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BACKGROUND: Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy. METHODS: In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%. RESULTS: Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified. CONCLUSIONS: Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).
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Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/genética , Receptores ErbB/antagonistas & inhibidores , Genes ras , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Fluorouracilo/uso terapéutico , GTP Fosfohidrolasas/genética , Humanos , Leucovorina/uso terapéutico , Proteínas de la Membrana/genética , Mutación , Metástasis de la Neoplasia , Compuestos Organoplatinos/uso terapéutico , Panitumumab , Proteínas Proto-Oncogénicas p21(ras)RESUMEN
Pathologic complete response after neoadjuvant systemic treatment appears to be a valid surrogate for better overall survival in breast cancer patients. Currently, together with standard clinicopathologic assessment, novel molecular biomarkers are being exhaustively tested in order to look into the heterogeneity of breast cancer. The aim of our study was to examine an association between 23-gene real-time-PCR expression assay including ABCB1, ABCC1, BAX, BBC3, BCL2, CASP3, CYP2D6, ERCC1, FOXC1, GAPDH, IGF1R, IRF1, MAP2, MAPK 8, MAPK9, MKI67, MMP9, NCOA3, PARP1, PIK3CA, TGFB3, TOP2A, and YWHAZ receptor status of breast cancer core biopsies sampled before neoadjuvant chemotherapy (anthracycline and taxanes) and pathologic response. Core-needle biopsies were collected from 42 female patients with inoperable locally advanced breast cancer or resectable tumors suitable for downstaging, before any treatment. Expressions of 23 genes were determined by means of TagMan low density arrays. Analysis of variance was used to select genes with discriminatory potential between receptor subtypes. We introduced a correction for false discovery rates (presented as q values) due to multiple hypothesis testing. Statistical analysis showed that seven genes out of a 23-gene real-time-PCR expression assay differed significantly in relation to pathologic response regardless of breast cancer subtypes. Among these genes, we identified: BAX (p = 0.0146), CYP2D6 (p = 0.0063), ERCC1 (p = 0.0231), FOXC1 (p = 0.0048), IRF1 (p = 0.0022), MAP2 (p = 0.0011), and MKI67 (p = 0.0332). The assessment of core biopsy gene profiles and receptor-based subtypes, before neoadjuvant therapy seems to predict response or resistance and to define new signaling pathways to provide more powerful classifiers in breast cancer, hence the need for further research.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Antraciclinas/uso terapéutico , Biomarcadores de Tumor/genética , Quimioterapia Adyuvante , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Terapia Neoadyuvante , Receptor ErbB-2/genética , Taxoides/uso terapéutico , Resultado del TratamientoRESUMEN
Non-melanoma skin cancers (NMSCs) are the most common malignancies diagnosed in Caucasian populations. Basal cell carcinoma (BCC) is the most frequent skin cancer, followed by squamous cell carcinoma (SCC). Unfortunately, most European cancer registries do not record individual types of NMSC. To evaluate the incidence of primary BCCs and SCCs regarding age, sex, tumour site and tumour subtype to determine trends in epidemiology of both cancers. Retrospective analysis of BCCs and SCCs diagnosed and treated across seven sites in Poland from 1999 to 2019. We recorded 13,913 NMSCs occurring in 10,083 patients. BCC represented 85.2% of all cases. SCC patients were older than BCC patients (77.1 ± 11.3 years vs. 70.1 ± 12.3 years, p < 0.01). The nodular subtype was the most common subtype of BCC, followed by the superficial and infiltrative subtypes. The superficial BCC subtype was more common on photoprotected areas (p < 0.01), whereas the nodular BCC subtype occurred on the face (p < 0.01). The high-risk SCC subtypes were more common on face compared to low-risk SCC subtypes (p < 0.01). BCC and SCC are common malignancies developing at various ages and anatomical sites. These data underline the need for better registration policies regarding NMSC in order to improve prevention and treatment strategies for these tumours.
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Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Polonia/epidemiología , Vigilancia en Salud Pública , Sistema de Registros , Factores Sexuales , Neoplasias Cutáneas/etiología , Adulto JovenRESUMEN
Basosquamous carcinoma (BSC) is a rare non-melanoma skin cancer that shares the characteristic features of both basal and squamous cell carcinomas (BCC, SCC). Our research enables better characterization of BSC in comparison to high-risk subtypes of BCC and SCC. Paper includes a retrospective analysis of BSC cases regarding sex, age, number of tumors and anatomical distribution in comparison to BCC and SCC evaluating the differences and defining the implications. Histologically confirmed carcinomas recorded between 1999 and 2019 were studied. 181 diagnosed BSC cases were identified, making this study the largest cohorts of BSC patients reported worldwide. Most cases were reported on head and neck. Analysis of facial anatomic distribution shows that most commonly affected sites were the nose (43%) and the cheek (25%). The age at excision of metatypical BCC was higher than those of low-risk BCC (P < 0.05), however similar to high-risk BCC (P = 0.20). We revisited that the concept of BSC is the most similar to high-risk subtypes of BCC. Patients with diagnosed BSC have higher risk of second nonmelanoma skin cancer. Therefore, the frequency of follow-up examination should be adjusted to the individual risk of another skin cancer.
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Carcinoma Basocelular/epidemiología , Carcinoma Basoescamoso/epidemiología , Carcinoma de Células Escamosas/epidemiología , Neoplasias Cutáneas/epidemiología , Anciano , Carcinoma Basocelular/patología , Carcinoma Basoescamoso/patología , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Riesgo , Neoplasias Cutáneas/patologíaRESUMEN
PURPOSE: Single-agent oral chemotherapy is widely used in patients with bone metastases without visceral involvement, especially in hormone receptor-positive metastatic breast cancer (mBC). However, this option has been poorly evaluated in clinical trials. METHODS: Eligible patients had mBC with predominantly bone but not visceral metastases, were receiving bisphosphonate therapy, and had previously received endocrine therapy (any setting) but not chemotherapy for mBC. Patients received oral vinorelbine 60 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (escalating to 80 mg/m2 from cycle 2 in the absence of grade 3/4 toxicity) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included clinical benefit rate (complete/partial response or ≥24 weeks' stable disease), overall survival, and safety. RESULTS: Seventy patients were treated for a median of 6 cycles (range 1-18). Most (73%) continued treatment until disease progression. After 43 months' median follow-up, median PFS was 8.2 months (95% confidence interval [CI], 5.5-9.8). The clinical benefit rate was 56% (95% CI, 43%-68%). Median overall survival was 35.2 months (95% CI, 26.8-47.1). The most common grade 3/4 adverse event was neutropenia (38% of patients); febrile neutropenia was absent. The most common grade 1/2 adverse events were bone pain, fatigue, and gastrointestinal toxicities. Alopecia was infrequent. CONCLUSIONS: In patients with hormone receptor-positive mBC, bone disease, and prior endocrine therapy, first-line oral vinorelbine chemotherapy demonstrated long PFS and good tolerability. In this setting, it could be considered as an active oral alternative to intravenous chemotherapy.
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Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Vinorelbina/uso terapéutico , Administración Oral , Adulto , Anciano , Neoplasias Óseas/secundario , Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neutropenia Febril Inducida por Quimioterapia/epidemiología , Neutropenia Febril Inducida por Quimioterapia/etiología , Progresión de la Enfermedad , Fatiga/inducido químicamente , Fatiga/epidemiología , Femenino , Humanos , Persona de Mediana Edad , Supervivencia sin Progresión , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Resultado del TratamientoRESUMEN
The cell's susceptibility to mutagens and its ability to repair DNA lesions are important for cancer induction, promotion and progression. Both the mutagens' sensitivity and the efficacy of DNA repair may be affected by variation in several genes, including DNA repair genes. The hOGG1 gene encodes glycosylase of base excision repair and RAD51 specifies a key protein in homologues recombination repair. Both can be involved in the repair of oxidative DNA lesions, which can contribute to stomach cancer. In the present work we determined the level of basal and oxidative DNA damage and the kinetics of removal of DNA damage induced by hydrogen peroxide in peripheral blood lymphocytes of 30 gastric cancer patients and 30 healthy individuals. The metrics from DNA damage and repair study were correlated with the genotypes of common polymorphisms of the hOGG1 and RAD51 genes: a G-->C transversion at 1245 position of the hOGG1 gene producing a Ser-->Cys substitution at the codon 326 (the Ser326Cys polymorphism) and a G-->C substitution at position 135 (5'-untranslated region) of the RAD51 gene (the G135C polymorphism). DNA damage and repair were evaluated by alkaline single cell gel electrophoresis (comet assay) assisted by DNA repair enzymes: endonuclease III (Nth) and formamidopyrimidine-DNA glycosylase (Fpg), preferentially recognizing oxidized DNA bases. The genotypes of the polymorphism were determined by restriction fragment length polymorphism PCR. We observed a strong association between gastric cancer occurrence, impaired DNA repair in human lymphocytes and the G/C genotype of the G135C polymorphism of the RAD51 gene. Moreover, there was a strong correlation between that genotype and stomach cancer occurrence in subjects with high level of oxidatively damaged DNA. We did not observe any correlation between the Ser1245Cys polymorphism of the hOGG1 gene and gastric cancer, including subjects with impaired DNA repair and/or high levels of endogenous oxidative DNA lesions. Therefore, our result suggest that the G135C polymorphism of the RAD51 gene may be linked with gastric cancer by the modulation of the cellular response to oxidative stress and this polymorphism may be a useful additional marker in this disease along with the genetic or/and environmental indicators of oxidative stress.
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Daño del ADN/genética , ADN Glicosilasas/genética , Reparación del ADN/genética , Polimorfismo Genético/genética , Recombinasa Rad51/genética , Neoplasias Gástricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Ensayo Cometa , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Peróxido de Hidrógeno/farmacología , Linfocitos/citología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , Neoplasias Gástricas/sangreRESUMEN
PURPOSE: This open label phase II study evaluated the safety and efficacy of vinflunine in patients with breast cancer previously treated with a vinorelbine-based regimen and who progressed during or within 6 months of completing this chemotherapy. PATIENTS AND METHODS: Thirty eight patients received vinflunine 320 mg/m(2) once every 3 weeks. The primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: ORR was 8.3% (95% CI: 1.75-22.4) and DCR was 75% (95% CI: 57.8-87.9). PFS was 4.0 months (95% CI: 2.5-6.1) and OS was 13.6 months (95% CI: 8.7-18.9). Toxicities not hampering dose intensity were as expected neutropenia (75.6% of patients), fatigue (44.7%), constipation (28.9%) and abdominal pain (26.3%). CONCLUSION: Vinflunine demonstrated antitumour activity and can be safely administered in breast cancer patients refractory/resistant to vinorelbine.
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Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Vinblastina/análogos & derivados , Adulto , Anciano , Antineoplásicos Fitogénicos/efectos adversos , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Persona de Mediana Edad , Estudios Prospectivos , Tasa de Supervivencia , Insuficiencia del Tratamiento , Resultado del Tratamiento , Vinblastina/efectos adversos , Vinblastina/uso terapéutico , VinorelbinaRESUMEN
PURPOSE: Metastatic breast cancer (MBC) remains an incurable illness in the majority of cases, despite major therapeutic advances. This may be related to the ability of breast tumors to induce neoangiogenesis, even in the face of cytotoxic chemotherapy. Sunitinib, an inhibitor of key molecules involved in neoangiogenesis, has an established role in the treatment of metastatic renal cell and other cancers and demonstrated activity in a phase II trial in MBC. We performed a randomized phase III trial comparing sunitinib plus capecitabine (2,000 mg/m2) with single-agent capecitabine (2,500 mg/m2) in patients with heavily pretreated MBC. PATIENTS AND METHODS: Eligibility criteria included MBC, prior therapy with anthracyclines and taxanes, one or two prior chemotherapy regimens for metastatic disease or early relapse after a taxane plus anthracycline adjuvant regimen, and adequate organ function and performance status. The primary end point was progression-free survival, for which the study had 90% power to detect a 50% improvement (from 4 to 6 months). RESULTS: A total of 442 patients were randomly assigned. Progression-free survival was not significantly different between the treatment arms, with medians of 5.5 months (95% CI, 4.5 to 6.0) for the sunitinib plus capecitabine arm and 5.9 months (95% CI, 5.4 to 7.6) for the capecitabine monotherapy arm (hazard ratio, 1.22; 95% CI, 0.95 to 1.58; one-sided P = .941). There were no significant differences in response rate or overall survival. Toxicity, except for hand-foot syndrome, was more severe in the combination arm. CONCLUSION: The addition of sunitinib to capecitabine does not improve the clinical outcome of patients with MBC pretreated with anthracyclines and taxanes.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Prospectivos , Pirroles/administración & dosificación , Pirroles/efectos adversos , Sunitinib , Adulto JovenRESUMEN
INTRODUCTION: Pathologic complete response (pCR) after neoadjuvant systemic treatment for inoperable locally advanced breast cancer is defined as complete microscopic disappearance of invasive cancer in both the breast and axilla in the postoperative specimen. The aim of the study was to characterize the groups of younger (≤ 40 years old) and older (≥ 70 years old) breast cancer patients who achieved a pCR. MATERIAL AND METHODS: One hundred thirty-eight consecutive patients aged between 30 and 78 years with locally advanced breast cancer, operated on after neoadjuvant systemic treatment between November 2007 and June 2010, were analyzed. In this group 9 women (6.5%) were 40 years of age or younger, and 12 patients (8.7%) were 70 years of age or older. RESULTS: In the younger group, pCR was achieved in 1 patient with triple negative, invasive ductal breast cancer, G3, BRCA 1 mutation, treated with cisplatin. A near pCR was achieved in 2 other patients, with triple negative, invasive ductal breast cancer, G3, treated with AT. The pCR in the breast was found in a HER2 positive patient. In older patients, pCR was achieved in 2 patients with triple negative, invasive ductal breast cancer, G3, treated with AT or FEC. Pathologic complete response in the axilla was achieved in 1 patient with triple negative, ductal carcinoma. The pCR rates were significantly higher in triple negative breast cancer in both groups (p = 0.047 and p = 0.018, respectively). CONCLUSIONS: Pathologic complete response was significantly associated with receptor- based subtypes in both young and old women.
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PURPOSE: The phase III, randomized, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study found that erlotinib maintenance therapy extended progression-free survival (PFS) and overall survival in patients with advanced non-small-cell lung cancer (NSCLC) who had nonprogressive disease following first-line platinum-doublet chemotherapy. This study included prospective analysis of the prognostic and predictive value of several biomarkers. PATIENTS AND METHODS: Mandatory diagnostic tumor specimens were collected before initiating first-line chemotherapy and were tested for epidermal growth factor receptor (EGFR) protein expression by using immunohistochemistry (IHC), EGFR gene copy number by using fluorescent in situ hybridization (FISH), and EGFR and KRAS mutations by using DNA sequencing. An EGFR CA simple sequence repeat in intron 1 (CA-SSR1) polymorphism was evaluated in blood. RESULTS: All 889 randomly assigned patients provided tumor samples. EGFR IHC, EGFR FISH, KRAS mutation, and EGFR CA-SSR1 repeat length status were not predictive for erlotinib efficacy. A profound predictive effect on PFS of erlotinib relative to placebo was observed in the EGFR mutation-positive subgroup (hazard ratio [HR], 0.10; P < .001). Significant PFS benefits were also observed with erlotinib in the wild-type EGFR subgroup (HR, 0.78; P = .0185). KRAS mutation status was a significant negative prognostic factor for PFS. CONCLUSION: This large prospective biomarker study found that patients with activating EGFR mutations derive the greatest PFS benefit from erlotinib maintenance therapy. No other biomarkers were predictive for outcomes with erlotinib, although the study was not powered for clinical outcomes in biomarker subgroups other than EGFR IHC-positive [corrected]. KRAS mutations were prognostic for reduced PFS. The study demonstrated the feasibility of prospective tissue collection for biomarker analyses in NSCLC.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Mutación , Proteínas Proto-Oncogénicas/genética , Quinazolinas/uso terapéutico , Proteínas ras/genética , Adulto , Anciano , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , ADN de Neoplasias/análisis , Supervivencia sin Enfermedad , Esquema de Medicación , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib , Estudios de Factibilidad , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo Genético , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Quinazolinas/administración & dosificación , Análisis de Secuencia de ADN , Proteínas ras/metabolismoRESUMEN
PURPOSE: Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. PATIENTS AND METHODS: In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. RESULTS: KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. CONCLUSION: This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.
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Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Regulación Neoplásica de la Expresión Génica , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Panitumumab , Valor Predictivo de las Pruebas , Estudios Prospectivos , Proteínas Proto-Oncogénicas p21(ras) , Resultado del TratamientoRESUMEN
PURPOSE: Combination of intravenous (i.v.) vinorelbine and docetaxel was shown to be feasible and effective in metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated in first-line treatment a regimen alternating i.v. and oral vinorelbine in combination with docetaxel. PATIENTS AND METHODS: Forty-nine patients (median age, 53 years) with MBC received a maximum of 6 cycles consisting of i.v. vinorelbine 20 mg/m(2) plus docetaxel 60 mg/m(2) given on day 1, and oral vinorelbine 60 mg/m(2) on day 15 every 3 weeks in an open-label, multicentre phase II study (recommended dose established in phase I study [1]). RESULTS: Sixty-three percent of the patient had received prior adjuvant chemotherapy and 78% presented visceral involvement. Twenty-four responses were documented and validated by an independent panel review, yielding response rates of 49% (95% CI: 34-64) in the 49 enrolled patients and 55.8% (95% CI: 40-71) in the 43 evaluable patients. Median duration of response was 9.4 months. Median progression-free survival and median overall survival were 5.5 and 33.2 months, respectively. Neutropenia was the main dose-limiting toxicity but complications were uncommon, four patients having experienced febrile neutropenia and one having developed neutropenic infection. Other frequently reported adverse events included alopecia, fatigue, stomatitis, constipation, diarrhoea and nausea, which were rarely severe. CONCLUSIONS: This regimen alternating oral and i.v. vinorelbine in combination with docetaxel is effective and manageable. Vinorelbine i.v. per oral day 1 per day 15-docetaxel day 1 every 3 weeks represents a convenient option to combine docetaxel and vinorelbine for the palliative treatment of MBC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/secundario , Administración Oral , Adulto , Anciano , Neoplasias de la Mama/patología , Docetaxel , Femenino , Humanos , Inyecciones Intravenosas , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia , Taxoides/administración & dosificación , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , VinorelbinaRESUMEN
BACKGROUND: Doxorubicin and pemetrexed have both shown single-agent activity in breast cancer. Preclinical and clinical evidence indicates that a combination of the 2 agents might have an additive or synergistic effect. A phase II trial was initiated to assess the antitumor activity and safety of pemetrexed plus doxorubicin in women with advanced breast cancer. PATIENTS AND METHODS: Anthracycline-naive patients with advanced breast cancer received doxorubicin 50 mg/m(2) plus pemetrexed 500 mg/m(2) (both intravenously) on day 1 of 21-day cycles, as first-line therapy, with standard vitamin supplementation. Seventy-nine women were enrolled (median age, 55.3 years). Seventy-six patients (96.2%) had an Eastern Cooperative Oncology Group performance status of < or = 1. RESULTS: At baseline, 35 patients (44.3%) had visceral metastases. Three (4.2%) patients were HER2/neu positive, and 30 (42.3%) patients were HER2/ neu negative. The objective response rate was 55.7% (95% exact CI, 44.1%-66.9%), including 2 (2.5%) complete responses. Median progression-free survival was 8 months (95% CI, 6.5-13.3 months). Two-year survival rate was 61.7% (95% CI, 49.7%-71.6%). Grade 3/4 drug-related toxicities in > or = 10% patients included neutropenia (24.1%) and leukopenia (10.1%). CONCLUSION: In patients with advanced breast cancer, the combination of doxorubicin plus pemetrexed was well tolerated and showed promising antitumor activity that warrants further study.
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Antibióticos Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Glutamatos/administración & dosificación , Guanina/análogos & derivados , Adulto , Anciano , Antibióticos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Doxorrubicina/efectos adversos , Esquema de Medicación , Inhibidores Enzimáticos/efectos adversos , Femenino , Glutamatos/efectos adversos , Guanina/administración & dosificación , Guanina/efectos adversos , Humanos , Persona de Mediana Edad , Pemetrexed , Factores de Tiempo , Resultado del TratamientoRESUMEN
Tamoxifen (TAM) is a non-steroidal anti-estrogen used widely in the treatment and chemoprevention of breast cancer. TAM treatment can lead to DNA damage, but the mechanism of this process is not fully understood and the experimental data are often inconclusive. We compared the DNA-damaging potential of TAM in normal human peripheral blood lymphocytes and MCF-7 breast cancer cells by using the comet assay. In order to assess whether oxidative DNA damage may contribute to TAM-induced lesions, we employed two DNA repair enzymes: endonuclease III (Endo III) and formamidopyrimidine-DNA glycosylase (Fpg). The kinetics of repair of DNA damage was also measured. In order to evaluate the involvement of free radicals in the genotoxicity of TAM we pre-treated the cells with nitrone spin traps: DMPO and POBN. The use of common antioxidants: vitamin C, amifostine and genistein, helped to assess the contribution of free radicals. TAM damaged DNA in both normal and cancer cells, inducing mainly DNA strand breaks but not alkali-labile sites. The drug at 5 and 10 microM induced DNA double strand breaks (DSBs) in lymphocytes and at 10 microM in MCF-7 cells. We observed complete repair of DSBs in cancer cells by contrast with incomplete repair of these lesions in lymphocytes. In both types of cells TAM induced oxidized purines and pyrimidines. Incubation of the cells with nitrone spin traps and antioxidants decreased, with exception of amifostine in MCF-7 cells, the extents of DNA damage in both kinds of cells, but the results were more distinct in cancer cells. Our results indicate that TAM can be genotoxic for normal and cancer cells by free radicals generation. It seems to have a higher genotoxic potential for normal cells, which can be the result of incomplete repair of DNA DSBs. Free radicals scavengers can modulate TAM-induced DNA damage interfering with its antitumour activity in cancer cells.
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Neoplasias de la Mama/tratamiento farmacológico , Daño del ADN , ADN/efectos de los fármacos , Moduladores de los Receptores de Estrógeno/toxicidad , Linfocitos/efectos de los fármacos , Mutágenos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Tamoxifeno/toxicidad , Adulto , Amifostina/farmacología , Ácido Ascórbico/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayo Cometa/métodos , ADN/metabolismo , Roturas del ADN de Doble Cadena , Roturas del ADN de Cadena Simple , Reparación del ADN/efectos de los fármacos , ADN-Formamidopirimidina Glicosilasa/metabolismo , Relación Dosis-Respuesta a Droga , Endodesoxirribonucleasas/metabolismo , Femenino , Depuradores de Radicales Libres/farmacología , Genisteína/farmacología , Humanos , Concentración de Iones de Hidrógeno , Cinética , Linfocitos/metabolismo , Masculino , Especies Reactivas de Oxígeno/metabolismoRESUMEN
PURPOSE: The purpose of this study was to assess humoral response to influenza vaccine in patients (pts) with non-Hodgkin lymphoma (NHL) as compared to healthy subjects (ctrl). PATIENTS AND METHODS: In two epidemic seasons, 2003/2004 and 2004/2005, 163 pts and 92 ctrl were vaccinated. Antibody titers to hemagglutinin (HA) and neuraminidase (NA) were measured in serum samples collected before vaccination, and 1 and 6 months apart. Changes in antibody titers were assessed by comparing geometric mean titers (GMT), mean fold increases (MFI), and seroprotection and seroresponse rates to baseline values. RESULTS: Pts vaccinated in 2003/2004 had, after 1 month, increase in GMT by a factor of 8.64-26.60 for antihemagglutinin antibodies (HI) and 6.93-12.66 for antineuraminidase antibodies (NI), as compared to factor of 9.12-24.41 for HI and 4.83-10.31 for NI in ctrl. At 1 month after vaccination, seroprotection and seroresponse rates were similar in both groups, ranging from 68.42 to 84.21% and 71.93 to 94.74% in NHL, and 66.67-82.22% and 62.22-86.67% in ctrl, respectively. Pts vaccinated in 2004/2005 had increase in the GMT by a factor of 38.76-41.49 for HI and 26.59-30.31 for NI, as compared to factor of 81.19-104.32 for HI and 52.16-54.52 for NI in ctrl. Seroprotection and seroresponse rates were lower in the former group, ranging from 62.11 to 65.26% and 74.47 to 77.66%, respectively. In both seasons, pts achieved titres of antibodies greater than the protective threshold, irrespective of the previous chemotherapy administration. CONCLUSIONS: The results indicate that influenza vaccination induces sufficient immune response in pts with NHL, irrespective of previous chemotherapy.