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Alena Novakova-Jiresova,1 Katerina Kopeckova,2 Ludmila Boublikova,1 Renata Chloupkova,3 Bohuslav Melichar,4 Lubos Petruzelka,5 Jindrich Finek,6 Ondrej Fiala,6,7 Peter Grell,8 Stanislav Batko,2 Zdenek Linke,2 Igor Kiss,8 Jana Prausova,2 Tomas Buchler1 1Department of Oncology, First Faculty of Medicine and Thomayer Hospital, Charles University, Prague, Czech Republic; 2Department of Oncology, University Hospital in Motol, Charles University, Prague, Czech Republic; 3Institute of Biostatistics and Analysis, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 4Department of Oncology, Palacky University Medical and Teaching Hospital, Olomouc, Czech Republic; 5Department of Oncology, General Faculty Hospital, Charles University, Prague, Czech Republic; 6Department of Oncology and Radiotherapy, Medical School and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic; 7Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic; 8Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech RepublicCorrespondence: Tomas BuchlerDepartment of Oncology, First Faculty of Medicine and Thomayer Hospital, Charles University, Videnska 800, Prague 140 59, Czech RepublicTel +420-261-082-637Fax +420-261-082-522Email tomas.buchler@ftn.czPurpose: Regorafenib is an oral multikinase inhibitor approved for the therapy of previously treated metastatic colorectal carcinoma (mCRC). The aim of the present study was to analyze the outcomes of treatment with regorafenib in real-world clinical practice based on data from a national registry.Methods: The CORECT registry, the Czech non-interventional database of patients with mCRC treated with targeted agents, searched for patients with metastatic CRC treated with regorafenib. In total, 555 evaluable patients were identified.Results: The median age at diagnosis was 61.7 years. All patients had disease progression on or after previous systemic treatment. Most patients were treated with an initial dose of 160 mg daily (n = 463; 83.6%). The median duration of treatment was 2.7 months (range 0.0– 23.4 months). By the data cut-off date, 472 patients (85%) had completed treatment with regorafenib and were evaluable for treatment response evaluation. Partial response was reported in 13 patients (2.8%) and disease stabilization in 130 patients (27.5%). Median progression-free survival (PFS) and overall survival (OS) were 3.5 months (95% confidence interval [CI] 3.2– 3.7 months) and 9.3 months (95% CI 8.3– 10.3 months), respectively. The 6-month OS rate was 67.7% (95% CI 63.4– 72.1%). Multivariable analysis showed that female gender, longer interval from diagnosis of metastatic disease, M0 stage at diagnosis, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 were associated with longer PFS, while higher body-mass index (BMI), longer interval from diagnosis of metastatic disease, and ECOG PS of 0 were associated with longer OS.Conclusion: OS of patients treated with regorafenib in the real-world clinical practice in this cohort exceeded that reported in randomized trials. Regorafenib is a safe and active treatment option for a subgroup of patients with mCRC who are progressing after other systemic therapies and maintain good performance status.Keywords: colorectal cancer, regorafenib, registry, survival, outcome analysis

Tomas Buchler,1 Renata Chloupkova,2 Alexandr Poprach,3 Ondrej Fiala,4,5 Igor Kiss,3 Katerina Kopeckova,6 Ladislav Dusek,2 Veronika Veskrnova,1 Lubomir Slavicek,7 Milan Kohoutek,8 Jindrich Finek,4 Marek Svoboda,3 Lubos Petruzelka,9 Bohuslav Melichar10 1Department of Oncology, First Faculty of Medicine, Charles University and Thomayer University Hospital, 140 59 Prague, Czech Republic; 2Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic; 3Department of Comprehensive Cancer Care and Faculty of Medicine, Masaryk Memorial Cancer Institute and Masaryk University, Brno 656 53, Czech Republic; 4Department of Oncology, University Hospital, 304 60 Pilsen, Czech Republic; 5Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Prague, Czech Republic; 6Department of Oncology, Motol University Hospital and Second Faculty of Medicine, Charles University, 150 00 Prague, Czech Republic; 7Department of Oncology, Jihlava Hospital Comprehensive Cancer Centre, Jihlava, Czech Republic; 8Department of Oncology, T Bata Hospital and Comprehensive Cancer Centre, Zlin, Czech Republic; 9Department of Oncology, General University Hospital and Charles University First Faculty of Medicine, 128 08 Prague, Czech Republic; 10Department of Oncology, Palacky University Medical School and Teaching Hospital, 775 20 Olomouc, Czech Republic Purpose: Although inhibitors of vascular endothelial growth factor and inhibitors of epidermal growth factor receptor (EGFRi) are commonly used for the treatment of metastatic colorectal cancer (mCRC), the optimal sequencing of these agents is currently unclear. Methods: A national registry of targeted therapies was used to analyze baseline ­characteristics and outcomes of patients with mCRC and wild-type KRAS exon 2 status who received ­bevacizumab and EGFRi (cetuximab or panitumumab) as a part of first- and second-line ­treatment in either sequence. Results: The cohort included 490 patients (181 patients treated with first-line EGFRi and second-line bevacizumab and 309 patients treated with first-line bevacizumab and second-line EGFRi). Median overall survival (OS) from the initiation on first-line therapy was similar for patients treated with either sequence, reaching 31.8 (95% CI 27.5–36.1) vs 31.4 months (95% CI 27.8–35.0) for EGFRi → bevacizumab vs bevacizumab → EGFRi cohort, respectively. Time from first-line initiation to progression on the second-line therapy [progression-free survival (PFS)] was 21.1 (95% CI 19.3–23.0) vs 19.3 months (95% CI 17.3–21.3) for bevacizumab → EGFRi vs EGFRi → bevacizumab cohort, respectively (P=0.016). Conclusion: This retrospective analysis of real-world data of patients with wild-type KRAS exon 2 mCRC showed no differences in OS between cohorts treated with bevacizumab → EGFRi vs the reverse sequence while combined PFS favored the bevacizumab → EGFRi sequence. Keywords: colorectal carcinoma, bevacizumab, panitumumab, cetuximab, sequence

Triple-positive breast cancer (TPBC), i.e. HER2-positive (HER2+) and hormone receptors-positive breast cancer, is a specific subgroup of breast cancers. TPBC biology is characterized by strong mutual interactions between signaling pathways stimulated by estrogens and HER2 amplification. The present study aims to carry out a population-based analysis of treatment outcomes in a cohort of hormone receptor (HR) positive and negative breast cancer patients who were treated with anti-HER2 therapy in the Czech Republic. The BREAST research database was used as the data source for this retrospective analysis. The database covers approximately 95% of breast cancer patients treated with targeted therapies in the Czech Republic. The analysis included 6,122 HER2-positive patients. The patients were divided into two groups, based on estrogen receptor (ER) or progesterone receptor (PR) positivity: hormone receptor negative (HR-) patients had both ER- and PR-negative tumors (n=2,518), unlike positive (HR+) patients (n=3,604). HR+ patients were more often diagnosed premenopausal at the time of diagnosis, presented more often at stage I or II and their tumors were less commonly poorly differentiated. The overall survival (OS) was significantly higher in subgroups of HR+ patients according to treatment setting. When evaluated by stages, significantly higher OS was observed in HR+ patients diagnosed at stages II, III, and IV and regardless of tumor grade. [ABSTRACT FROM AUTHOR]

Abstract A large proportion of colorectal carcinomas (CRC) evolve from colorectal adenomas. However, not all individuals with colonic adenomas have a risk of CRC substantially higher than those of the general population. The aim of the study was to determine the differences or similarities of mutation profile among low- and high-grade adenomas and in situ carcinoma with detailed follow up. We have investigated the mutation spectrum of well-known genes involved in CRC (such as APC, BRAF, EGFR, NRAS, KRAS, PIK3CA, POLE, POLD1, SMAD4, PTEN, and TP53) in a large, well-defined series of 96 adenomas and in situ carcinomas using a high-throughput genotyping technique. Besides, the microsatellite instability and APC and MLH1 promoter methylation were studied as well. We observed a high frequency of pathogenic variants in the studied genes. The APC, KRAS and TP53 mutation frequencies were slightly lower in adenoma samples than in in situ carcinoma samples. Further, when we stratified mutation frequency based on the grade, the frequency distribution was as follows: low-grade adenoma—high-grade adenomas—in situ carcinoma: APC gene 42.9–56.0–54.5%; KRAS gene 32.7–32.0–45.5%; TP53 gene 8.2–20.0–18.2%. The occurrence of KRAS mutation was associated with the presence of villous histology and methylation of the APC promoter was significantly associated with the presence of POLE genetic variations. However, no association was noticed with the presence of any singular mutation and occurrence of subsequent adenoma or CRC. Our data supports the multistep model of gradual accumulation of mutations, especially in the driver genes, such as APC, TP53 and KRAS.

Ondřej Fiala,1,2 Pavel Ostašov,3 Aneta Rozsypalová,4 Milan Hora,5 Ondřej Šorejs,1,2 Jan Šustr,1 Barbora Bendová,5 Ivan Trávníček,5 Jan Filipovský,6 Jindřich Fínek,1 Tomáš Büchler4 1Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic; 2Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech, Czech Republic; 3Laboratory of Tumor Biology and Immunotherapy, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech, Czech Republic; 4Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic; 5Department of Urology, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic; 6 2nd Department of Internal Medicine, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech RepublicCorrespondence: Ondřej FialaDepartment of Oncology and Radiotherapy, Faculty of Medicine and University Hospital Pilsen, Charles University Prague, Alej Svobody 80, Pilsen, CZ-304 60, Czech RepublicTel +42 0728655488Email fialao@fnplzen.czBackground: The anticancer properties of metformin have been suggested in numerous experimental studies and several retrospective clinical studies show that its use is associated with improved outcome of patients with cancer. However, limited data are available for patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy. The aim of this retrospective study was to assess the impact of the metformin use on survival of mRCC patients treated with sunitinib or pazopanib.Methods: Clinical data from 343 patients with mRCC treated with sunitinib or pazopanib in the first line were analyzed. Progression-free survival (PFS) and overall survival (OS) were compared according to the use of metformin.Results: The median PFS and OS for patients using metformin was 31.1 (95% CI 20.6– 35.1) and 51.6 (95% CI 44.7-NR) months compared to 9.3 (95% CI 8.0– 12.0) and 22.4 (95% CI 19.4– 26.8) months for patients not using metformin (p< 0.0001 and p=0.0002, respectively). Cox multivariate analysis shows that the use of metformin remains a significant factor for PFS (HR=0.55 [95% CI 0.343– 0.883], p=0.013) and also for OS (HR=0.45 [95% CI 0.256– 0.794], p=0.006).Conclusion: The present study results suggest that the use of metformin was associated with favorable outcome of mRCC patients treated with sunitinib or pazopanib.Keywords: renal cell carcinoma, metformin, sunitinib, pazopanib, tyrosine kinase inhibitors, outcome