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BACKGROUND: The prognostic effect of tumour budding was retrospectively analysed in a cohort of 173 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the prospective clinical multicentre CONKO-001 trial. METHODS: Haematoxylin and eosin (H&E)-stained whole tissue slides were evaluated. In two independent approaches, the mean number of tumour buds was analysed according to the consensus criteria in colorectal cancer, in one 0.785 mm2 field of view and additionally in 10 high-power fields (HPF) (HPF = 0.238 mm2). RESULTS: Tumour budding was significantly associated with a higher tumour grade (p < 0.001) but not with distant or lymph node metastasis. Regardless of the quantification approach, an increased number of tumour buds was significantly associated with reduced disease-free survival (DFS) and overall survival (OS) (10 HPF approach DFS: HR = 1.056 (95% CI 1.022-1.092), p = 0.001; OS: HR = 1.052 (95% CI 1.018-1.087), p = 0.002; consensus method DFS: HR = 1.037 (95% CI 1.017-1.058), p < 0.001; OS: HR = 1.040 (95% CI 1.019-1.061), p < 0.001). Recently published cut-offs for tumour budding in colorectal cancer were prognostic in PDAC as well. CONCLUSIONS: Tumour budding is prognostic in the CONKO-001 clinical cohort of patients. Further standardisation and validation in additional clinical cohorts are necessary.
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Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Carga TumoralRESUMEN
PURPOSE: First-line therapy options in advanced cholangiocarcinoma (CCA) are based on the ABC-02 trial regimen (gemcitabine/cisplatin [G/C]). The NIFE trial examined nanoliposomal irinotecan/fluorouracil/leucovorin (nal-IRI/FU/LV) as alternative first-line therapy in advanced CCA. METHODS: NIFE is a prospective, open-label, randomized, multicenter phase II study that aimed at detecting efficacy comparable with the standard treatment. Patients with advanced CCA were randomly assigned (1:1) to receive nal-IRI/FU/LV (arm A) or G/C (arm B). Stratification parameters were intrahepatic versus extrahepatic CCA, sex, and Eastern Cooperative Oncology Group (ECOG; 0/1). Arm A was designed as a Simon's optimal two-stage design and arm B served as a randomized control group. The primary goal was to exclude an inferior progression-free survival (PFS) at 4 months of only 40%, while assuming a rate of 60% on G/C population. RESULTS: Between 2018 and 2020, overall 91 patients were randomly assigned to receive nal-IRI/FU/LV (n = 49) or G/C (n = 42). The NIFE trial formally met its primary end point with a 4-month PFS rate of 51% in patients receiving nal-IRI/FU/LV. The median PFS was 6 months (2.4-9.6) in arm A and 6.9 months (2.5-7.9) in arm B. Median overall survival (OS) was 15.9 months (10.6-20.3) in arm A and 13.6 months (6.5-17.7) in arm B. The exploratory comparison of study arms suggested a numerical but statistically not significant advantage for nal-IRI/FU/LV (hazard ratio for PFS, 0.85 [95% CI, 0.53 to 1.38] and for OS, 0.94 [95% CI, 0.58 to 1.50]). Analysis for stratification parameters revealed no differences for sex and ECOG, but for tumor localization. The objective response rate was 24.5% with nal-IRI/FU/LV and 11.9% with G/C. No unexpected toxicities occurred. AEs related to nal-IRI/FU/LV were mainly GI and to G/C hematologic. CONCLUSION: Treatment of advanced CCA with nal-IRI/FU/LV demonstrated efficacy in first-line therapy without new safety findings and merits further validation.
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BACKGROUND: Long-term survival (LTS) in patients (pts) with pancreatic cancer is still uncommon, little data is available to identify long-term survivors. The CONKO-001 study, which established gemcitabine after resection as adjuvant therapy, may provide data to answer this question. METHODS: CONKO-001 pts with an overall survival ≥5 years were compared to those who survived <5 years. Central re-evaluation of primary histology was performed. Univariate analysis with the χ(2) -test identified qualifying factors. Logistic regression was used to investigate the influence of these covariates on LTS. RESULTS: Of the evaluable 354 CONKO-001 pts, 54 (15%) with an overall survival ≥5 years were identified. It was possible to obtain tumor specimens of 39 pts (72%). Histological re-evaluation confirmed adenocarcinoma in 38 pts, 1 showed a high-grade neuroendocrine tumor. Univariate analysis for all 53 LTS pts with adenocarcinoma compared to the remaining 300 non-LTS pts revealed as relevant active treatment, tumor grading, tumor size, lymph nodes. No significance could be demonstrated for resection margin, sex, age, Karnofsky performance status, CA 19-9 at study entry. In multivariate analysis, tumor grading, active treatment, tumor size, lymph node involvement were independent prognostic factors for LTS. CONCLUSION: Long-term survival can be achieved in adenocarcinoma of the pancreas.
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Adenocarcinoma/mortalidad , Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Pronóstico , Factores de Riesgo , Factores de Tiempo , GemcitabinaRESUMEN
Purpose: Prognosis of sarcoma patients is improving, with a better understanding of sarcomagenesis revealing novel therapeutic targets. However, aggressive chemotherapy remains an essential part of treatment, bearing the risk of severe side effects that require intensive medical treatment. Available data on the characteristics and clinical outcome of sarcoma patients admitted to intensive care units (ICU) are sparse. Patients and Methods: We performed a retrospective analysis of sarcoma patients admitted to the ICU from 2005 to 2022. Patients ≥18 years with histologically proven sarcoma were included in our study. Results: Sixty-six patients were eligible for analysis. The following characteristics had significant impact on overall survival: sex (p=0.046), tumour localization (p=0.02), therapeutic intention (p=0.02), line of chemotherapy (p<0.001), SAPS II score (p=0.03) and SOFA score (p=0.02). Conclusion: Our study confirms the predictive relevance of established sepsis and performance scores in sarcoma patients. For overall survival, common clinical characteristics are also of significant value. Further investigation is needed to optimize ICU treatment of sarcoma patients.
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BACKGROUND: Primary objective of this present trial was to define the maximum tolerable dose of lapatinib in combination with oxaliplatin, 5-fluorouracil, and folinic acid (OFF) in refractory pancreatic cancer. The secondary objective was to assess the safety and efficacy of lapatinib plus OFF. METHODS: We conducted a phase I trial using an accelerated dose escalation design in patients with refractory pancreatic cancer. Lapatinib was given on days 1 to 42 in combination with folinic acid 200 mg/m2 day + 5-fluorouracil 2000 mg/m2 (24 h) on days 1, 8, 15, and 22, and oxaliplatin 85 mg/m2 days 8 and 22 of a 43-day cycle (OFF). Toxicity and efficacy were evaluated. RESULTS: In total, eighteen patients were enrolled: dose level 1 (1000 mg) was assigned to seven patients, dose level 2 (1250 mg), five patients; and dose level 3 (1500 mg), six patients. Dose-limiting toxicities were diarrhea and/or neutropenic enterocolitis observed in two of six patients: one diarrhea III°, one diarrhea IV°, as well as neutropenic enterocolitis. The maximum tolerable dose of lapatinib was 1250 mg OD. CONCLUSIONS: The combination of lapatinib 1250 mg OD with platinum-containing chemotherapy is safe and feasible in patients with refractory pancreatic cancer and warrants further investigation.
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Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8+ T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC.
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Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Antígenos de Histocompatibilidad Clase I/genética , Neoplasias Pancreáticas/genética , Progranulinas/genética , Escape del Tumor/genética , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Adenocarcinoma/terapia , Animales , Anticuerpos Neutralizantes/farmacología , Antígenos Virales/genética , Antígenos Virales/inmunología , Autofagia/efectos de los fármacos , Autofagia/genética , Autofagia/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/terapia , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Estudios de Cohortes , Citotoxicidad Inmunológica , Expresión Génica , Glicoproteínas/genética , Glicoproteínas/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Virus de la Coriomeningitis Linfocítica/genética , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Progranulinas/antagonistas & inhibidores , Progranulinas/inmunología , Proteolisis , Análisis de Supervivencia , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Proteínas Virales/genética , Proteínas Virales/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) represents one of the most fatal malignancies worldwide. It is suggested that survival in PDAC depends, among other things, on pattern of disease recurrence. PATIENTS AND METHODS: We performed a pooled analysis of the adjuvant therapy studies CONKO-001, CONKO-005, and CONKO-006, including a total of 912 patients with regard to prognostic factors in patients with recurrent disease. Overall survival from disease recurrence (OS 2) and disease-free survival (DFS) from the day of surgery were expressed by Kaplan-Meier method and compared using log-rank testing and Cox regression. RESULTS: Of 912 patients treated within the previously mentioned CONKO trials, we identified 689 patients with disease recurrence and defined site of relapse. In multivariable analysis, the presence of isolated pulmonary metastasis, low tumour grading, and low postoperative level of CA 19-9 remained significant factors for improved OS 2 and DFS. Furthermore, completeness of adjuvant gemcitabine-based treatment (OS 2: P = 0.006), number of relapse sites (OS 2: P = 0.015), and type of palliative first-line treatment (OS 2: P < 0.001) significantly affected overall survival after disease recurrence in PDAC. CONCLUSIONS: Determining tumour subgroups using prognostic factors may be helpful to stratify PDAC patients for future clinical trials. In case of disease recurrence, the site of relapse may have a prognostic impact on subsequent survival. Further investigations are needed to identify differences in tumour biology, reflecting relapse patterns and the differing survival of PDAC patients.
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Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/terapia , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/secundario , Recurrencia Local de Neoplasia , Pancreatectomía , Neoplasias Pancreáticas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Carbohidratos Asociados a Tumores/sangre , Antimetabolitos Antineoplásicos/efectos adversos , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/secundario , Quimioterapia Adyuvante , Bases de Datos Factuales , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Cuidados Paliativos , Pancreatectomía/efectos adversos , Pancreatectomía/mortalidad , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Adulto Joven , GemcitabinaRESUMEN
Upfront KRAS and NRAS gene testing ('RAS') is the standard of care for metastatic colorectal cancer (mCRC), to guide first-line treatment. The presence of RAS mutation (MT) is a negative predictor for the efficacy of anti-EGFR antibodies and the use of cetuximab and panitumumab is restricted to RAS wild-type (WT) mCRC. Conversion from RAS WT to RAS MT mCRC after treatment with anti-EGFR antibodies is a known and well-described acquired resistance mechanism. The by far less frequent 'NeoRAS wild-type' phenomenon (reversion from RAS MT to RAS WT) has recently drawn attention. The proposed effect of chemotherapy on RAS status in mCRC patients is not fully understood. Because of the intriguing biological consequence of a RAS MT to RAS WT reversion, subsequent treatment of NeoRAS WT patients with anti-EGFR antibodies is increasingly being discussed. Here, we report three clinical cases of NeoRAS WT mCRC patients, which received standard-of-care regimens for RAS MT mCRC. Anti-EGFR antibodies were used in two out of three patients after progression of the disease. One of the patients had a long-term response. In line with our observations, NeoRAS WT phenomenon occurs in clinical practice. Retesting of RAS status during treatment should be discussed in patients with unusual long-term clinical courses of RAS MT mCRC to optimise treatment strategy and to evaluate the use of anti-EGFR antibodies.
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ADN Tumoral Circulante/metabolismo , Neoplasias Colorrectales/genética , Proteínas ras/genética , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la NeoplasiaRESUMEN
PURPOSE: We performed next-generation sequencing (NGS) in the CONKO-001 phase III trial to identify clinically relevant prognostic and predictive mutations and conducted a functional validation in The Cancer Genome Atlas (TCGA) sequencing data. EXPERIMENTAL DESIGN: Patients of the CONKO-001 trial received curatively intended surgery for pancreatic adenocarcinoma (PDAC) followed by adjuvant chemotherapy with gemcitabine (Gem) or observation only (Obs). Tissue samples of 101 patients were evaluated by NGS of 37 genes. Cox proportional hazard models were applied for survival analysis. In addition, functional genomic analyses were performed in an NGS and RNA-sequencing dataset of 146 pancreatic tumors from TCGA. RESULTS: The most common mutations in the CONKO cohort were KRAS (75%), TP53 (60%), SMAD4 (10%), CDKNA2 (9%), as well as SWI/SNF (12%) complex alterations. In untreated patients, TP53 mutations were a negative prognostic factor for disease-free survival (DFS; HR mut vs. WT 2.434, P = 0.005). With respect to gemcitabine treatment, TP53 mutations were a positive predictive factor for gemcitabine efficacy [TP53mut: HR for DFS Gem vs. Obs, 0.235 (0.130 - 0.423; P < 0.001); TP53wt: HR for DFS Gem vs. Obs, 0.794 (0.417 - 1.513; P = 0.483)] with a significant test for interaction (P = 0.003). In the TCGA dataset, TP53 mutations were associated with shortened DFS. CONCLUSIONS: In CONKO-001, the benefit from adjuvant gemcitabine was confined to the TP53mut patient group. This potentially clinical relevant observation needs to be confirmed in independent prospective studies. The sensitivity of TP53mut PDAC to gemcitabine in CONKO-001 provides a lead for further mechanistic investigations.
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Carcinoma Ductal Pancreático/terapia , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/genética , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Pancreáticas/terapia , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Quimioterapia Adyuvante/métodos , Ensayos Clínicos Fase III como Asunto , Análisis Mutacional de ADN , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/genética , Pancreatectomía , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , GemcitabinaRESUMEN
BACKGROUND: We studied the prognostic effect of CD3-, CD8- and CD103-positive T lymphocytes in a cohort of 165 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the treatment group (adjuvant gemcitabine) and the untreated control group of the CONKO-001 study. METHODS: Immunohistochemical stainings on tissue microarrays (TMAs) against CD3, CD8 and CD103 were performed according to standard procedures. RESULTS: A high number of CD8-positive lymphocytes were significantly and independently associated with longer disease-free survival (DFS) and overall survival (OS) in the overall study population. Median DFS/OS were 7.4/18.1 months for patients with a low number of CD8-positive intratumoural lymphocytes (≤42 per 1 mm tissue core) and 12.7/25.2 months for patients with high numbers (>42 per 1-mm tissue core; p = 0.008/0.020; HR 0.62/0.65). The ratio of intraepithelial to total CD103-positive lymphocytes, but not total numbers of CD103-positive lymphocytes or CD103-positive intraepithelial lymphocytes, was associated with significantly improved DFS and OS in the overall study population (p = 0.022/0.009). Median DFS/OS was 5.9/15.7 for patients with a ratio of intraepithelial to total CD103-positive intratumoural lymphocytes higher than 0.3 and 11.6/24.7 for patients with a lower ratio. CONCLUSION: T-lymphocyte subpopulations might be prognostic in resectable PDAC but need standardization and verification by further studies.
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Linfocitos T CD8-positivos/inmunología , Carcinoma Ductal Pancreático/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Pancreáticas/inmunología , Linfocitos T Citotóxicos/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/uso terapéutico , Complejo CD3/metabolismo , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/terapia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Integrina beta4/análisis , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Pronóstico , GemcitabinaRESUMEN
Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m2 days 1, 8, 15, every 4 weeks plus erlotinib 100 mg once per day (GemErlo) or gemcitabine (Gem) alone for six cycles. The primary end point of the study was to improve disease-free survival (DFS) from 14 to 18 months by adding erlotinib to gemcitabine. Results In all, 436 patients were randomly assigned at 57 study centers between April 2008 and July 2013. A total of 361 instances (83%) of disease recurrence were observed after a median follow-up of 54 months. Median treatment duration was 22 weeks in both arms. There was no difference in median DFS (GemErlo 11.4 months; Gem 11.4 months) or median overall survival (GemErlo 24.5 months; Gem 26.5 months). There was a trend toward long-term survival in favor of GemErlo (estimated survival after 1, 2, and 5 years for GemErlo was 77%, 53%, and 25% v 79%, 54%, and 20% for Gem, respectively). The occurrence or the grade of rash was not associated with a better survival in the GemErlo arm. Conclusion To the best of our knowledge, CONKO-005 is the first study to investigate the combination of chemotherapy and a targeted therapy in the adjuvant treatment of PDAC. GemErlo for 24 weeks did not improve DFS or overall survival over Gem.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/terapia , Desoxicitidina/análogos & derivados , Clorhidrato de Erlotinib/administración & dosificación , Pancreatectomía , Neoplasias Pancreáticas/terapia , Pancreaticoduodenectomía , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno CA-19-9/sangre , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Clorhidrato de Erlotinib/efectos adversos , Femenino , Alemania , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pancreatectomía/efectos adversos , Pancreatectomía/mortalidad , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pancreaticoduodenectomía/efectos adversos , Pancreaticoduodenectomía/mortalidad , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven , GemcitabinaRESUMEN
In pancreatic cancer there is a need for prognostic risk stratification and subsequent therapy strategies. Molecular analysis has shown in different cancers that variation in clinical behavior can be associated with specific alterations. The cell cycle regulators p16 and p53 belong to the most often alterated genes in pancreatic ductal adenocarcinoma (PDAC). We analyzed protein expression of p16, p53 and Ki67 by immunohistochemistry in 162 tumours of the CONKO-001 trial that investigated the role of adjuvant gemcitabine in pancreatic cancer patients. We could show that high proliferation of tumours and strong and consistent nuclear p53 expression by tumour cells is associated with a worse disease-free survival and overall survival in the overall study population. However, stratified analysis according to treatment arm revealed that the effect of deregulated p53 expression and high Ki67 expression was restricted to the disease free survival of patients treated with adjuvant gemcitabine. In multivariable survival analysis, p53 did not retain its prognostic status. Our study supports the important role of p53 and Ki67 expression in PDAC. They provide prognostic information in patients with adjuvant gemcitabine treatment and may contribute to treatment decision. However, these results should be validated in further studies.
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Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/metabolismo , Desoxicitidina/análogos & derivados , Antígeno Ki-67/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Anciano , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Quimioterapia Adyuvante , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Tasa de Supervivencia , Resultado del Tratamiento , Regulación hacia Arriba , GemcitabinaRESUMEN
OBJECTIVE: Mutations in the KRAS and P53 genes belong to the most frequently observed genetic alterations in pancreatic ductal adenocarcinoma. The aim of this study was to examine the frequency and prognostic impact of KRAS mutations. In addition, we attempted to define molecular subgroups with distinct biologic behavior by combination of KRAS sequencing data with p53 protein expression data. METHODS: KRAS mutational analyses were performed in a study group of 153 patients by Sanger sequencing. Immunohistochemistry for p53 was performed on tissue microarrays. RESULTS: KRAS mutations in codon 12 or 13 were found in 68% of cases. Nuclear staining for p53 was detectable in 110 (68%) of 162 evaluable cases. We found no correlation between KRAS mutational status and p53 expression. KRAS mutational status but not p53 immunohistochemistry was an independent prognostic factor in the study group (P = 0.02). In a stratified analysis according to KRAS mutational status, p53 expression failed to define prognostic groups beyond the impact of KRAS mutational status. CONCLUSIONS: Our results support the crucial role of KRAS mutational status in pancreatic cancer biology. KRAS mutational status may serve as a prognostic marker. However, its predictive role for targeted therapies remains to be evaluated.