RESUMEN
BACKGROUND: In the Italian Breast Cancer Intergroup Studies (IBIS) 3 phase III trial, we compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF) alone to sequential epirubicin/CMF regimens in patients with rapidly proliferating early breast cancer (RPEBC). We performed a post hoc analysis in the subgroup of patients with hormone-receptor-positive RPEBC on the prognostic role of progesterone receptor (PgR) status. METHODS: RPEBC was defined by thymidine labeling index (TLI) >3% or grade 3 or S-phase >10% or Ki67 >20%. We analyzed 466 patients with hormone-receptor-positive RPEBC receiving sequential epirubicin/CMF regimens followed by tamoxifen, and for whom the status of ER and PgR was available. RESULTS: Considering both cut-off values of 10% and 20%, PgR expression was significantly associated with age, menopausal status, and ER expression; HER2 status was associated with PgR status only at a cutoff value of 20% PgR. Upon univariate analysis, tumor size, nodal status, and PgR were significantly associated with disease-free survival (DFS) and overall survival (OS), while age class and local treatment type were associated only with DFS. Patients with PgR <20% showed lower 5- and 10-year DFS [hazard ratio (HR) = 1.48; 95%CI: 1.01-2.18; p = 0.044] and OS (HR = 1.85; 95%CI: 1.08-3.19, p = 0.025) rates compared with patients with PgR ⩾20%. Upon multivariate analysis, only tumor size, nodal status, and PgR were independent prognostic factors. CONCLUSIONS: Our results highlight the independent prognostic relevance of PgR expression in patients with hormone-receptor-positive RPEBC treated with adjuvant chemotherapy and endocrine therapy, where the definition of prognostic subgroups is still a major need.
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Ductal carcinoma in situ (DCIS) is a highly heterogenous tumor that is now more frequently diagnosed because of the increased number of screening programs. Women with DCIS are mainly treated with conservative surgery almost always followed by radiotherapy. Although conventional biomarkers, i.e. ER, PgR, Ki67, and HER2, have been extensively investigated in invasive tumors, little is known about their role in DCIS, especially that of the androgen receptor (AR). In the present study, the expression of conventional biomarkers and AR was determined by immunohistochemistry in 85 DCIS samples from patients monitored for a maximum of 13 years: 43 patients were treated with quadrantectomy and 42 patients underwent quadrantectomy and radiotherapy. Of these, 5 and 11 patients relapsed, respectively. Our findings showed that ER and PgR were higher in nonrelapsed than in relapsed patients (P=0.025 and 0.0038). In contrast, AR expression and the AR/ER ratio were higher in relapsed patients than in the nonrelapsed group (P=0.0069 and 0.0012). At the best cut-off value of 1.1, the AR/ER ratio showed an overall accuracy of 92% and 80% in predicting in situ relapse or progression to invasive carcinoma in DCIS patients treated with surgery and those treated with surgery plus radiotherapy, respectively. AR would therefore appear to be an independent prognostic biomarker in the latter group. Our preliminary results highlight the potentially important role of the AR/ER ratio as a predictive indicator of DCIS relapse, independently of treatment.
Asunto(s)
Biomarcadores de Tumor/biosíntesis , Neoplasias de la Mama , Carcinoma Ductal de Mama , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/biosíntesis , Recurrencia Local de Neoplasia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/terapia , Femenino , Humanos , Inmunohistoquímica , Mastectomía Segmentaria , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Ductal carcinoma in situ (DCIS) is a heterogeneous disease that has not been investigated as widely as invasive breast cancer. Thus, the search for biomarkers capable of identifying DCIS lesions that may recur or progress to invasive cancer is ongoing. Although conventional steroid hormone receptors, cell proliferation and other important tumor markers have been extensively studied in invasive tumors, little is known about the role played by androgen receptors (ARs), widely expressed in breast cancer, in DCIS. METHODS: We performed a retrospective study in a series of 43 DCIS patients treated with quadrantectomy only and followed up for a period ranging from 5 to 13 years, to evaluate the prognostic relevance of conventional biomarkers (estrogen receptor [ER], progesterone receptor [PgR], Ki67, human epidermal growth factor receptor 2 [HER2]) and AR. RESULTS: Our findings showed that AR and ER were not independent prognostic variables and that an AR/ER ratio cutoff of 1.13 showed a sensitivity of 75% and a specificity of 94% in predicting in situ relapse or progression to the invasive phenotype. Moreover, while the variables considered singly showed area under the curve (AUC) values ranging from 0.52% to 0.77%, the AR/ER ratio reached a very high AUC (0.92%). CONCLUSIONS: These preliminary results highlight the potentially important role of AR and ER and, in particular, of their ratio, as prognostic indicators of DCIS evolution.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Intraductal no Infiltrante/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/metabolismo , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Femenino , Humanos , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Estudios RetrospectivosRESUMEN
Although combination chemotherapy and radiotherapy have become the standard of care in numerous tumors, the mechanisms of interaction are often still unclear. The purpose of this study was to analyze the efficacy of radiation treatment and cisplatin sequences and to investigate their mechanisms of interaction. Three melanoma cell lines were used to evaluate in vitro radiation-induced cytotoxicity before and after cisplatin treatment. Expression levels of a panel of genes were determined by real-time RT-PCR. Cytotoxic effect was evaluated by flow cytometry analysis and Comet assay. We also used normal human dermal fibroblasts (HUDE) to evaluate the cytotoxicity of the two treatments by clonogenic assay. Radiation and cisplatin used singly were not particularly effective in reducing proliferation in melanoma cells. Conversely, radiation treatment followed by cisplatin showed a strong synergistic interaction in all cell lines, with a ratio index ranging from 16 to >100. The synergistic effect was accompanied by apoptosis induction (up to 40%) and an increase in the percentage of comet-shaped nucleoids from 85% to 99%. In parallel, our results also showed that radiation treatment of HUDE fibroblasts followed by cisplatin only induced weak cytotoxicity. Our findings highlight the efficacy of the sequence radiation â cisplatin in reducing cell proliferation and in inducing apoptosis in melanoma cell lines. This sequence also modulated a network of proteins involved in DNA damage repair.
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Antineoplásicos/farmacología , Quimioradioterapia/métodos , Cisplatino/farmacología , Melanoma/patología , Neoplasias Cutáneas/patología , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Quimioradioterapia/efectos adversos , Cisplatino/toxicidad , Ensayo Cometa , Daño del ADN , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Esquema de Medicación , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Humanos , Concentración 50 Inhibidora , Melanoma/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias Cutáneas/genética , Factores de TiempoRESUMEN
Advanced prostate cancers, initially sensitive to androgen deprivation therapy, frequently progress to the castration-resistant prostate cancer phenotype (CRPC) through mechanisms not yet fully understood. In this study we investigated mitochondrial involvement in the establishment of refractoriness to hormone therapy. Two human prostate cancer cell lines were used, the parental LNCaP and the resistant LNCaP-Rbic, the latter generated after continuous exposure to 20 µM of (R)-bicalutamide, the active enantiomer of Casodex®. We observed a significant decrease in mtDNA content and a lower expression of 8 mitochondria-encoded gene transcripts involved in respiratory chain complexes in both cell lines. We also found that (R)-bicalutamide differentially modulated dynamin-related protein (Drp-1) expression in LNCaP and LNCaP-Rbic cells. These data seem to indicate that the androgen-independent phenotype in our experimental model was due, at least in part, to alterations in mitochondrial dynamics and to a breakdown in the Drp-1-mediated mitochondrial network.
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Anilidas/farmacología , Genoma Mitocondrial/genética , Nitrilos/farmacología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Compuestos de Tosilo/farmacología , Andrógenos/farmacología , Animales , Células COS , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Células Clonales , ADN Mitocondrial/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Dinaminas , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Dinámicas Mitocondriales/efectos de los fármacos , Dinámicas Mitocondriales/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Neoplasias de la Próstata/ultraestructura , Transcripción Genética/efectos de los fármacosRESUMEN
There are no validated predictors of benefit from anthracyclines. We compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF), and epirubicin in different sequences with CMF alone in a phase III trial on operable breast cancers. Outcomes were analyzed in relation to tumor biological profiles to identify potential predictors of the efficacy of different treatments/drug combinations. Patients with N- or 1-3N+ tumors, were randomized to receive (a) epirubicin (4 cycles) followed by CMF (4 cycles); (b) CMF (4 cycles) followed by epirubicin (4 cycles), or (c) CMF (6 cycles) alone. Immunohistochemical assessments of estrogen (ER) and progesterone (PgR) receptors, HER2 and Ki67 were available for 705 patients (arm A/B/C: 276/269/160). Prognostic and predictive relevance was analyzed by log-rank tests and Cox models. Ki67 > 20 % and absent/low expression of ER and PgR were associated with worsen disease-free (DFS) and overall survival (OS). In patients with triple negative tumors (ER-, PgR-, HER2-), epirubicin-containing regimens yielded better DFS (HR 0.33, 95 % CI 0.17-0.62, P = 0.0007) and OS (HR 0.24, 95 % CI 0.10-0.57, P = 0.001) compared with CMF alone, whereas no differences were found in patients with HER2-positive (HER2+, ER-, PgR-) subtype. Treatment by subtype interaction (HER2-positive vs. others) was significant for DFS (χ (2) = 6.72, P = 0.009). In triple unfavorable (ER-, PgR-, Ki67 > 20 %) tumors, the use of epirubicin yielded better DFS (HR 0.45,95 % CI 0.26-0.78, P = 0.005) and OS (HR 0.30, 95 % CI 0.15-0.63, P = 0.001). Epirubicin-containing regimens seem to be superior to CMF alone in patients with highly proliferating, triple negative or triple unfavorable tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/biosíntesis , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Inmunohistoquímica , Antígeno Ki-67/biosíntesis , Metotrexato/administración & dosificación , Persona de Mediana Edad , Receptor ErbB-2/biosíntesis , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/biosíntesisRESUMEN
BACKGROUND: Although non muscle invasive bladder cancer (NMIBC) generally has a good long-term prognosis, up to 80% of patients will nevertheless experience local recurrence after the primary tumor resection. The search for markers capable of accurately identifying patients at high risk of recurrence is ongoing. We retrospectively evaluated the methylation status of a panel of 24 tumor suppressor genes (TIMP3, APC, CDKN2A, MLH1, ATM, RARB, CDKN2B, HIC1, CHFR, BRCA1, CASP8, CDKN1B, PTEN, BRCA2, CD44, RASSF1, DAPK1, FHIT, VHL, ESR1, TP73, IGSF4, GSTP1 and CDH13) in primary lesions to obtain information about their role in predicting local recurrence in NMIBC. METHODS: Formaldehyde-fixed paraffin-embedded (FFPE) samples from 74 patients operated on for bladder cancer were analyzed by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA): 36 patients had relapsed and 38 were disease-free at the 5-year follow up. Methylation status was considered as a dichotomous variable and genes showing methylation ≥20% were defined as "positive". RESULTS: Methylation frequencies were higher in non recurring than recurring tumors. A statistically significant difference was observed for HIC1 (P = 0.03), GSTP1 (P = 0.02) and RASSF1 (P = 0.03). The combination of the three genes showed 78% sensitivity and 66% specificity in identifying recurrent patients, with an overall accuracy of 72%. CONCLUSIONS: Our preliminary data suggest a potential role of HIC1, GSTP1 and RASSF1 in predicting local recurrence in NMIBC. Such information could help clinicians to identify patients at high risk of recurrence who require close monitoring during follow up.
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Metilación de ADN , Recurrencia Local de Neoplasia/genética , Neoplasias de la Vejiga Urinaria/genética , Anciano , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , Técnicas de Amplificación de Ácido Nucleico/métodos , Pronóstico , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Although two-dimensional (2-D) monolayer cell cultures provide important information on basic tumor biology and radiobiology, they are not representative of the complexity of three-dimensional (3-D) solid tumors. In particular, new models reproducing clinical conditions as closely as possible are needed for radiobiological studies to provide information that can be translated from bench to bedside. METHODS: We developed a novel system for the irradiation, under sterile conditions, of 3-D tumor spheroids, the in vitro model considered as a bridge between the complex architectural organization of in vivo tumors and the very simple one of in vitro monolayer cell cultures. The system exploits the same equipment as that used for patient treatments, without the need for dedicated and highly expensive instruments. To mimic the passage of radiation beams through human tissues before they reach the target tumor mass, 96-multiwell plates containing the multicellular tumor spheroids (MCTS) are inserted into a custom-built phantom made of plexiglass, the material most similar to water, the main component of human tissue. RESULTS: The system was used to irradiate CAEP- and A549-derived MCTS, pre-treated or not with 20 µM cisplatin, with a dose of 20 Gy delivered in one session. We also tested the same treatment schemes on monolayer CAEP and A549 cells. Our preliminary results indicated a significant increment in radiotoxicity 20 days after the end of irradiation in the CAEP spheroids pre-treated with cisplatin compared to those treated with cisplatin or irradiation alone. Conversely, the effect of the radio- chemotherapy combination in A549-derived MCTS was similar to that induced by cisplatin or irradiation alone. Finally, the 20 Gy dose did not affect cell survival in monolayer CAEP and A549 cells, whereas cisplatin or cisplatin plus radiation caused 100% cell death, regardless of the type of cell line used. CONCLUSIONS: We set up a system for the irradiation, under sterile conditions, of tumor cells grown in 3-D which allows for the use of the same dose intensities and schedules utilized in clinical practice. This irradiation system, coupled with 3-D cell cultures, has the potential to generate information that could be used to individually tailor radiotherapy.
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Técnicas de Cultivo de Célula/métodos , Radioterapia/métodos , Esferoides Celulares/patología , Esferoides Celulares/efectos de la radiación , Animales , Reactores Biológicos , Línea Celular Tumoral , Supervivencia Celular , Células Cultivadas , Cisplatino/administración & dosificación , Fraccionamiento de la Dosis de Radiación , Humanos , Inmunohistoquímica , Modelos Lineales , Microscopía Electrónica de Transmisión , Radiobiología/métodos , Radiometría/métodos , Proyectos de Investigación , Células Tumorales CultivadasRESUMEN
BACKGROUND: The release of DNA into peripheral blood is a common event in cancer patients, occurring as a consequence of necrotic and apoptotic processes typical of tumor cells. However, free circulating DNA (fcDNA) is also present in patients with benign diseases and in healthy individuals. Both quantitative and qualitative aspects of fcDNA have been studied as potential biomarkers in a number of tumor types. In particular, quantitative analysis of fcDNA has been shown to play an important role in the diagnosis of non-small cell lung cancer (NSCLC), because of its ability to discriminate between healthy subjects and individuals with NSCLC. Additionally, fcDNA in cancer patients derives predominantly from tumor tissue and, as such, it can be used for the molecular characterization of the primary tumor. Targeted therapies in NSCLC have, in recent years, produced promising results, highlighting the importance of molecular profiling of the primary cancer lesions. Considering that little or no tumor material is available for at least some of the patients, the possibility of using fcDNA for molecular analysis becomes increasingly important. In the present review we evaluated several quantitative and qualitative aspects of fcDNA that could be instrumental for the differential diagnosis of lung disease. CONCLUSIONS: There is ample evidence in the literature to support the possible use of peripheral blood-derived fcDNA in the early diagnosis and molecular characterization of lung cancer. This non-invasive method may also turn out to be valuable in monitoring drug response and in identifying induced mechanisms of drug resistance. Before it can be implemented in routine clinical practice, however, additional efforts are needed to standardize the methodology.
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Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , ADN de Neoplasias/sangre , Neoplasias Pulmonares/sangre , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , ADN de Neoplasias/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mutación , Sensibilidad y EspecificidadRESUMEN
PURPOSE: The increasing use of breast-conserving surgery makes it essential to identify biofunctional profiles responsible for the progression of in situ to invasive carcinomas to facilitate the detection of lesions that are most likely to relapse or progress and, thus, to be able to offer patients tailored treatment options. Our objective was to analyse and compare biofunctional profiles in ductal carcinomas in situ (DCIS) and invasive ductal carcinomas (IDC). We also aimed to identify markers in tumor and normal surrounding tissues that may be predictive of locoregional recurrence in patients with DCIS. METHODS: Biofunctional parameters including mitotic activity, estrogen receptor, progesterone receptor, microvessel density (MVD), c-kit and p27 expression were evaluated in 829 in situ and invasive carcinomas. The impact of the biomarker profiles of DCIS, IDC and normal surrounding tissues on loco-regional recurrence was analyzed. RESULTS: A progressive increase in cell proliferation and a concomitant decrease in steroid hormone receptor-positive lesions was observed during the transition from in situ to invasive carcinomas, as also within each subgroup as grade increased. Conversely, p27 expression and MVD dramatically decreased during the transition from in situ to invasive carcinomas. Finally, we found that a low c-kit expression was indicative of IDC relapse. CONCLUSIONS: Cell proliferation, hormonal and differentiation characteristics differed in DCIS with respect to IDC, and the main variation in the transition between the two histologic lesions was the decrease in p27 expression and MVD.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal no Infiltrante/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/terapia , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/terapia , Línea Celular Tumoral , Proliferación Celular , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Recurrencia Local de Neoplasia , Neovascularización Patológica/patología , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Pronóstico , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
Lung cancer is often diagnosed at an advanced stage, with subsequently poor prognosis. There are no biomarkers available to facilitate early diagnosis or to discriminate between benign and malignant nodules. MicroRNAs (miRNAs) are stable molecules that can be found and measured in peripheral blood, thus representing potential diagnostic biomarkers. We evaluated 100 individuals comprising 86 patients with predominantly early-stage non-small cell lung cancer (NSCLC) and 24 healthy donors. RNA was extracted from peripheral blood samples and the expression of a panel of miRNAs was analyzed by Real-Time PCR method. Expression levels of miR-328, miR-18a, miR-339 and miR-140 were significantly higher in NSCLC patients than in healthy donors (p < 0.05). In particular, miR-328 showed good diagnostic accuracy in discriminating between patients with early NSCLC and healthy donors (AUC ROC 0.82, 95% CI 0.72-0.92), with 70% sensitivity and 83% specificity at the best relative expression cut-off of 300. Moreover, miR-339 was a good discriminant between healthy donors and late-stage NSCLC patients (AUC ROC 0.79, 95% CI 0.68-0.91). In conclusion, miR-328 represents a potential diagnostic biomarker of NSCLC, especially for the identification of early-stage tumors. Its role in discriminating between benign and malignant nodules detected by spiral CT warrants further investigation.
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Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Detección Precoz del Cáncer/métodos , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , MicroARNs/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/diagnóstico , Masculino , MicroARNs/sangre , Persona de Mediana Edad , Curva ROC , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The present study investigated whether tumor markers such as cell proliferation and steroid receptor status, which have been shown to have relevance for important endpoints (relapse-free and overall survival), can also predict axillary disease in elderly patients with breast cancer. We evaluated 351 consecutive elderly women with breast cancer ≥70 years of age with estrogen receptor (ER)positive tumors with no palpable axillary nodes, for whom information on cell proliferation determined by the 3H-thymidine labeling index (TLI) and progesterone receptor (PgR) was available. Patients underwent quadrantectomy (70.1%) or quadrantectomy plus radiotherapy (29.9%) without axillary node dissection, followed by adjuvant tamoxifen for at least 2 years. Univariable (cumulative incidence curves) and multivariable analyses (Fine and Gray models) were carried out. After a median follow-up of 16 years, ipsilateral axillary relapse was not related to PgR status but was strongly associated with tumor cell proliferation in both small (pT1) and large (pT2-4b) tumors. Axillary relapse cumulative incidence increased from 1% in patients with low-TLI (≤3%), PgR-positive and pT1 tumors to a maximum of 20% in patients with high-TLI, PgR-negative and pT2-4b tumors. Tumor cell proliferation, determined by TLI at primary surgery, is an important predictor of axillary relapse in elderly ER-positive breast cancer patients and could help to identify patients who should undergo axillary surgery.
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Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/secundario , Proliferación Celular , Ganglios Linfáticos/patología , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/uso terapéutico , Axila , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/epidemiología , Carcinoma Ductal de Mama/terapia , Quimioterapia Adyuvante , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Metástasis Linfática , Curva ROC , Tamoxifeno/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Non-invasive early detection of lung cancer could reduce the number of patients diagnosed with advanced disease, which is associated with a poor prognosis. We analyzed the diagnostic accuracy of a panel of peripheral blood markers in detecting non small cell lung cancer (NSCLC). METHODS: 100 healthy donors and 100 patients with NSCLC were enrolled onto this study. Free circulating DNA, circulating mRNA expression of peptidylarginine deiminase type 4 (PAD4/PADI4), pro-platelet basic protein (PPBP) and haptoglobin were evaluated using a Real-Time PCR-based method. RESULTS: Free circulating DNA, PADI4, PPBP and haptoglobin levels were significantly higher in NSCLC patients than in healthy donors (p<0.0001, p<0.0001, p=0.0002 and p=0.0001, respectively). The fitted logistic regression model demonstrated a significant direct association between marker expression and lung cancer risk. The odds ratios of individual markers were 6.93 (95% CI 4.15-11.58; p<0.0001) for free DNA, 6.99 (95% CI 3.75-13.03; p<0.0001) for PADI4, 2.85 (95% CI 1.71-4.75; p<0.0001) for PPBP and 1.16 (95% CI 1.01-1.33; p=0.031) for haptoglobin. Free DNA in combination with PPBP and PADI4 gave an area under the ROC curve of 0.93, 95% CI=0.90-0.97, with sensitivity and specificity over 90%. CONCLUSIONS: Free circulating DNA analysis combined with PPBP and PADI4 expression determination appears to accurately discriminate between healthy donors and NSCLC patients. This non-invasive multimarker approach warrants further research to assess its potential role in the diagnostic or screening workup of subjects with suspected lung cancer.
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Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Neoplasias Pulmonares/sangre , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Circulating cell-free DNA has been recognized as an accurate marker for the diagnosis of prostate cancer, whereas the role of urine cell-free DNA (UCF DNA) has never been evaluated in this setting. It is known that normal apoptotic cells produce highly fragmented DNA while cancer cells release longer DNA. We thus verified the potential role of UCF DNA integrity for early prostate cancer diagnosis. UCF DNA was isolated from 29 prostate cancer patients and 25 healthy volunteers. Sequences longer than 250 bp (c-Myc, BCAS1, and HER2) were quantified by real-time PCR to verify UCF DNA integrity. Receiver operating characteristic (ROC) curve analysis revealed an area under the curve of 0.7959 (95% CI 0.6729-0.9188). At the best cut-off value of 0.04 ng/µL, UCF DNA integrity analysis showed a sensitivity of 0.79 (95% CI 0.62-0.90) and a specificity of 0.84 (95% CI 0.65-0.94). These preliminary findings indicate that UCF DNA integrity could be a promising noninvasive marker for the early diagnosis of prostate cancer and pave the way for further research into this area.
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ADN/orina , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/orina , Anciano , Biomarcadores de Tumor/orina , Estudios de Casos y Controles , Sistema Libre de Células , Detección Precoz del Cáncer , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Antígeno Prostático Específico/metabolismo , Curva ROC , Reacción en Cadena en Tiempo Real de la Polimerasa , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Análisis de Secuencia de ADNRESUMEN
UNLABELLED: Peritoneal carcinomatosis (PC) is observed in approximately 10% of patients with colorectal cancer at the time of primary cancer resection. Most of these patients receive 5-fluorouracil (5-FU)- or oxaliplatin-containing chemotherapy regimens as first-, second-, or third-line treatment. In the present study, sensitivity and resistance to drugs used to treat PC were better defined by a conventional chemosensitivity test than by biomarker expression. BACKGROUND: 5-Fluorouracil- or oxaliplatin-based regimens are the treatments of choice in patients with PC from colon cancer. There are currently no useful preclinical evaluations to guide the decision-making process for tailored therapy. The aim of the present study was to compare the advantages and limits of a conventional in vitro chemosensitivity test with those of a panel of biomolecular markers in predicting clinical response to different drugs used to treat colon cancer-derived PC. PATIENTS AND METHODS: Fresh surgical biopsy specimens were obtained from 28 patients with peritoneal carcinomatosis from colon cancer. TS, TP, DPD, MDR1, MRP-1, MGMT, BRCA1, ERCC1, GSTP1, and XPD gene expression levels were determined by real-time reverse transcription polymerase chain reaction. An in vitro chemosensitivity test was used to define a sensitivity or resistance profile to the drugs used to treat each patient. RESULTS: Expression levels of the genes analyzed were generally poorly related to each other. TS and ERCC1 expression was inversely related to response to 5-FU-and/or oxaliplatin-containing regimens. Significant predictivity in terms of sensitivity but poor predictivity of resistance (56.2%) (P=.037) were observed for ERCC1 expression (90%), and high predictivity of resistance (100%) but very low predictivity of sensitivity (40%) (P=.014) were registered for TS. The best overall and significant predictivity was observed for chemosensitivity test results (62.5% sensitivity and 89% resistance; P=.005). CONCLUSIONS: Sensitivity and resistance to drugs used in vivo was better defined by the chemosensitivity test than by biomarker expression.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias del Colon/patología , Regulación Neoplásica de la Expresión Génica , Neoplasias Peritoneales/tratamiento farmacológico , Adulto , Anciano , Biomarcadores de Tumor/genética , Toma de Decisiones , Resistencia a Antineoplásicos , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/secundario , Valor Predictivo de las Pruebas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: Urine cell-free (UCF) DNA has recently been proposed as a potential marker for early bladder cancer diagnosis. It is known that normal apoptotic cells produce highly fragmented DNA while cancer cells release longer DNA. Therefore, we verified the potential role of UCF DNA integrity in early bladder cancer diagnosis. MATERIALS AND METHODS: UCF DNA was isolated from 51 bladder cancer patients, 46 symptomatic patients, and 32 healthy volunteers. To verify UCF DNA integrity, sequences longer than 250 bp, c-Myc, BCAS1, and HER2, were quantified by real time PCR. RESULTS: At the best cutoff value of 0.1 ng/µl, UCF DNA integrity analysis showed a sensitivity of 0.73 (95% CI 0.61-0.85), and a specificity of 0.84 (95% CI 0.71-0.97) in healthy individuals and 0.83 (95% CI 0.72-0.94) in symptomatic patients. Receiver operating characteristic (ROC) curve analysis revealed an area under the curve of 0.834 (95% CI 0.739-0.930) for healthy individuals and 0.796 (95% CI 0.707-0.885) for symptomatic patients. CONCLUSIONS: These preliminary data suggest that UCF DNA integrity is a potentially good marker for early noninvasive diagnosis of bladder cancer. Its diagnostic performance does not seem to vary significantly, even in an "at risk" population of symptomatic individuals.
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Biomarcadores de Tumor/orina , ADN/orina , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/orina , Anciano , Biomarcadores de Tumor/genética , ADN/genética , Detección Precoz del Cáncer , Femenino , Humanos , Masculino , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-myc/genética , Curva ROC , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor ErbB-2/genética , Valores de Referencia , Espectrofotometría , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
BACKGROUND: Melanoma radioresistance has been attributed to the presence of tumor cells with highly efficient DNA damage repair mechanisms. We examined the expression of genes involved in DNA damage repair and DNA damage sensing, and assessed their modulation by SLUG silencing, which is potentially capable of increasing radiosensitivity. METHODS: Two melanoma cell lines (M14 and M79) were used to evaluate in vitro radiation-induced cytotoxicity before and after SLUG silencing. mRNA expression levels of BRCA1, ERCC1, DNA-PK, PARP, MGMT, ATM and TGM2 were determined by real-time RT-PCR, and protein expression levels of SLUG, caspase 3, p21, PUMA and pMAPK by Western blotting. RESULTS: The cytotoxic effect of radiation was high in M14 and low in M79 cells. SLUG silencing increased the interference of radiation on cell cycle distribution and cell killing by 60 % and 80 % in M79 cells after a 2.4 Gy and 5 Gy radiation dose, respectively. It also led to a significant inhibition of expression of genes involved in DNA damage repair and DNA damage sensing in all cell lines maintained after radiation. An almost total inhibition was observed for TGM2, which is expressed at a high basal level in the most radioresistant cell line (M79). Protein expression of PUMA was induced by radiation and was enhanced after SLUG silencing. CONCLUSIONS: Our results reveal a pivotal role of SLUG in regulating a cellular network involved in the response to DNA damage, and highlight the importance of TGM2 in radiosensitivity modulation. SLUG silencing appears to increase radiation sensitivity of the melanoma cells tested.
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Ciclo Celular/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Interferencia de ARN , Factores de Transcripción/genética , Apoptosis/genética , Apoptosis/efectos de la radiación , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Western Blotting , Ciclo Celular/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Supervivencia Celular/efectos de la radiación , Daño del ADN/genética , Relación Dosis-Respuesta en la Radiación , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Factores de Transcripción de la Familia Snail , Factores de Tiempo , Factores de Transcripción/metabolismoAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja Fina , Broncoscopía , Carcinoma de Pulmón de Células no Pequeñas/genética , Biología Celular , Femenino , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas p21(ras)RESUMEN
Telomerase, a fundamental marker of neoplastic transformation, is widely expressed in both premalignant intraepithelial lesions and in most malignant lesions of the uterine cervix. We determined telomerase activity (TA) in uterine cervix by Repeat Amplification Protocol (TRAP) in a series of 62 cases, 44 with benign diseases (inflammation and/or metaplasia and/or acanthosis) and 18 with cervical intraepithelial neoplasia (CIN). No significant differences in TA were observed between benign lesions (median AEU value 36, range 0-119) and CIN (median AEU value 30, range 0-65). Conversely, TA was significantly higher in subjects who showed CIN evolution (65 range 45-119) than in disease-free individuals (34 range 0-95, ρ = 0.017) and in 1 patient with a CIN2 lesion who relapsed after 5 years. Our results suggest that TA of the uterine cervix is capable of predicting CIN evolution or relapse, thus indicating its potential usefulness as a prognostic marker in clinical surveillance programs.
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Cuello del Útero/enzimología , Cuello del Útero/patología , Telomerasa/metabolismo , Displasia del Cuello del Útero/enzimología , Displasia del Cuello del Útero/patología , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/patología , Adulto , Femenino , Humanos , Persona de Mediana Edad , Curva ROC , Resultado del TratamientoRESUMEN
Lung cancer is the leading cause of cancer mortality worldwide and despite efforts made to improve clinical results, continuing poor survival rates indicate that novel therapeutic approaches are needed. Valproic acid (VPA), a short-chain branched fatty acid used mainly for the treatment of epilepsy and bipolar disorder, has been shown to inhibit class I histone deacetylases (HDAC-I), a group of enzymes involved in chromatin remodeling and which are thought to play a role in tumor development. Although evidence of VPA's therapeutic efficacy has also been observed in patients with solid tumors, the very high concentration required to induce antitumor activity limits its clinical usefulness. We used a panel of NSCLC cell lines to evaluate the activity and mechanisms of action of organosulfur valproic acid derivatives, a promising new class of compounds designed to improve the safety and efficacy of the valproic acid molecule and created by coupling it with a hydrogen sulfide (H(2) S)-releasing moiety. Our results highlighted the increased cytotoxic activity of the novel organosulfur derivatives, ACS33 and ACS2, with respect to VPA, starting from low concentrations. In particular, ACS2 exhibited important pro-apoptotic activity triggered by the mitochondrial pathway and also showed anti-invasion potential. Furthermore, our in vitro results identified a highly effective combination schedule of ACS2 and cisplatin capable of inducing a synergistic interaction even when the two drugs were used at low concentrations, which could prove a valid alternative to traditional chemotherapeutic regimens used for advanced lung cancer. Further studies are needed to confirm these preliminary findings.