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INTRODUCTION: Survival of patients suffering from metastatic colorectal cancer (mCRC) has increased over the last decades. These benefits appear to be restricted to patients aged 50 and above. However, among the population aged <50, colorectal cancer incidence and mortality rates are significantly rising. The clinical benefit of treatment in this population still is a matter of debate. We aim to compare the clinical outcome between patients aged 50 and younger. METHODS: In this retrospective, observational study, we analyzed data from 1,077 patients treated for mCRC at three cancer centers in Austria from January 2005 to December 2019. Patients were divided into two groups based on age at diagnosis: <50 years (eo-CRC) and >50 years (regular-onset CRC, ro-CRC). Propensity score matching was used to control for potential biases, and survival outcomes were compared between the two groups. RESULTS: The differences in tumor characteristics between eo-CRC and ro-CRC in the overall population were primarily related to tumor sidedness and disease-free survival following intended curative resection. Our data show that eo-CRC patients underwent metastases resection more often and received significantly more lines of treatment in the palliative setting. Overall survival was superior in eo-CRC compared to ro-CRC, even after adjusting for sidedness, timing of metastases, sex, number of treatment lines, and resection of metastases by propensity scoring. CONCLUSION: Our study suggests that younger patients benefit at least to the same magnitude or even more from mCRC-treatment than patients aged 50 or above.
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Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Neoplasias Colorretais/patologia , Estudos Retrospectivos , Análise por PareamentoRESUMO
INTRODUCTION: Intraductal papillary mucinous neoplasms (IPMNs) represent the most common precancerous cystic lesions of the pancreas. The aim of our study was to investigate if resection for non-invasive IPMNs alters quality of life (QoL) in a long-term follow-up. METHODS: Patients (n = 50) included in the analysis were diagnosed and resected from 2010 to 2016. QoL was assessed at a median of 5.5 years after resection. At that point in time, the current QoL as well as the QoL before resection was evaluated retrospectively. The standardised European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Pancreatic Cancer (EORTC QLQ - PAN26) was applied for the QoL assessment. RESULTS: After a median of 66 months postoperatively, the total QoL score significantly worsened (92.13 vs. 88.04, p = 0.020, maximum achievable score = 100) for patients (median age at surgery 68.0 years), mostly due to digestive symptoms. During the same follow-up period, median Eastern Cooperative Oncology Group (ECOG) performance status did not worsen (p = 0.003). CONCLUSIONS: Long-term QoL statistically significantly worsened after pancreatic resection for IPMN. The extent of worsening, however, was small, and QoL still remained excellent. Therefore, resection in cases of IPMN is appropriate, if indicated carefully.
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Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Carcinoma Papilar , Neoplasias Intraductais Pancreáticas , Neoplasias Pancreáticas , Adenocarcinoma Mucinoso/cirurgia , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Papilar/cirurgia , Humanos , Pancreatectomia , Neoplasias Intraductais Pancreáticas/cirurgia , Neoplasias Pancreáticas/cirurgia , Qualidade de Vida , Estudos RetrospectivosRESUMO
BACKGROUND: Adenocarcinoma of the esophagogastric junction (AEG) is a rare but rising tumor entity in the Western world. Treatment is complex, as multimodality is key to optimal results. However, trials solely including AEG are rare, and the question if neoadjuvant radiochemotherapy (NRCT) or neoadjuvant/perioperative chemotherapy (NACT) is superior remains unanswered. PATIENTS AND METHODS: Patients with AEG I-III treated between October 2010 and August 2019 at the Ordensklinikum Linz or the Kepler University Hospital were identified either from a monitored tumor registry or by chart review. Time-to-event data were analyzed by Kaplan-Meier product limit estimation. The Kruskal-Wallis test and Fisher's exact test were used for comparing continuous and categorical data, respectively. RESULTS: A total of 85 patients (median age 63 years; median Charlson Comorbidity Index 3; 98.8% ECOG PS 0-1) were analyzed. Of these, 52 patients received NRCT (81% CROSS protocol) and 33 NACT (65% EOX and 35% FLOT protocol). There was a significantly higher pathological complete response rate in the NRCT group (30 vs. 12%; p = 0.010); distant relapse rates were higher in the NRCT group and local relapse rates were higher in the NACT group (both not significant). These differences, however, did not translate into a different disease-free survival (20 months; 95% CI: 13-34) or overall survival (44 months; 95% CI: 33-NA). Patients >65 years old had the same advantage from treatment as patients <65 years of age. CONCLUSIONS: Although treatment of AEG is complex, the progress documented over the last centuries can be reproduced in our real-life setting. Data regarding the superiority of either type of neoadjuvant/perioperative treatment are sparse. We assume no difference between EOX-based NACT and NRCT.
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Neoplasias Esofágicas/terapia , Junção Esofagogástrica/patologia , Neoplasias Gástricas/terapia , Idoso , Quimiorradioterapia Adjuvante , Estudos de Coortes , Intervalo Livre de Doença , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Junção Esofagogástrica/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Assistência Perioperatória , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Metastatic colorectal cancer (mCRC) remains a lethal disease. Survival, however, is increasing due to a growing number of treatment options. Yet due to the number of prognostic factors and their interactions, prediction of mortality is difficult. The aim of this study is to provide a clinical model supporting prognostication of mCRC mortality in daily practice. METHODS: Data from 1104 patients with mCRC in three prospective cancer datasets were used to construct and validate Cox models. Input factors for stepwise backward method variable selection were sex, RAS/BRAF-status, microsatellite status, treatment type (no treatment, systemic treatment with or without resection of metastasis), tumor load, location of primary tumor, metastatic patterns and synchronous or metachronous disease. The final prognostic model for prediction of survival at two and 3 years was validated via bootstrapping to obtain calibration and discrimination C-indices and dynamic time dependent AUC. RESULTS: Age, sidedness, number of organs with metastases, lung as only site of metastasis, BRAF mutation status and treatment type were selected for the model. Treatment type had the most prominent influence on survival (resection of metastasis HR 0.26, CI 0.21-0.32; any treatment vs no treatment HR 0.31, CI 0.21-0.32), followed by BRAF mutational status (HR 2.58, CI 1.19-1.59). Validation showed high accuracy with C-indices of 72.2 and 71.4%, and dynamic time dependent AUC's of 76.7 ± 1.53% (both at 2 or 3 years), respectively. CONCLUSION: The mCRC mortality prediction model is well calibrated and internally valid. It has the potential to support both, clinical prognostication for treatment decisions and patient communication.
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Neoplasias Colorretais/mortalidade , Nomogramas , Idoso , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: High rates of venous thromboembolic events (VTEs), mainly in advanced disease, are reported for patients with cancer of the upper gastrointestinal tract (stomach, pancreas) and for treatment with cisplatin. METHODS: Exploratory analysis of VTEs reported as adverse events and serious adverse events in a prospective, randomised, multicentre, multimodal phase III trial according to VTEs reported as adverse events and severe adverse events. Patients with resectable oesophageal cancer (T2N1-3, T3-4aNx) were randomized to 2 cycles of chemotherapy with docetaxel 75 mg/m2, cisplatin 75 mg/m2 followed by chemo-radiotherapy (CRT) and subsequent surgery (control arm) or the same treatment with addition of cetuximab (investigational arm). RESULTS: VTEs occurred in 26 of 300 patients included in the trial, resulting in an incidence rate (IR) of 8.7% [95% CI 5.7-12.4%]. A total of 29 VTEs were reported:13 (45%) VTEs were grade 2, 13 (45%) grade 3 and three (10%) fatal grade 5 events. 72% (21/29) of all VTEs occurred preoperatively (IR 6.7%): 14% (4/29) during chemotherapy and 59% (17/29) during CRT. In multivariable logistic regression only adenocarcinoma (IR 11.1%, 21/189 patients) compared to squamous cell cancer (IR 4.5%, 5/111 patients) was significantly associated with VTE-risk during treatment, OR 2.9 [95%CI 1.0-8.4], p = 0.046. Baseline Khorana risk score was 0 in 73% (19/26), 1-2 in 23% (6/26) and 3 in only 4% (1/26) of patients with VTEs. CONCLUSION: A high incidence of VTEs during preoperative therapy of resectable oesophageal cancer is observed in this analysis, especially in patients with adenocarcinoma. The role of prophylactic anticoagulation during neoadjuvant therapy in resectable esophageal cancer should be further evaluated in prospective clinical trials. According to our data, which are in line with other analysis of VTE-risk in patients with oesophageal cancer patients treated with neoadjuvant cisplatin-based chemotherapy and CRT, prophylactic anticoagluation could be considered balanced against individual bleeding risks, especially in patients with adenocarcinoma. In addition to the established risk factors, oesophageal adenocarcinoma treated with neoadjuvant cisplatin-based therapy may be regarded as a high-risk situation for VTEs. TRIAL REGISTRATION: Registered at clinicaltrials.gov, NCT01107639, on 21 April 2010.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Esofágicas/terapia , Tromboembolia/epidemiologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/efeitos adversos , Quimiorradioterapia/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Neoplasias Esofágicas/patologia , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tromboembolia/induzido quimicamente , Resultado do TratamentoRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrated. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability (Mol Cancer 11:26 2012, J Thorac Oncol 4:87-92 2009, J Thorac Oncol 7:1032-1040, 2012). Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC. METHODS: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease according to RECIST criteria 1.1 are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), the efficacy and safety of the combination will be further evaluated (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include progression-free survival, safety, and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within 2 years. DISCUSSION: Based on preclinical and clinical findings an ixazomib and carboplatin combination is thought to be effective in metastatic TNBC patients. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination. TRIAL REGISTRATION: EudraCT Number: 2016-001421-13 received on March 31, 2016, ClinicalTrials.gov Identifier: NCT02993094 first posted on December 15, 2016. This trial was registered prospectively.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos de Boro/administração & dosagem , Carboplatina/administração & dosagem , Glicina/análogos & derivados , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Áustria , Compostos de Boro/efeitos adversos , Bortezomib/administração & dosagem , Carboplatina/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Qualidade de Vida , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Myeloid and lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) abnormalities, also known as 8p11 myeloproliferative syndrome (EMS), represent rare and aggressive disorders, associated with chromosomal aberrations that lead to the fusion of FGFR1 to different partner genes. We report on a third patient with a fusion of the translocated promoter region (TPR) gene, a component of the nuclear pore complex, to FGFR1 due to a novel ins(1;8)(q25;p11p23). The fact that this fusion is a rare but recurrent event in EMS prompted us to examine the localization and transforming potential of the chimeric protein. TPR-FGFR1 localizes in the cytoplasm, although the nuclear pore localization signal of TPR is retained in the fusion protein. Furthermore, TPR-FGFR1 enables cytokine-independent survival, proliferation, and granulocytic differentiation of the interleukin-3 dependent myeloid progenitor cell line 32Dcl3, reflecting the chronic phase of EMS characterized by myeloid hyperplasia. 32Dcl3 cells transformed with the TPR-FGFR1 fusion and treated with increasing concentrations of the tyrosine kinase inhibitors ponatinib (AP24534) and infigratinib (NVP-BGJ398) displayed reduced survival and proliferation with IC50 values of 49.8 and 7.7 nM, respectively. Ponatinib, a multitargeted tyrosine kinase inhibitor, is already shown to be effective against several FGFR1-fusion kinases. Infigratinib, tested only against FGFR1OP2-FGFR1 to date, is also efficient against TPR-FGFR1. Taking its high specificity for FGFRs into account, infigratinib could be beneficial for EMS patients and should be further investigated for the treatment of myeloproliferative neoplasms with FGFR1 abnormalities.
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Cromossomos Humanos Par 8/genética , Imidazóis/farmacologia , Transtornos Mieloproliferativos/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas/genética , Piridazinas/farmacologia , Pirimidinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoplasma/metabolismo , Humanos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Transtornos Mieloproliferativos/tratamento farmacológico , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Compostos de Fenilureia/uso terapêutico , Proteínas Proto-Oncogênicas/metabolismo , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
Purpose: The aim of this retrospective analysis was to determine if the response to preoperative radio(chemo)therapy is predictive for survival among patients with locally advanced rectal cancer and may act as a potential surrogate endpoint for disease free survival and overall survival. Results: Eight hundred seventy-eight patients from five centers were analyzed. There were 304 women and 574 men; the median age was 64.7 years. 77.6% and 22.4% of patients received neoadjuvant radiochemotherapy or short-course radiotherapy, resulting in a pathological complete response in 7.3%. T-downstaging and N-downstaging occurred in 50.5% and 37% of patients after neoadjuvant therapy. In patients with T-downstaging, the 10-year DFS and 10-year OS were 64.8% and 66.8% compared to 37.1% and 45.9% in patients without T-downstaging. N-downstaging resulted in 10-year DFS and 10-year OS in 56.2% and 62.5% compared to 47.3% and 52.3% without N-downstaging. Based on routinely evaluated clinical parameters, an absolute risk prediction calculator was generated for 5-year disease-free survival, and 5-year overall survival. Conclusion: T-downstaging and N-downstaging after neoadjuvant radiochemotherapy or short-course radiotherapy resulted in better DFS and OS compared to patients without response. Based on clinical parameters, 5-year DFS, and 5-year OS can be predicted using a prediction calculator.
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Over the last decade, therapeutic options for patients with gastric cancer have improved significantly. However, despite these recent advances, mortality is still substantial. Surgery and chemotherapy represent the cornerstones of patient management. Immune checkpoint inhibitors as well as targeted treatments such as HER2-directed therapies and antiangiogenic agents contribute to improved patient prognosis. Herein, we present the updated version of an Austrian consensus on the systemic treatment of patients with gastric adenocarcinoma and adenocarcinoma of the lower gastroesophageal junction, including those with human epidermal growth receptor 2 (HER2) overexpression, microsatellite instability, programmed death-ligand 1 (PD-L1)-positive disease, and claudin 18.2 positivity. The consensus considers the curative setting as well as first-line and later-line systemic treatment options in advanced disease. For HER2-positive disease, HER2 testing is discussed in addition to a review of first-line and later-line therapies. Potential future therapies are also listed, with a focus on targeted [e.g., fibroblast growth factor receptor 2 (FGRF2)-directed] treatments that might provide a further step forward in the management of patients with gastric cancer.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Áustria , Consenso , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Algoritmos , Junção Esofagogástrica/patologia , Receptor ErbB-2/metabolismo , Neoplasias Esofágicas/patologiaRESUMO
Locally advanced or metastatic cholangiocarcinoma is an aggressive carcinoma with a dismal prognosis. For the first-line treatment of locally advanced or metastatic cholangiocarcinoma, cisplatin/gemcitabine has been the standard of care for more than 10 years. Its combination with the immune checkpoint inhibitor durvalumab resulted in an efficiency improvement in the phase III setting. Regarding the use of chemotherapy in the second line, positive phase III data could only be generated for FOLFOX. The evidence base for nanoliposomal irinotecan (Nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) is contradictory. After the failure of first-line treatment, targeted therapies can be offered if the molecular targets microsatellite instability-high (MSI-H), IDH1, FGFR2, BRAF V600E, and NTRK are detected. These targeted agents are generally preferable to second-line chemotherapy. Broad molecular testing should be performed, preferably from tumor tissue, at the initiation of first-line therapy to timely identify potential molecular targets.
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Background: Serial analysis of circulating tumor DNA (ctDNA) levels is a promising tool for both relapse prediction in the curative setting, as well as predicting clinical benefit from systemic treatment in metastasic colorectal cancer (mCRC). Most data in this context are derived from treatment naive patients. Objective: To predict progressive disease (PD) as early as possible through monitoring of changes in ctDNA levels during systemic treatment in pretreated patients with mCRC. Design: A prospective, single-center, observational study. Methods: Patients treated beyond first-line were prospectively included between February 2020 and September 2021. Blood for ctDNA detection was taken before every treatment cycle from start of treatment until first restaging by CT-scan. ctDNA was detected by mutation- (mut-ctDNA) and methylation-specific ddPCR. Receiver Operating Characteristic (ROC)-analysis was used to describe sensitivity and specificity for prediction of PD at restaging for all time points. Results: A total of 42 patients were included who all carried a mutation in tumor tissue. Detection rate of mut-ctDNA was 88.1% and 74.4% for meth-ctDNA. Absolute ctDNA levels before treatment were prognostic in terms of overall survival. Levels of ctDNA were significantly higher in patients with PD at restaging. Median time from start of treatment to restaging was 93 days (95% CI 88.8-96). After a median of 19 days of treatment (95% CI 16.1-20.2), a decline of either mutation- or methylation-specific ctDNA levels of ⩽58% predicted PD at restaging with a sensitivity/specificity of 92.9/85.7% and 85.7/100%, respectively. Median time to restaging was 66 days (95% CI 56.8-75.2). There was no significant increase of sensitivity/specificity at later time points of ctDNA measurements. Conclusion: Monitoring early changes of ctDNA levels either by mut- or meth-ctDNA allows for early prediction of PD in pretreated patients with mCRC. This has the potential to complement RECIST-based treatment assessment with the aim to switch potentially insufficient treatments as early as possible, which is of particular interest in higher treatment lines.
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Biliary tract cancers are rare cancers with poor prognosis due to a lack of therapeutic options, especially after the failure of first-line systemic treatment. Targeted treatments for this clinical situation are promising and have entered clinical practice. We aimed to describe the overall survival of matched targeted treatment after first-line treatment in patients with biliary tract cancers in an Austrian real-world multicenter cohort. We performed a multicenter retrospective chart review of patients with biliary tract cancer between September 2015 and January 2022. Data, including comprehensive molecular characteristics-next generation sequencing (NGS) and immunohistochemistry (IHC), clinical history, surgical procedures, ablative treatments, patient history, and systemic chemotherapy, were extracted from the records of the participating institutions. Targeted treatment was matched according to the ESMO scale for the clinical actionability of molecular targets (ESCAT). We identified 159 patients with the available molecular characteristics. A total of 79 patients underwent second-line treatment. Of these, 36 patients received matched targeted treatment beyond the first-line and were compared with 43 patients treated with cytotoxic chemotherapy in terms of efficacy outcomes. For Tier I/II alterations, we observed a progression free survival ratio (PFStargeted/PFSpre-chemotherapy) of 1.86, p = 0.059. The overall survival for patients receiving at least two lines of systemic treatment significantly favored the targeted approach, with an overall survival of 22.3 months (95% CI 14.7-29.3) vs. 17.5 months (95% CI 1.7-19.8; p = 0.048). Our results underscore the value of targeted treatment approaches based on extended molecular characterization of biliary tract cancer to improve clinical outcomes.
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Neoplasias do Sistema Biliar , Humanos , Estudos Retrospectivos , Neoplasias do Sistema Biliar/tratamento farmacológico , Administração Cutânea , Áustria , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Cancer stem cells (CSC) are increasingly recognized as key target cells for cancer therapy because they are both tumorigenic and chemoresistant and, therefore, can give rise to recurrent disease. Side population (SP) sorting using an ultraviolet (UV) laser is an established method to isolate CSC based on ABC drug transporter-dependent (e.g., ABCG2) Hoechst 33342 efflux. We here show that Vybrant® DyeCycle™ Violet (DCV), a DNA-binding fluorophor allowing SP sorting using a non-UV laser (such as violet laser), is transported via P-glycoprotein (PgP). Because PgP might be particularly abundant in multidrug-resistant cancer cells rather than bona fide CSC, investigators using DCV should be aware that this strategy might also detect PgP-expressing non-CSC.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/análise , Separação Celular/métodos , Proteínas de Neoplasias/análise , Células-Tronco Neoplásicas/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Benzimidazóis , Transporte Biológico , Reações Falso-Positivas , Citometria de Fluxo , Corantes Fluorescentes , Humanos , Células K562 , Lasers , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/patologia , Raios UltravioletaRESUMO
PURPOSE: Incidence and mortality of colorectal cancer (CRC) declined over the last decades. However, survival depends on the primary tumor location. It is unknown if all progress in outcomes vary depending on left-sided (LCRC) versus right-sided (RCC) colorectal cancer. We compare incidence and mortality rates over time according to the primary tumor location. METHODS: Data from the Austrian National Cancer Registry spanning from 1983 to 2018 were used to calculate annual incidence and mortality rates and survival stratified by primary tumor localization and stage. Joinpoint regression with linear regression models were used on different subgroups to identify significant changes of incidence- and mortality slopes. RESULTS: A total of 168,260 (incidence dataset) and 87,355 cases (mortality dataset) were identified. Survival of disseminated RCC was worse compared to LCRC (HR 1.14; CI 1.106-1.169). Total and LCRC incidence and mortality rates declined steadily over time, whereas the rates of RCC did not. Incidence of disseminated RCC declined significantly less (slope - 0.07; CI - 0.086; - 0.055) than in LCRC (slope - 0.159; CI - 0.183; - 0.136); mortality rate of RCC was unchanged over time. Incidence and mortality of localized RCC remained unchanged over time, whereas both rates declined independently of stage in LCRC. CONCLUSION: Colorectal cancer outcomes during the last 35 years have preferentially improved in LCRC but not in RCC, indicating that the progress made is limited to LCRC. It is necessary to define RCC as a distinct form of CRC and to focus on specific strategies for its early detection and treatment.
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Carcinoma de Células Renais , Neoplasias Colorretais , Neoplasias Renais , Áustria , Neoplasias Colorretais/patologia , Humanos , IncidênciaRESUMO
Anti-EGFR targeting is one of the key strategies in the treatment of metastatic colorectal cancer (mCRC). For almost two decades oncologists have struggled to implement EGFR antibodies in the mCRC continuum of care. Both sidedness and RAS mutational status rank high among the predictive factors for the clinical efficacy of EGFR inhibitors. A prospective phase III trial has recently confirmed that anti-EGFR targeting confers an overall survival benefit only in left sided RAS-wildtype tumors when given in first line. It is a matter of discussion if more clinical benefit can be reached by considering putative primary resistance mechanisms (e.g., HER2, BRAF, PIK3CA, etc.) at this early stage of treatment. The value of this procedure in daily routine clinical utility has not yet been clearly delineated. Re-exposure to EGFR antibodies becomes increasingly crucial in the disease journey of mCRC. Yet re- induction or re-challenge strategies have been problematic as they relied on mathematical models that described the timely decay of EGFR antibody resistant clones. The advent of liquid biopsy and the implementation of more accurate next-generation sequencing (NGS) based high throughput methods allows for tracing of EGFR resistant clones in real time. These displays the spatiotemporal heterogeneity of metastatic disease compared to the former standard radiographic assessment and re-biopsy. These techniques may move EGFR inhibition in mCRC into the area of precision medicine in order to apply EGFR antibodies with the increase or decrease of EGFR resistant clones. This review critically discusses established concepts of tackling the EGFR pathway in mCRC and provides insight into the growing field of liquid biopsy guided personalized approaches of EGFR inhibition in mCRC.
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Minimally invasive detection of circulating tumor DNA (ctDNA) in peripheral blood or other body fluids of patients with gastrointestinal malignancies via liquid biopsy has emerged as a promising biomarker. This is urgently needed, as conventional imaging and plasma protein-derived biomarkers lack sensitivity and specificity in prognosis, early detection of relapse or treatment monitoring. This review summarizes the potential role of liquid biopsy in diagnosis, prognosis and treatment monitoring of gastrointestinal malignancies, including upper gastrointestinal, liver, bile duct, pancreatic and colorectal cancer. CtDNA can now be part of the clinical routine as a promising, highly sensitive and specific biomarker with a broad range of applicability. Liquid-biopsy based postoperative relapse prediction could lead to improved survival by intensification of adjuvant treatment in patients identified to be at risk of early recurrence. Moreover, ctDNA allows monitoring of antineoplastic treatment success, with identification of potentially developed resistance or therapeutic targets during the course of treatment. It may also assist in early change of chemotherapy in metastatic gastrointestinal malignancies prior to imaging findings of relapse. Nevertheless, clinical utility is dependent on the tumor's entity and burden.
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INTRODUCTION: Circulating tumor DNA (ctDNA) represents a promising tool for diagnosis, prognosis and treatment monitoring of several malignancies. Its association with tumor burden in pancreatic ductal cancer (PDAC), especially in localized disease, is not fully explored yet. We aimed to investigate the association of pretherapeutic ctDNA levels in localized and metastatic PDAC with tumor volume and clinical outcomes. MATERIAL AND METHODS: Liquid biopsy for ctDNA detection was prospectively obtained from patients with localized or disseminated PDAC prior to either resection or systemic treatment. Detection rates and levels of ctDNA (digital droplet PCR) were correlated to tumor volume, relapse rate and survival. RESULTS: 60 patients with localized and 47 patients with metastatic PDAC were included. ctDNA was detected in 10% of localized and 57.4% of metastasized PDAC samples. In localized disease, ctDNA detection significantly correlated with the numbers of involved locoregional lymph nodes (p = 0.030). Primary tumor volume did not correlate with ctDNA levels in neither localized (p = 0.573) nor metastasized disease (p = 0.878). In disseminated disease, ctDNA levels correlated with total tumor volume (p = 0.026) and especially with liver metastases volume (p = 0.004), but not with other metastases. Detection of pretherapeutic ctDNA was associated with shorter DFS in localized (3.3 vs. 18.1 months, p = 0.000), whereas ctDNA levels were associated with worse survival in metastatic PDAC (5.7 vs. 7.8 months, p = 0.036). CONCLUSION: ctDNA positivity indicates major nodal involvement or even presence of undetected distant metastases associated with early recurrence in localized PDAC. Moreover, it predicts worse clinical outcome in both localized and metastatic disease.
Assuntos
Carcinoma Ductal Pancreático , DNA Tumoral Circulante , Neoplasias Pancreáticas , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/patologia , DNA Tumoral Circulante/genética , Humanos , Mutação , Recidiva Local de Neoplasia/genética , Neoplasias Pancreáticas/patologia , Prognóstico , Carga Tumoral , Neoplasias PancreáticasRESUMO
Introduction: Pretherapeutic detectable circulating tumor DNA (ctDNA) represents a promising prognostic biomarker for predicting relapse and overall survival in patients with metastatic pancreatic cancer. However, the prognostic value of ctDNA dynamics during treatment has not been studied thus far. We aimed to investigate the correlation between the change of ctDNA levels and response to treatment in patients treated by systemic therapy. Material and methods: CtDNA detection using liquid biopsy (droplet digital PCR (ddPCR) utilizing KRAS G12/13 and, if negative, Q61 commercial test kits) was prospectively performed on patients with stage IV pancreatic cancer i) prior to initiation of systemic chemotherapy and ii) serially every 2 weeks until restaging. Detection rates, levels of ctDNA, and the course of the relative ctDNA change (ctDNA kinetics) were correlated to treatment response and clinical outcome. Results: The detection rate at baseline was 64.3% (45/70), and complete serial measurement records were available for 32 ctDNA-positive patients. Reduction of ctDNA levels below 57.9% of its baseline value at week 2 after treatment initiation was significantly predictive of response to treatment (area under the curve (AUC) = 0.918, sensitivity 91.67%, and specificity 100%) and was associated with prolonged overall survival (OS) (5.7 vs. 11.4 months, p = 0.006) and progression-free survival (PFS) (2.5 vs. 7.7 months, p < 0.000) regardless of treatment line. Pretherapeutic ctDNA detection was independently associated with worse OS in patients receiving a first-line regimen (7 vs. 11.3 months, p = 0.046) and regardless of treatment line (11.4 vs. 15.9 months, p = 0.045) as well as worse PFS (3.4 vs. 10.8 months, p = 0.018). Conclusion: The change in magnitude of ctDNA during systemic treatment allows the prediction of treatment response and is associated with both OS and PFS. This finding adds significant clinical potential to the already established prognostic value of ctDNA positivity in metastatic pancreatic cancer.
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This data article subsumes the data acquiration process, analysis and results of 'Circulating tumor DNA correlates with tumor burden and predicts outcome in pancreatic cancer irrespective of tumor stage' published in European Journal of Surgical Oncology (Eur J Surg Oncol. 2021 Dec 1:S0748-7983(21)00947-1. doi:10.1016/j.ejso.2021.11.138. PMID: 34876329) (Kirchweger et al., 2021). 28.5 mL of blood was obtained from 60 patients with localized pancreatic cancer directly prior to curative intended surgery as well as from 47 patients with metastasized pancreatic cancer (PDAC) directly prior to palliative intended systemic treatment initiation. Cell-free DNA preparation was done on the Chemagic 360 (Perkin Elmer, Waltham, Massachusetts, USA) using the kits CMG-1304 and CMG-844 from the same provider and quantified using the Quantus fluorometer (Promega, Madison, Wisconsin, USA). Screening for most common KRAS alterations (KRAS G12/G13 screening kit and additionally for KRAS Q61 if screening was negative) was performed utilizing the QX200™ Droplet Digital™ PCR System from Bio-Rad (Bio-Rad Laboratories, Hercules, CA, USA). Volumetric analysis was performed on contrast enhanced dual-energy CT scans in the arterial and portal venous phase prior to treatment initiation using Syngo.via (Siemens Healthcare, Forchheim, Germany) on MM Oncology Workflow adhering to RECIST 1.1 criteria (Eisenhauer et al., 2009). CtDNA predicts outcome in localized and disseminated disease. Moreover, it correlates with distant metastasis volume and positive lymph nodes but not primary tumor volume and therefore could indicate subclinical synchronous distant metastases in localized PDAC undetectable by current gold standard (computed tomography).
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Background: Associations between height, cancer risk and worse outcome have been reported for several cancers including breast cancer. We hypothesized that in breast cancer clinical trials, tall women should be overrepresented and might have worse prognosis. Methods: Data of 4,935 women, included from 1990 to 2010 in 5 trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG), were analyzed retrospectively. The primary objective was to determine differences in height distribution between the ABCSG cohort and the Austrian female population according to a cross-sectional health survey conducted by the Austrian Statistic Center in 2006 and 2007. Secondary endpoints were disease-free survival (DFS) and overall survival (OS) in different height classes and differences of body mass index (BMI) distribution. Results: Breast cancer patients in the ABCSG cohort were only slightly but statistically significantly smaller compared to unselected Austrian adult females (mean 164.3 vs. 164.8 cm; p < 0.0001) and significantly more patients were seen in the lower body height class (50 vs. 46%; p < 0.0001) when using the median as a cutoff. However, after adjustment for age, the difference in body height between the two cohorts was no longer significant (p = 0.089). DFS and OS in the two upper height groups (≥170 cm) compared to the two lowest height groups (<160 cm) was not significantly different (5-year DFS: 84.7 vs. 83.0%; HR 0.91, 95% CI 0.73-1.13, p = 0.379; 5-year OS: 94.8 vs. 91.7%; HR 0.74, 95% CI 0.55-1.00, p = 0.051). The BMI of ABCSG patients was significantly higher than in the reference population (mean BMI 24.64 vs. 23.96; p < 0.0001). Conclusions: Our results do not confirm previous findings that greater body height is associated with a higher breast cancer risk and worse outcome.