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2027 KRAS status and risk of venous thromboembolic events in patients with metastatic colorectal cancer: A case-control study
Abstracts to evaluate pharmacokinetics, safety, anti-tumor activity, and effects on electrocardiogram (ECG) intervals. QT intervals were assessed by Holter ECG and corrected using the methods of Fridericia (QTcF) and Bazett (QTcB). LVEF was measured by multigated acquisition (MUGA) scanning. Results: A total of 53 patients were enrolled and received at least one dose of regorafenib 160 mg. 25 patients received regorafenib 160 mg for 21 days without dose modification and were evaluable for the analysis of posttreatment ECGs on Day 21 Cycle 1 or 2. The mean change from baseline in QTcF at tmax was −2 ms (90%CI: −8, 3). No patient had a change from baseline in QTcF >60 ms and two patients had QTcF changes between 30 and 60 ms. No patient had QTcF or QTcB >480 ms. LVEF was evaluated in two sets of patients. In one set of 27 patients who had baseline and post-treatment LVEF data and received at least 80 mg of regorafenib, the mean change from baseline in LVEF% was 1.7±7.8. In the second set of 14 evaluable patients who did not have a dose reduction, the mean change from baseline in LVEF% was −0.1±8.6 at Cycle 2 Day 21. Four patients with a history of hypertension had a decrease in LVEF between 10% and 20%. In two cases, LVEF decreased to <50%, but normalized without treatment modification; in the other two, medical conditions may have had a role (atrial fibrillation, new onset clonidine therapy). After 4 cycles of therapy the mean LVEF% change was −2.4±6.6 (n = 20). Longterm data collected at Cycle 20 Day 1 showed a mean LVEF% change of 4.7±5.5 (n = 3). Conclusions: The effects of regorafenib on the QT/QTc interval and LVEF were modest and unlikely to be of clinical significance in patients with advanced cancer. Conflict of interest: Ownership: Diefenbach and Boix: Bayer. Advisory Board: Jones: Immune Design. Daiichi Sankyo. Merck. Blueprint Medicines. Moore: Astrazeneca. Immunogen. Genentech. Amgen. Advaxis. Corporatesponsored Research: Lockhart: Amgen. Bayer. Daiichi Sankyo. EMD Serono. Genentech/Roche. Lilly. Millennium Takeda. Novartis. Sanofi. Teva. Zenyaku Kogyo. Smith: Bayer. Other Substantive Relationships: Jones: Bayer, Eisai, Novartis, Johnson & Johnson, Pharmamar, Infinity Pharmaceuticals, Threshold Pharmaceuticals, Morphotek. Diefenbach, Lettieri, Boix: employees of Bayer. O’Bryant and Bendell: Nothing to disclose. 2027 POSTER KRAS status and risk of venous thromboembolic events in patients with metastatic colorectal cancer: A case-control study K. Rihawi1 , C. Fontanella1 , D. Rossini2 , M. Schirripa2 , E. De Carlo1 , L. Salvatore2 , E. Ongaro1 , M. Casagrande1 , L. Ferrari1 , N. Pella1 , G.G. Cardellino1 , M. Giovannoni1 , E. Iaiza1 , P. Ermacora1 , F. Puglisi1 , F. Loupakis2 , F. Alfredo2 , G. Fasola1 , G. Aprile1 . 1 Azienda Ospedaliera Universitaria, Department of Oncology, Udine, Italy; 2 Azienda Ospedaliero Universitaria Pisana − Universita` di Pisa, Oncology, Pisa, Italy Background: Cancer patients (pts) are at increased risk of venous thrombotic events (VTE) which are associated with both increased morbidity and mortality. Tissue factor (TF) is the primary initiator of blood coagulation and preclinical data suggest that its expression is also controlled by KRAS. TF overexpression in cancer cells seems to be associated with KRAS mutation; the latter therefore might be a plausible link to hypercoagulability and increased VTE risk for metastatic colorectal cancer (mCRC) pts. Current guidelines do not recommend routine pharmacological VTE prophylaxis for such pts. Identifying novel predictors of VTE risk, based on the tumour molecular profile, would allow detecting pts more likely to benefit from thromboprophylaxis. Material and Methods: A retrospective case-control study was conducted. Cases had VTE (deep vein thrombosis (DVT), pulmonary embolism (PE), and/or migratory superficial thrombophlebitis) occurring within six months of the diagnosis of metastatic disease or to any time thereafter. Controls were pts with mCRC without VTE, matched for age, sex, year of diagnosis of metastatic disease, and presence of a central venous access device. Cases and controls were identified from the electronic health records of the Department of Oncology, Udine, and of the Department of Oncology, Pisa. Formalin-fixed, paraffin-embedded samples were reviewed and tested by pyrosequencing for KRAS status (codons 12, 13, 61 and 146). Nonmetastatic cases or those with indeterminate KRAS results, were excluded. Estimating that about 40% of mCRC harbor a KRAS mutation and with a cases/controls ratio of 1:2, the sample size needed to determine a significant odds ratio (OR) of 2.5 was approximately 77 cases and 154 controls, with a = 0.05 and a power of 80%. Logistic regression was used to determine whether there was an association between KRAS mutational status and VTE occurrence. Results: Between Jan 2008 and Dec 2014 a total of 68 cases with VTE and 177 controls without VTE were included. Thirty-four of the cases had DVT, 34 had PE. Of note, 6 patients had both thrombotic events. When VTE
S337 occurred, 37% of pts were receiving a bevacizumab-containing regimen. Among the controls, 38% received bevacizumab. Fifty-three (78%) of the cases and 137 (77%) of the controls had a central venous access device. In our analysis, KRAS mutated status (codon 12, 13, 61 and 146) was not associated with a higher risk of thrombosis with an OR of 1.34 (95% CI 0.77–2.36, p = 0.303) for VTE. Conclusions: Despite the trend towards an increased risk of VTE for pts with KRAS-mutant mCRC, our results were not statistically significant. Further studies are needed to investigate the link between KRAS mutation, TF overexpression and and VTE. No conflict of interest. 2028 POSTER Self-expandable colonic stent increases plasma level of circulating cell free DNA significantly in patients with obstructive colorectal cancer G. Takahashi1 , T. Yamada1 , H. Kan1 , S. Matsumoto2 , M. Koizumi1 , S. Shinji1 , A. Matsuda2 , Y. Yokoyama1 , T. Iwai1 , A. Watanabe3 , M. Nakayama4 , S. Kitano4 , E. Uchida1 . 1 Nippon Medical School, Digestive Surgery, Tokyo, Japan; 2 Nippon Medical School Chiba Hokusou Hospial, Surgery, Chiba, Japan; 3 Nippon Medical School, Biochemistry and Molecular Biology, Tokyo, Japan; 4 Toppan Printing CO., LTD, Toppan Technical Institute, Saitama, Japan Background: Obstructive colorectal cancer (OCC) accounts for 10% of colorectal cancer. In OCC patients, primary anastomosis with curative resection for OCC has a higher risk of anastomotic leakage, selfexpandable metallic stent (SEMS) is expected not only for a palliative therapy but also a preoperative procedure for OCC (Bridge to Surgery; BTS). It can reduce the pressure of dilated intestinal tract, prevent anastomotic leakage and colostomy formation. Although it was reported that SEMS might have negative impact on long-term survival of OCC, the mechanisms are still unknown. Replacement of SEMS causes continuous compression on tumor and colonic wall, therefore the manipulation is considered the cause of poor survival. On the other hand, in Japan, transanal drainage tube (TDT) has developed as a preoperative procedure for OCC, and there are no reports that indicate negative effects of TDT. Circulating cell free DNA (ccfDNA) is a new biomarker for various clinical conditions including malignancy. We have reported that increasing levels of ccfDNA can be a negative prognostic biomarker in patients with metastatic colorectal cancer. In this study, we investigated the ccfDNA levels in OCC patients before and after decompression by using SEMS or TDT. Patients and Method: ccfDNA was purified from 1 mL plasma using the QIAamp Circulating Nucleic Acid Kit. ccfDNA was measured using fluorescence determination. We measured ccfDNA 4 points, before and 1, 4, 7days after decompression. Results: We enrolled 7 patients (4 male and 3 female). Five patients were diagnosed with sigmoid colon cancer and 2 were rectal cancer (Stage II: 2, Stage III: 2, Stage IV: 3). Four patients were decompressed with SEMS and 3 were TDT. All procedures were performed successfully and no complication was observed. ccfDNA concentrations of SEMS increased significantly on the next day after decompression, and return to the same level on 4th days after decompression (pre; 1352 ng/ml, day 1; 6865 ng/ml, day 4; 1782 ng/ml). In contrast, those of TDT remained at the pre-decompression level after decompression (pre; 992 ng/ml, day 1; 1572 ng/ml, day4; 1021 ng/ml). There were no differences in biochemical examination of blood between 2 procedures. Conclusion: Compared with TDT, SEMS increases plasma levels of ccfDNA significantly in patients with OCC. This may negatively affect longterm survival of OCC. No conflict of interest. 2029 POSTER Histological subtype analysis of colon cancer: A population-based study − Mucinous histology is a different disease A. De Giorgi1 , F. Negri1 , E.M. Silini2 , P. Sgargi3 , C. Azzoni2 , L. Bottarelli2 , A. Gilli1 , M. Michiara3 , L. Manotti4 , C. Pinto1 . 1 Azienda Ospedaliero-Universitaria di Parma, Medical Oncology Unit, Parma, Italy; 2 Azienda Ospedaliero-Universitaria di Parma, Pathology Unit, Parma, Italy; 3 Azienda Ospedaliero-Universitaria di Parma, Medical Oncology Unit and Cancer Registry of Parma Province, Parma, Italy; 4 Azienda Istituti Ospitalieri, Pathology Unit, Cremona, Italy Background: Several retrospective studies suggested unfavourable outcome of mucinous tumours. However, if mucinous histology is a predictive and prognostic factor in colon cancer is uncertain.
S337 occurred, 37% of pts were receiving a bevacizumab-containing regimen. Among the controls, 38% received bevacizumab. Fifty-three (78%) of the cases and 137 (77%) of the controls had a central venous access device. In our analysis, KRAS mutated status (codon 12, 13, 61 and 146) was not associated with a higher risk of thrombosis with an OR of 1.34 (95% CI 0.77–2.36, p = 0.303) for VTE. Conclusions: Despite the trend towards an increased risk of VTE for pts with KRAS-mutant mCRC, our results were not statistically significant. Further studies are needed to investigate the link between KRAS mutation, TF overexpression and and VTE. No conflict of interest. 2028 POSTER Self-expandable colonic stent increases plasma level of circulating cell free DNA significantly in patients with obstructive colorectal cancer G. Takahashi1 , T. Yamada1 , H. Kan1 , S. Matsumoto2 , M. Koizumi1 , S. Shinji1 , A. Matsuda2 , Y. Yokoyama1 , T. Iwai1 , A. Watanabe3 , M. Nakayama4 , S. Kitano4 , E. Uchida1 . 1 Nippon Medical School, Digestive Surgery, Tokyo, Japan; 2 Nippon Medical School Chiba Hokusou Hospial, Surgery, Chiba, Japan; 3 Nippon Medical School, Biochemistry and Molecular Biology, Tokyo, Japan; 4 Toppan Printing CO., LTD, Toppan Technical Institute, Saitama, Japan Background: Obstructive colorectal cancer (OCC) accounts for 10% of colorectal cancer. In OCC patients, primary anastomosis with curative resection for OCC has a higher risk of anastomotic leakage, selfexpandable metallic stent (SEMS) is expected not only for a palliative therapy but also a preoperative procedure for OCC (Bridge to Surgery; BTS). It can reduce the pressure of dilated intestinal tract, prevent anastomotic leakage and colostomy formation. Although it was reported that SEMS might have negative impact on long-term survival of OCC, the mechanisms are still unknown. Replacement of SEMS causes continuous compression on tumor and colonic wall, therefore the manipulation is considered the cause of poor survival. On the other hand, in Japan, transanal drainage tube (TDT) has developed as a preoperative procedure for OCC, and there are no reports that indicate negative effects of TDT. Circulating cell free DNA (ccfDNA) is a new biomarker for various clinical conditions including malignancy. We have reported that increasing levels of ccfDNA can be a negative prognostic biomarker in patients with metastatic colorectal cancer. In this study, we investigated the ccfDNA levels in OCC patients before and after decompression by using SEMS or TDT. Patients and Method: ccfDNA was purified from 1 mL plasma using the QIAamp Circulating Nucleic Acid Kit. ccfDNA was measured using fluorescence determination. We measured ccfDNA 4 points, before and 1, 4, 7days after decompression. Results: We enrolled 7 patients (4 male and 3 female). Five patients were diagnosed with sigmoid colon cancer and 2 were rectal cancer (Stage II: 2, Stage III: 2, Stage IV: 3). Four patients were decompressed with SEMS and 3 were TDT. All procedures were performed successfully and no complication was observed. ccfDNA concentrations of SEMS increased significantly on the next day after decompression, and return to the same level on 4th days after decompression (pre; 1352 ng/ml, day 1; 6865 ng/ml, day 4; 1782 ng/ml). In contrast, those of TDT remained at the pre-decompression level after decompression (pre; 992 ng/ml, day 1; 1572 ng/ml, day4; 1021 ng/ml). There were no differences in biochemical examination of blood between 2 procedures. Conclusion: Compared with TDT, SEMS increases plasma levels of ccfDNA significantly in patients with OCC. This may negatively affect longterm survival of OCC. No conflict of interest. 2029 POSTER Histological subtype analysis of colon cancer: A population-based study − Mucinous histology is a different disease A. De Giorgi1 , F. Negri1 , E.M. Silini2 , P. Sgargi3 , C. Azzoni2 , L. Bottarelli2 , A. Gilli1 , M. Michiara3 , L. Manotti4 , C. Pinto1 . 1 Azienda Ospedaliero-Universitaria di Parma, Medical Oncology Unit, Parma, Italy; 2 Azienda Ospedaliero-Universitaria di Parma, Pathology Unit, Parma, Italy; 3 Azienda Ospedaliero-Universitaria di Parma, Medical Oncology Unit and Cancer Registry of Parma Province, Parma, Italy; 4 Azienda Istituti Ospitalieri, Pathology Unit, Cremona, Italy Background: Several retrospective studies suggested unfavourable outcome of mucinous tumours. However, if mucinous histology is a predictive and prognostic factor in colon cancer is uncertain.