Natural and orthogonal interaction framework for modeling gene-environment interactions with application to lung cancer.

OBJECTIVES: We aimed at extending the Natural and Orthogonal Interaction (NOIA) framework, developed for modeling gene-gene interactions in the analysis of quantitative traits, to allow for reduced genetic models, dichotomous traits, and gene-environment interactions. We evaluate the performance of the NOIA statistical models using simulated data and lung cancer data. METHODS: The NOIA statistical models are developed for additive, dominant, and recessive genetic models as well as for a binary environmental exposure. Using the Kronecker product rule, a NOIA statistical model is built to model gene-environment interactions. By treating the genotypic values as the logarithm of odds, the NOIA statistical models are extended to the analysis of case-control data. RESULTS: Our simulations showed that power for testing associations while allowing for interaction using the NOIA statistical model is much higher than using functional models for most of the scenarios we simulated. When applied to lung cancer data, much smaller p values were obtained using the NOIA statistical model for either the main effects or the SNP-smoking interactions for some of the SNPs tested. CONCLUSION: The NOIA statistical models are usually more powerful than the functional models in detecting main effects and interaction effects for both quantitative traits and binary traits.

[Detection of specific T cells for 264-272 and 149-157 peptides of p53 protein in peripheral blood of patients with breast cancer]. / Detección de linfocitos T citotóxicos contra los epítopos 264-272 y 149-157 de la proteína p53 en sangre periférica de pacientes con cáncer de mama.

BACKGROUND AND OBJECTIVE: p53 protein is overexpressed in nearly half of all human tumours. An HLA-A2.1-restricted immunological response mediated by anti-p53 CD8+ T cells directed against the wild type p53 264-272 epitope has been demonstrated in patients with head and neck squamous carcinomas. The existence of such a response in patients with other cancer types could be determinant for the development of specific antitumour vaccines targeting the p53 protein. We aimed to determine the presence of anti-p53 specific CD8+ T cells in peripheral blood of breast cancer patients in vivo. PATIENTS AND METHOD: p53 264-272-specific CD8+ T cells were directly enumerated in the peripheral circulation of patients with breast cancer using tetrameric p53 264-272/HLA-A2.1 complexes by multicolor flow cytometry. The same procedure was used to enumerate T cells specific for another HLA-A2.1 restricted wild type p53 epitope, p53 (149-157). RESULTS: The 99th percentile of the concentration of anti-p53 cells in 6 HLA A2- breast cancer patients was 1/5634 (cut-off point). The median counts of anti-p53264-272 and anti-p53149-157 lymphocytes in 14 HLA A2.1+ patients were 1/2383 and 1/2335 respectively. All of the HLA A2+ patients had concentrations of anti-p53 lymphocytes above the cut-off point for at least one of the epitopes: 13/14 (93%) for p53(264-272) and 11/12 (92%) for p53(149-157). CONCLUSIONS: A specific immunological response mediated by anti-p53 CD8+ T cells has been detected in patients with breast carcinoma. More studies are needed to confirm these results and to determine its usefulness for the development of p53-based vaccines.

Results of a pilot trial of immunotherapy with dendritic cells pulsed with autologous tumor lysates in patients with advanced cancer.

AIMS AND BACKGROUND: The purpose of the study was to test the immunological and clinical effects of infusions of dendritic cells pulsed with autologous tumor lysate in patients with advanced cancer. PATIENTS AND METHODS: Peripheral blood mononuclear cells from 15 patients with metastatic cancer (melanoma in 10, lung cancer in 2, renal cell carcinoma in 1, sarcoma in 1, breast cancer in 1) were harvested by leukapheresis after mobilization with GM-CSF (5 microg/kg/day s.c. for 4 days). Mononuclear cells were separated and cultured in GM-CSF (1000 U/ml) and interleukin-4 (1000 U/ml) for 7 days. Phenotype was assessed by 2-color flow cytometry and immunocytochemistry. On day 6, dendritic cells were pulsed with 1 g of fresh autologous tumor lysate for 24 h and infused intravenously. Interleukin-2 (6 million IU), interferon a (4 million IU) and GM-CSF (400 microg) were injected s.c. daily for 10 days beginning on the day of dendritic cell infusion. Treatment was repeated every 21 days for 3 courses. RESULTS: The morphology, immunocytochemistry and phenotype of cultured cells was consistent with dendritic cells: intense positivity for HLA-DR and CD86, with negativity for markers of other lineages, including CD3, CD4, CD8 and CD14. More than 5 x 10(7) dendritic cells were injected in all patients. Nine patients developed >5 mm delayed type cutaneous hypersensitivity reactions to tumor lysate+/-GM-CSF after the first immunization (larger than GM-CSF in all cases). Median delayed type cutaneous hypersensitivity to lysate +/- GM-CSF was 3 cm after the third immunization. One melanoma patient with skin, liver, lung and bone metastases had a partial response lasting 8 months (followed by progression in the brain). Seven patients had stable disease for >3 months, and 7 had progression. CONCLUSIONS: Infusion of tumor lysate-pulsed dendritic cells induces a strong cell-mediated antitumor immune reaction in patients with advanced cancer and has some clinical activity.

Spinal Cord Injury due to Tumour or Metastasis in Aragón, Northeastern Spain (1991-2008): Incidence, Time Trends, and Neurological Function.

PURPOSE: Understanding the presentation of spinal cord injury (SCI) due to tumours considering population distribution and temporal trends is key to managing SCI health services. This study quantified incidence rates, function scores, and trends of SCI due to tumour or metastasis over an 18-year time period in a defined region in Spain. METHODS: A retrospective cohort study included in-and outpatients with nontraumatic SCI due to tumour or metastasis admitted to a metropolitan hospital in Spain between 1991 and 2008. Main outcome measures were crude and age- and sex-adjusted incidence rates, tumour location and type, distribution by spinal level, neurological level of injury, and impairment ASIA scores. RESULTS: Primary tumour or metastasis accounted for 32.5% of nontraumatic SCI with an incidence rate of 4.1 per million population. Increasing rates with age and over time were observed. Major pathology groups were intradural-extramedullary masses from which meningiomas and neurinomas accounted for 40%. Lesions were mostly incomplete with predominant ASIA Grade D. CONCLUSIONS: Increasing incidence rates of tumour-related SCI over time in the middle-aged and the elderly suggest a growing need for neurooncology health resources in the future.

Serum endostatin and bFGF as predictive factors in advanced breast cancer patients treated with letrozole.

INTRODUCTION: To investigate the value of baseline serum levels of VEGF, bFGF, endostatin and their ratio as predictive factors of response to endocrine therapy in patients with metastatic breast cancer (MBC) and positive ER treated with letrozole after tamoxifen failure. MATERIALS AND METHOD: The serum levels of endostatin, VEGF and bFGF were determined in postmenopausal patients with progressing MBC from serum samples obtained before initiation of letrozole. The relation between serum angiogenic factor levels and TTP was investigated. RESULTS: Seventy-six patients (45.2%) presented a high endostatin level (> 24.6 ng/ml), 40% low bFGF levels (0 pg/ml) and 50.4% low VEGF (=/< 187 ng/ml). With a median follow-up of 22 months, the median TTP was 12.3 months. Median TTP was worse in patients with high endostatin concentration as well as in the low bFGF group, but was not affected when VEGF was considered. When the two factors were combined, the median TTP of patients with endostatin > 24.6 ng/ml and bFGF equal 0 pg/ml was 9.5 months versus 19.5 months in patients with endostatin =/< 24.6 ng/ml and bFGF > 0 pg/ml. CONCLUSIONS: The baseline levels of bFGF and endostatin are predictive factors of efficacy in patients with MBC treated with letrozole and can select groups with different TTP.

Gemcitabine/capecitabine in patients with metastatic breast cancer pretreated with anthracyclines and taxanes.

PURPOSE: Gemcitabine and capecitabine are 2 anticancer drugs with a mechanism of action involving metabolism of pyrimidine nucleotides. Both are among the few agents active in patients with metastatic breast cancer (MBC) progressing after therapy with anthracyclines and taxanes. We have conducted a phase II trial of gemcitabine/capecitabine in patients with disease progression after treatment with anthracyclines and taxanes. PATIENTS AND METHODS: Treatment included gemcitabine 2000 mg/m2 on day 1 every 3 weeks and capecitabine 2500 mg/m2 daily (divided into 2 doses) on days 1-14 every 3 weeks; treatment was administered until disease progression or unacceptable toxicity was documented. All patients received concomitant oral pyridoxine 300 mg twice daily to prevent hand-foot syndrome (HFS). Of 39 patients treated, 33 had received previous treatment with anthracyclines, 6 had medical contraindication to anthracyclines, 35 had previously received taxanes, and 23 had received vinorelbine. Fourteen patients had previous high-dose chemotherapy with stem cell rescue and 5 had previously received trastuzumab. Patients were 31-79 years of age (median, 55 years) and, altogether, were given 386 courses of therapy (range, 1-36 courses per patient; median, 6 courses). RESULTS: Grade 3/4 toxicities included HFS (11 courses, 6 patients), stomatitis (6 courses, 2 patients), diarrhea (5 courses, 4 patients), anemia (5 courses, 2 patients), thrombocytopenia (5 courses, 2 patients), and neutropenia (1 course, 1 patient). Response rate (all 39 patients were evaluable) was 48.7% (partial response, n = 19; stable disease, n = 7; progressive disease, n = 13). Thirty-six patients died because of disease progression, and 3 are alive with progressive disease. Median follow-up was 26 months or until death. Median duration of response was 15 months (range, 3-26 months). Median time to disease progression was 5 months (range, 1-26 months). Median overall survival duration was 10 months (range, 1-37 months). CONCLUSION: In this cohort of patients heavily pretreated with anthracyclines and taxanes, the response rate to gemcitabine/capecitabine is encouraging, although response duration is limited.

Advances in cutaneous melanoma.

After several decades of slow progress in the field of melanoma, significant advances have been reported in recent years. These include a better understanding of the molecular biology of the tumour, a new staging classification system, insights into the patterns of relapse in early stage, and new drugs for the treatment of advanced disease. Ipilimumab and vemurafenib have just been approved and provide a survival benefit in stage IV. Both compounds are under evaluation in the adjuvant setting, where interferon remains the only drug with proven efficacy. Further investigation is required to treat patients with primary or secondary resistance to new drugs.

Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium.

BACKGROUND: Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies. METHODS: Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided. RESULTS: Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, P(trend) = 2 x 10(-26)), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, P(trend) = 1 x 10(-10)) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, P(trend) = 5 x 10(-8)) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, P(trend) = 2 x 10(-5); rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, P(trend) = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer. CONCLUSIONS: In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.

Retrospective cost analysis of management of febrile neutropenia in cancer patients in Spain.

BACKGROUND: Febrile neutropenia (FN) is associated with disruption of planned chemotherapy and increased management costs. However, the economic impact of FN in Spanish clinical practice has not been documented hitherto. RESEARCH DESIGN AND METHODS: A multicenter, retrospective chart review of adults with breast or lung cancer or non-Hodgkin's lymphoma (NHL) who had > or = 1 FN episode during chemotherapy. Resource use, direct costs, and FN effect on planned chemotherapy were assessed. MAIN OUTCOME MEASURES: 238 episodes of FN were analyzed in 194 patients. The mean + or - SD length of FN-related hospitalization was 8.7 + or - 6.9 days (median [p(25)-p(75)] = 7 [5-11] days). At least one transfusion was needed in 77 (32.3%) FN episodes, blood tests were done in 233 (97.9%) and blood cultures in 207 (87.0%). Antibiotics were used in all episodes (100%), other drugs in 186 (78.2%) episodes and the granulocyte colony-stimulating factor (G-CSF) in 161 (67.7%) episodes. The distribution of costs per episode of FN were: hospitalization 79%, antibiotics 10%, G-CSF 5%, complementary tests 4%; other drugs 1%, blood transfusions 1%. The estimated mean (95% CI) cost per FN episode was euro3841 (95% CI: euro3476-4206). FN management was costlier in NHL patients euro4514 (95% CI: euro3805-5223) than in breast or lung cancer patients (euro3519 [95% CI: euro2976-4061] and euro3311 [95% CI: euro2817-3805] respectively) (P < 0.05 both comparisons). Planned chemotherapy was disrupted in 139 (58.4%) episodes (dose reductions in 75 [34.9%], dose delays in 60 [28.0%] and withdrawal in 33 [14.7%]). CONCLUSIONS: FN substantially affects healthcare resource use and costs in breast cancer, lung cancer and, NHL. In this study, hospitalization and antibiotics were the main drivers of cost. A limitation of the analysis was that it did not include the indirect costs associated with FN episodes.

Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer.

PURPOSE: Patients with metastatic breast cancer who are pretreated with anthracyclines frequently receive taxane-based combinations. This phase III study compared the efficacy and safety of gemcitabine-docetaxel (GD) with capecitabine-docetaxel (CD) in advanced breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to GD (G 1,000 mg/m(2) days 1 and 8; D 75 mg/m(2) day 1) or CD (C 1,250 mg/m(2) twice daily days 1 through 14; D 75 mg/m(2) day 1) every 21 days. Comparison of progression-free survival (PFS) was the primary objective. RESULTS: Patient characteristics were balanced between arms (N = 305). Median PFS was 8.05 months (95% CI, 6.60 to 8.71) for GD and 7.98 (95% CI, 6.93 to 8.77) for CD (log-rank P = .121). Overall response rate (ORR) was 32% in both arms, and overall survival (OS) was not different between arms (P = .983). Time to treatment failure (TTF; defined as discontinuation, progressive disease, death as a result of any cause, or the start of a new anticancer therapy) was superior in the GD arm (P = .059). Hematologic toxicity was similar in both arms, except for grades 3 to 4 leukopenia (GD, 78%; CD, 66%; P = .025) and transfusions (GD, 17%; CD, 7%; P = .0051). Grades 3 to 4 diarrhea, mucositis, and hand-and-foot syndrome were significantly higher in the CD arm. Fewer patients in the GD arm discontinued because of drug-related adverse events (13% v 27% in CD; P = .002). CONCLUSION: No difference was observed between GD and CD arms in PFS, ORR, and OS. TTF was longer in the GD arm. These findings, combined with a nonhematologic toxicity profile that favors GD over approved doses of CD, suggest that gemcitabine may be a better option than capecitabine in combination with docetaxel in this clinical setting.

Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer.

We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 x 10(-10) and the allelic odds ratio was 1.15 (95% confidence interval 1.10-1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.

Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by Paclitaxel for early breast cancer.

BACKGROUND: Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting. METHODS: After breast cancer surgery, women with lymph node-positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study-5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided. RESULTS: Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment. CONCLUSIONS: Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy.

A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer.

PURPOSE: Increased epidermal growth factor receptor (EGFR) expression may promote breast cancer resistance to endocrine therapy. We have therefore investigated whether neoadjuvant gefitinib, an EGFR inhibitor, might overcome biologic and clinical resistance to neoadjuvant anastrozole in a phase II placebo-controlled trial. PATIENTS AND METHODS: Postmenopausal women with stage I to IIIB hormone receptor-positive early breast cancer received anastrozole 1 mg daily for 16 weeks and were randomly assigned at a ratio of 2:5:5 to receive, in addition, gefitinib 250 mg/d orally for 16 weeks: placebo 1 tablet/d orally for 2 weeks and then gefitinib for 14 weeks or placebo for 16 weeks. The primary end point was biologic change in proliferation as measured by Ki67 at 2 and 16 weeks; the main secondary end point was overall objective response (OR). RESULTS: Two hundred six women were randomly assigned. Mean changes in Ki67 with anastrozole and gefitinib versus anastrozole alone were -77.4% and -83.6%, respectively, between baseline and 16 weeks (geometric mean ratio = 1.37; 95% CI, 0.79 to 2.39; P = .26), -80.1% and -71.3% between baseline and 2 weeks (geometric mean ratio = 0.70; 95% CI, 0.39 to 1.25; P = .22) and -19.3% and -43% (geometric mean ratio = 1.42; 95% CI, 0.86 to 2.35; P = .16) between 2 and 16 weeks. ORs in the combination and anastrozole alone groups were 48% and 61% (estimated difference = -13.1%; 95% CI, -27.3% to 1.2%), respectively, with a nonsignificant trend against the combination (P = .08) and 48% versus 72% (estimated difference = -24.1%; 95% CI, -45.3% to -2.9%) in the progesterone-receptor-positive subgroup, which was significant (P = .03) and consistent with Ki67 changes. Common treatment-related adverse events included diarrhea, rash, alopecia, dry skin, and nausea. There was no evidence of a pharmacokinetic interaction. CONCLUSION: Addition of gefitinib to neoadjuvant anastrozole had no additional clinical or biologic effect, failing to support our original hypothesis.

Detección de linfocitos T citotóxicos contra los epítopos 264-272 y 149-157 de la proteína p53 en sangre periférica de pacientes con cáncer de mama / Detection of specific T cells for 264-272 and 149-157 peptides of p53 protein in peripheral blood of patients with breast cancer

FUNDAMENTO Y OBJETIVO: La proteína p53 está sobreexpresada en la mitad de los tumores humanos.Se ha descrito que se produce una respuesta inmunológica específica mediada por linfocitosT citotóxicos dirigidos contra el epítopo 264-272 de p53 en pacientes con cáncer de cabezay cuello. Demostrar que se produce ese tipo de respuesta en otros tumores podría serdeterminante para el desarrollo de vacunas antitumorales específicas anti-p53. El objetivo deeste estudio fue demostrar in vivo la existencia de linfocitos T citotóxicos específicos anti-p53en sangre periférica de pacientes con cáncer de mama.PACIENTES Y MÉTODO: Se realizó la determinación mediante citometría de flujo del recuento delinfocitos T citotóxicos específicos dirigidos contra los epítopos HLA A2 restringidos 264-272 y149-147 de la proteína p53 en sangre periférica de pacientes con cáncer de mama.RESULTADOS: El percentil 99 de la concentración de células T anti-p53 en los pacientes conHLA A2.1 negativo fue 1/5.634 (punto de corte). En los pacientes con HLA A2 positivo, la medianade linfocitos anti-p53264-272 fue de 1/2.383 y la de linfocitos anti-p53149-157, de 1/2.335.Todos los pacientes con HLA A2 positivo presentaron recuentos de linfocitos anti-p53 por encimadel punto de corte para al menos uno de los 2 epítopos: 13/14 (93%) para p53264-272 y11/12 (92%) para p53149-157.CONCLUSIONES: Ha sido posible demostrar in vivo que hay una respuesta inmunológica específicamediada por linfocitos T citotóxicos anti-p53 en pacientes con cáncer de mama. Son necesariosfuturos estudios para confirmar estos resultados y determinar su utilidad para el diseño y eldesarrollo de vacunas dirigidas contra la proteína p53

BACKGROUND AND OBJECTIVE: p53 protein is overexpresed in nearly half of all human tumours. AnHLA-A2.1-restricted immunological response mediated by anti-p53 CD8+ T cells directedagainst the wild type p53 264-272 epitope has been demonstrated in patients with head andneck squamous carcinomas. The existence of such a response in patients with other cancer typescould be determinant for the development of specific antitumour vaccines targeting thep53 protein. We aimed to determine the presence of anti-p53 specific CD8+ T cells in peripheralblood of breast cancer patients in vivo.PATIENTS AND METHOD: p53 264-272-specific CD8+ T cells were directly enumerated in the peripheralcirculation of patients with breast cancer using tetrameric p53 264-272/HLA-A2.1complexes by multicolor flow cytometry. The same procedure was used to enumerate T cellsspecific for another HLA-A2.1 restricted wild type p53 epitope, p53 (149-157).RESULTS: The 99th percentile of the concentration of anti-p53 cells in 6 HLA A2– breast cancerpatients was 1/5634 (cut-off point). The median counts of anti-p53264-272 and anti-p53149-157lymphocytes in 14 HLA A2.1+ patients were 1/2383 and 1/2335 respectively. All of the HLAA2+ patients had concentrations of anti-p53 lymphocytes above the cut-off point for at leastone of the epitopes: 13/14 (93%) for p53264-272 and 11/12 (92%) for p53149-157.CONCLUSIONS: A specific immunological response mediated by anti-p53 CD8+ T cells has beendetected in patients with breast carcinoma. More studies are needed to confirm these resultsand to determine its usefulness for the development of p53-based vaccines

Serum endostatin and bFGF as predictive factors in advanced breast cancer patients treated with letrozole

Introduction. To investigate the value of baselineserum levels of VEGF, bFGF, endostatin and theirratio as predictive factors of response to endocrinetherapy in patients with metastatic breast cancer(MBC) and positive ER treated with letrozole aftertamoxifen failure.Materials and method. The serum levels of endostatin,VEGF and bFGF were determined in postmenopausalpatients with progressing MBC fromserum samples obtained before initiation of letrozole.The relation between serum angiogenic factorlevels and TTP was investigated.Results. Seventy-six patients (45.2%) presented ahigh endostatin level (> 24.6 ng/ml), 40% low bFGFlevels (0 pg/ml) and 50.4% low VEGF ( 24.6 ng/ml and bFGF equal 0 pg/mlwas 9.5 months versus 19.5 months in patients withendostatin 0 pg/ml.Conclusions. The baseline levels of bFGF and endostatinare predictive factors of efficacy in patientswith MBC treated with letrozole and can selectgroups with different TTP

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