targeted triple combination approach will be clinically effective in the treatment of otherwise drug-resistant tumors, inducing robust responses in patients.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Estrógenos/uso terapéutico , Animales , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Inhibidores de Proteínas Quinasas/farmacología
6.
Curr Breast Cancer Rep ; 13(3): 216-226, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34457184

RESUMEN

PURPOSE OF REVIEW: In this review, we discuss targets of interest in Triple-negative breast cancer (TNBC), approved targeted agents and the results of the clinical trials that led to their approval. Additionally, we review ongoing clinical trials evaluating the use of novel targeted agents in the treatment of TNBC. RECENT FINDINGS: TNBC accounts for 15-20% of all breast cancer cases and is associated with worse clinical outcomes. Patients have a higher risk of metastatic recurrence and inferior overall survival compared to other breast cancer subtypes. Cytotoxic chemotherapy has historically been the mainstay of treatment for TNBC. In recent years, we have seen a surge in clinical trials investigating the use of targeted agents in TNBC and now have approval for targeted therapies in select patients. Inhibitors of PARP (olaparib and talazoparib), PD-L1 (atezolizumab) and an antibody drug conjugate targeting Trop-2 (sacituzumab govitecan-hziy) are now approved for the use in select groups of patients with TNBC. SUMMARY: Various novel targeted agents as monotherapy, dual targeted combinations, and chemotherapy combinations are currently under investigation. The results are promising and may significantly improve patient outcomes in TNBC.

7.
Breast Cancer Res Treat ; 187(3): 883-891, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33625615

RESUMEN

PURPOSE: Adjuvant pertuzumab and neratinib are independently FDA-approved for treatment of early-stage HER2-positive breast cancer in combination with or following trastuzumab for one year, respectively. Both agents reduce the risk of recurrence; however, the absolute benefit is modest for many patients with added risk of adverse effects. The purpose of this study was to evaluate the clinical use of adjuvant pertuzumab and neratinib in patients with early-stage HER2-positive breast cancer. METHODS: Patients diagnosed with stage I-III HER2-positive breast cancer treated with trastuzumab at four University of Colorado Health hospitals between July 2016 and April 2019 were identified. Patient demographics, cancer stage, treatment, and administration of pertuzumab and/or neratinib were obtained. RESULTS: We identified a total of 350 patients who received adjuvant trastuzumab for stage I-III HER2-positive breast cancer; 253 (73.1%) had tumors that were ≥ T2 or node-positive disease. The rate of adjuvant pertuzumab use increased following FDA approval; pertuzumab was administered to the majority of patients with node-positive HER2-positive breast cancer. The use of adjuvant pertuzumab was associated with younger age, premenopausal status, and node-positive disease. Rates of administration of adjuvant neratinib were lower, with only 15.2% of patients receiving this therapy within 3 months of completing adjuvant trastuzumab. CONCLUSION: In our cohort of patients treated within a diverse healthcare network, the majority of patients with node-positive HER2-positive breast cancer received adjuvant pertuzumab following FDA approval. The use of adjuvant neratinib was less common, potentially as a result of adverse effects, prolongation of therapy, previous administration of adjuvant pertuzumab, and modest benefit.


Asunto(s)
Neoplasias de la Mama , Receptor ErbB-2 , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Hospitales Universitarios , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Quinolinas , Receptor ErbB-2/genética , Trastuzumab
8.
Cancer Med ; 8(12): 5609-5618, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31407530

RESUMEN

Women who inherit a BRCA1 or BRCA2 mutation have an increased risk of breast cancer. Preliminary evidence suggests they may also have defects in bone marrow function. To test this hypothesis, we conducted a multicenter, retrospective, matched cohort study, comparing women with localized breast cancer requiring cytotoxic chemotherapy who carried an inherited BRCA1 or BRCA2 mutation to similar wild-type patients treated between 1995 and 2017 and matched based on age, race, site, and chemotherapy regimen. The proportion who developed specific hematologic toxicities, timing of these toxicities, and patterns of blood count fluctuations over time were compared among BRCA1 carriers vs matched wild-type patients and among BRCA2 carriers vs matched wild-type patients. 88 BRCA1 carriers and 75 BRCA2 carriers were matched to 226 and 242 wild-type patients, respectively. The proportions and timing of experiencing any grade or grade 3/4 cytopenias during chemotherapy were not significantly different for BRCA1 carriers or BRCA2 carriers vs matched wild-type patients. Proportions requiring treatment modifications and time to first modification were also similar. Patterns of blood count fluctuations over time in mutation carriers mirrored those in wild-type patients overall and by the most common regimens. Women with an inherited mutation in BRCA1 or BRCA2 experience similar frequency, severity, and timing of hematologic toxicities during curative intent breast cancer chemotherapy as matched wild-type patients. Our findings suggest that BRCA1 or BRCA2 haploinsufficiency is sufficient for adequate bone marrow reserve in the face of short-term repetitive hematopoietic stressors.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/tratamiento farmacológico , Mutación de Línea Germinal , Adulto , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Femenino , Haploinsuficiencia , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento
9.
Breast Cancer Res Treat ; 177(2): 369-382, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31254157

RESUMEN

PURPOSE: The serine-threonine kinases Aurora A (AURKA) and p21-activated kinase 1 (PAK1) are frequently overexpressed in breast tumors, with overexpression promoting aggressive breast cancer phenotypes and poor clinical outcomes. Besides the well-defined roles of these proteins in control of cell division, proliferation, and invasion, both kinases support MAPK kinase pathway activation and can contribute to endocrine resistance by phosphorylating estrogen receptor alpha (ERα). PAK1 directly phosphorylates AURKA and its functional partners, suggesting potential value of inhibiting both kinases activity in tumors overexpressing PAK1 and/or AURKA. Here, for the first time, we evaluated the effect of combining the AURKA inhibitor alisertib and the PAK inhibitor FRAX1036 in preclinical models of breast cancer. METHODS: Combination of alisertib and FRAX1036 was evaluated in a panel of 13 human breast tumor cell lines and BT474 xenograft model, with assessment of the cell cycle by FACS, and signaling changes by immunohistochemistry and Western blot. Additionally, we performed in silico analysis to identify markers of response to alisertib and FRAX1036. RESULTS: Pharmacological inhibition of AURKA and PAK1 synergistically decreased survival of multiple tumor cell lines, showing particular effectiveness in luminal and HER2-enriched models, and inhibited growth and ERα-driven signaling in a BT474 xenograft model. In silico analysis suggested cell lines with dependence on AURKA are most likely to be sensitive to PAK1 inhibition. CONCLUSION: Dual targeting of AURKA and PAK1 may be a promising therapeutic strategy for treatment of breast cancer, with a particular effectiveness in luminal and HER2-enriched tumor subtypes.


Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Neoplasias de la Mama/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Quinasas p21 Activadas/antagonistas & inhibidores , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Quimioterapia Combinada , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Inmunohistoquímica , Ratones , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Int J Breast Cancer ; 2018: 7835095, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30018827

RESUMEN

Triple positive breast cancers overexpress both the human epidermal growth factor receptor 2 (HER2) oncogene and the hormonal receptors (HR) to estrogen and progesterone. These cancers represent a unique therapeutic challenge because of a bidirectional cross-talk between the estrogen receptor alpha (ERα) and HER2 pathways leading to tumor progression and resistance to targeted therapy. Attempts to combine standard of care HER2-targeted drugs with antihormonal agents for the treatment of HR+/HER2+ breast cancer yielded encouraging results in preclinical experiments but did improve overall survival in clinical trial. In this review, we dissect multiple mechanisms of therapeutic resistance typical of HR+/HER2+ breast cancer, summarize prior clinical trials of targeted agents, and describe novel rational drug combinations that include antihormonal agents, HER2-targeted drugs, and CDK4/6 inhibitors for treatment of the HR+/HER2+ breast cancer subtype.

13.
Cancer Biol Ther ; 18(9): 694-704, 2017 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-28886275

RESUMEN

Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States. We analyzed 26 MSI-High and 558 non-MSI-High CRC tumors. BRCA2 mutations were highly enriched (50%) in MSI-High CRC. Immunohistochemistry showed that BRCA2-mutated MSI-High CRC had high c-MET (64%) expression compared with BRCA-WT (17%). We hypothesized a mechanistic link between BRCA2-deficiency and c-MET overexpression and synergistic interaction between drugs that treat BRCA-deficient tumors (mitomycin C (MMC) or PARP inhibitors) and c-MET inhibitors (crizotinib). We tested CRC cell lines for sensitivity to MMC plus crizotinib or other drug combinations including PARP-inhibitors. Combined treatment of tumor cells with crizotinib and MMC led to increased apoptosis as compared with each drug alone. Additionally, combination treatment with increasing concentrations of both drugs demonstrated a synergistic anti-cancer effect (CI = 0.006-0.74). However, we found no evidence for c-MET upregulation upon effective BRCA2 knockdown in tumor cells -/+DNA damage. Although we found no mechanistic link between BRCA2 deficiency and c-MET overexpression, c-MET is frequently overexpressed in CRC and BRCA2 is mutated especially in MSI-H CRC. The combination of crizotinib with MMC appeared synergistic regardless of MSI or BRCA2 status. Using an in-vivo CRC xenograft model we found reduced tumor growth with combined crizotinib and MMC therapy (p = 0.0088). Our preclinical results support clinical testing of the combination of MMC and crizotinib in advanced CRC. Targeting cell survival mediated by c-MET in combination with targeting DNA repair may be a reasonable strategy for therapy development in CRC or other cancers.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Mitomicina/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Alelos , Animales , Línea Celular Tumoral , Supervivencia Celular/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Crizotinib , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Genes BRCA2 , Humanos , Inmunohistoquímica , Ratones , Mutación , Proteínas Proto-Oncogénicas c-met , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Oncotarget ; 8(25): 39945-39962, 2017 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-28591715

RESUMEN

Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0.0000001). BRCA2 mutations in MSH2/MLH1-mutant CRCs included 75 unique mutations not known to occur in breast or pancreatic cancer per COSMIC v73. Only 5 deleterious BRCA2 mutations in CRC were previously reported in the BIC database as germ-line mutations in breast cancer. Some BRCA2 mutations were predicted to disrupt interactions with partner proteins DSS1 and RAD51. Some CRCs harbored multiple BRCA2 mutations. EGFR was mutated in 45.5% of MSH2/MLH1-mutant and 6.5% of non-MSH2/MLH1-mutant tumors (P < 0.0000001). Approximately 15% of EGFR mutations found may be actionable through TKI therapy, including N700D, G719D, T725M, T790M, and E884K. NTRK gene mutations were identified in MSH2/MLH1-mutant CRC including NTRK1 I699V, NTRK2 P716S, and NTRK3 R745L. Our findings have clinical relevance regarding therapeutic targeting of BRCA2 vulnerabilities, EGFR mutations or other identified oncogenic drivers such as NTRK in MSH2/MLH1-mutant CRCs or other tumors with mismatch repair deficiency.


Asunto(s)
Proteína BRCA2/genética , Neoplasias Colorrectales/genética , Receptores ErbB/genética , Mutación , Receptor trkA/genética , Receptor trkB/genética , Receptor trkC/genética , Proteína BRCA2/química , Estudios de Cohortes , Reparación de la Incompatibilidad de ADN/genética , Receptores ErbB/química , Frecuencia de los Genes , Humanos , Inestabilidad de Microsatélites , Modelos Moleculares , Homólogo 1 de la Proteína MutL/genética , Proteína 2 Homóloga a MutS/genética , Dominios Proteicos , Receptor trkA/química , Receptor trkB/química , Receptor trkC/química
15.
J Natl Compr Canc Netw ; 15(4): 494-503, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28404760

RESUMEN

Background: The 21-gene recurrence score (RS) assay is retrospectively validated for assessing prognosis and benefit from chemotherapy in hormone receptor-positive, early-stage breast cancer (EBC) with low RS. We hypothesized that oncologists have already incorporated the RS assay for decision-making in higher-risk, node-positive disease, despite the lack of prospective data and contrary to NCCN Guideline recommendations. This study provides the first analysis of trends and differences in RS use and therapeutic implications in a population-based data set of patients with node-positive EBC. It also assesses the impact of the RxPONDER trial on clinicians' chemotherapy recommendations. Methods: Node-positive EBC cases diagnosed during 2010 through 2012 and included in the National Cancer Data Base were used. Multivariate logistic regression was used to estimate test use and impact on chemotherapy recommendations. Results: The RS assay was ordered for 16.5% of the 80,405 identified patients. Of all variables, the RS assay had the strongest association with chemotherapy recommendation, with adjusted odds ratios (AORs) of 19 for scores >30. Odds of chemotherapy recommendation were significantly lower for the group who received the test (AOR, 0.21; 95% CI, 0.20-0.22). When divided based on the cutoff point of 25 adopted by the RxPONDER trial, those with an RS of 18 to 25 had significantly lower odds of chemotherapy recommendation compared with those with an RS of 26 to 30 (AOR, 0.32; 95% CI, 0.26-0.40). Test use was lower for blacks, community centers, uninsured/governmentally insured patients, higher tumor grade, larger tumor size, and more nodes involved. Chemotherapy recommendation was higher for patients of younger age, with private insurance, and with higher tumor grade, size, and number of nodes involved. Black patients had significantly higher RS (AOR, 1.37; 95% CI, 1.25-1.79). Conclusions: The RS assay influences clinicians' chemotherapy recommendation in node-positive EBC. Clinicians are using the inclusion criteria of the RxPONDER trial before its final release. Black patients have higher RS, likely representing worse biology. Significant differences exist in test use and clinical implications based on race, insurance, and facility.


Asunto(s)
Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Perfilación de la Expresión Génica/métodos , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Quimioterapia Adyuvante , Toma de Decisiones Clínicas , Ensayos Clínicos como Asunto , Comorbilidad , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Oportunidad Relativa , Pronóstico , Estudios Retrospectivos , Factores de Riesgo
16.
Oncology (Williston Park) ; 30(12): 1063-70, 2016 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-27987198

RESUMEN

Since most patients with Hodgkin lymphoma survive their disease, long-term issues such as development of second primary malignancies arise, especially in patients treated with multimodal therapy including radiation therapy plus chemotherapy. The risk of breast cancer is significantly elevated in women exposed to high-dose ionizing radiation to the chest before age 40. The case of a 48-year-old patient with a lump in her right breast is presented as a clinical scenario in this article. We review available strategies for screening and risk reduction through chemoprevention or risk-reducing surgery, as well as challenges for management of breast cancer in patients with prior exposure to radiation for Hodgkin lymphoma. The Children's Oncology Group clinical practice guidelines for long-term follow-up care of pediatric cancer survivors provide recommendations that have been endorsed by American and European oncologists.


Asunto(s)
Neoplasias de la Mama/prevención & control , Enfermedad de Hodgkin/radioterapia , Neoplasias Inducidas por Radiación/prevención & control , Neoplasias Primarias Secundarias/prevención & control , Conducta de Reducción del Riesgo , Neoplasias de la Mama/etiología , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Primarias Secundarias/etiología
17.
Mol Cancer Ther ; 15(10): 2486-2497, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27507850

RESUMEN

Clinical decision making for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is predominantly guided by disease stage and anatomic location, with few validated biomarkers. The epidermal growth factor receptor (EGFR) is an important therapeutic target, but its value in guiding therapeutic decision making remains ambiguous. We integrated analysis of clinically annotated tissue microarrays with analysis of data available through the TCGA, to investigate the idea that expression signatures involving EGFR, proteins regulating EGFR function, and core cell-cycle modulators might serve as prognostic or drug response-predictive biomarkers. This work suggests that consideration of the expression of NSDHL and proteins that regulate EGFR recycling in combination with EGFR provides a useful prognostic biomarker set. In addition, inactivation of the tumor suppressor retinoblastoma 1 (RB1), reflected by CCND1/CDK6-inactivating phosphorylation of RB1 at T356, inversely correlated with expression of EGFR in patient HNSCC samples. Moreover, stratification of cases with high EGFR by expression levels of CCND1, CDK6, or the CCND1/CDK6-regulatory protein p16 (CDKN2A) identified groups with significant survival differences. To further explore the relationship between EGFR and RB1-associated cell-cycle activity, we evaluated simultaneous inhibition of RB1 phosphorylation with the CDK4/6 inhibitor palbociclib and of EGFR activity with lapatinib or afatinib. These drug combinations had synergistic inhibitory effects on the proliferation of HNSCC cells and strikingly limited ERK1/2 phosphorylation in contrast to either agent used alone. In summary, combinations of CDK and EGFR inhibitors may be particularly useful in EGFR and pT356RB1-expressing or CCND1/CDK6-overexpressing HPV-negative HNSCC. Mol Cancer Ther; 15(10); 2486-97. ©2016 AACR.


Asunto(s)
Biomarcadores de Tumor , Receptores ErbB/metabolismo , Neoplasias de Cabeza y Cuello/etiología , Neoplasias de Cabeza y Cuello/metabolismo , Proteínas de Unión a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Receptores ErbB/genética , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos Biológicos , Estadificación de Neoplasias , Papillomaviridae , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Fosforilación , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Proteínas de Unión a Retinoblastoma/genética , Ubiquitina-Proteína Ligasas/genética
18.
Gene ; 567(1): 1-11, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-25967390

RESUMEN

Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases. Downstream, NEDD9 regulation of partners including CRKL, WAVE, PI3K/AKT, ERK, E-cadherin, Aurora-A (AURKA), HDAC6, and others allow NEDD9 to influence functions as pleiotropic as migration, invasion, survival, ciliary resorption, and mitosis. In this review, we summarize a growing body of preclinical and clinical data that indicate that while NEDD9 is itself non-oncogenic, changes in expression of NEDD9 (most commonly elevation of expression) are common features of tumors, and directly impact tumor aggressiveness, metastasis, and response to at least some targeted agents inhibiting NEDD9-interacting proteins. These data strongly support the relevance of further development of NEDD9 as a biomarker for therapeutic resistance. Finally, we briefly discuss emerging evidence supporting involvement of NEDD9 in additional pathological conditions, including stroke and polycystic kidney disease.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Neoplasias/genética , Fosfoproteínas/fisiología , Enfermedades Renales Poliquísticas/genética , Accidente Cerebrovascular/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Humanos , Fosfoproteínas/genética
19.
Expert Opin Ther Targets ; 19(2): 187-200, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25384454

RESUMEN

INTRODUCTION: Based on its role as a mitotic regulatory kinase, overexpressed and associated with aneuploidy in cancer, small-molecule inhibitors have been developed for Aurora-A (AURKA) kinase. In preclinical and clinical assessments, these agents have shown efficacy in inducing stable disease or therapeutic response. In optimizing the use of Aurora-A inhibitors, it is critical to have robust capacity to measure the kinase activity of Aurora-A in tumors. AREAS COVERED: We provide an overview of molecular mechanisms of mitotic and non-mitotic activation of Aurora-A kinase, and interaction of Aurora-A with its regulatory partners. Typically, Aurora-A activity is measured by use of phospho-antibodies targeting an autophosphorylated T288 epitope. However, recent studies have identified alternative means of Aurora-A activation control, including allosteric regulation by partners, phosphorylation on alternative activating residues (S51, S98), dephosphorylation on inhibitory sites (S342) and T288 phosphorylation by alternative kinases such as Pak enzymes. Additional work has shown that the relative abundance of Aurora-A partners can affect the activity of Aurora-A inhibitors, and that Aurora-A activation also occurs in interphase cells. EXPERT OPINION: Taken together, this work suggests the need for comprehensive analysis of Aurora-A activity and expression of Aurora-A partners in order to stratify patients for likely therapeutic response.


Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasa A/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Regulación Alostérica/fisiología , Animales , Aurora Quinasa A/metabolismo , Humanos , Mitosis/fisiología , Neoplasias/enzimología , Selección de Paciente , Fosforilación/fisiología , Inhibidores de Proteínas Quinasas/farmacología
20.
Cancer Lett ; 216(2): 221-6, 2004 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-15533598

RESUMEN

Genetic or epigenetic inactivation of the DNA mismatch repair genes in tumor precursor cells results in a strong mutator phenotype, known as the microsatellite mutator phenotype (MMP), or microsatellite instability (MSI). This mutator phenotype causes mutations in genes responsible for the regulation of cell growth and survival/death and thus promotes the development and progression of tumors. In the present study, we examined the DNA topoisomerase II genes (topIIalpha and topIIbeta) as mutational targets for MMP. We screened 10 MSI-positive human tumor cell lines and 30 MSI-positive colorectal tumors for mutations within the entire coding region of the topIIalpha gene and two coding poly(A)7 sequences of topIIbeta. Mutations in either the topIIalpha or topIIbeta gene were found with an overall frequency of 18% (in 10% of the primary tumors and in 44% of the cell lines). This indicates that modulation of the DNA topoisomerase II (TOPII) activity may be important for the development of MSI-positive cancer.


Asunto(s)
Neoplasias del Colon/genética , ADN-Topoisomerasas de Tipo II/genética , Proteínas de Neoplasias/genética , Línea Celular Tumoral , Neoplasias del Colon/enzimología , ADN-Topoisomerasas de Tipo II/metabolismo , Femenino , Mutación del Sistema de Lectura , Humanos , Masculino , Repeticiones de Microsatélite/genética , Mutación Missense , Proteínas de Neoplasias/metabolismo
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