Abstracts 1
BJUI
Abstracts
Differential expression of MET between primary and metastatic sites in clear cell Renal Cell Carcinomas (ccRCCs) Laurence Albiges1, Guillermo De Velasco1, André P. Fay1, Marcella Caella1, Ingrid Carvo1, Jiaxi Song1, Elizabeth M. Genega1, Mamta Gupta1, Rupal S. Bhatt1, David F. McDermott1, Michael B. Atkins2, George F. Vande Woude3, Toni K. Choueiri1, Sabina Signoretti1 1 Kidney Cancer Program, Dana-Farber/ Harvard Cancer Center, Boston, MA, USA; 2 Georgetown-Lombardi Comprehensive Cancer Center, DC, USA; 3Van Andel Research Institute, MI, USA
Background: Targeting MET with Tyrosine Kinase Inhibitors is currently actively being evaluated in ccRCC. MET expression has been correlated with worse prognosis in ccRCC (Gibney, 2013), but its value as a predictive biomarker remains unknown. Furthermore, some reports suggest that MET expression can be induced by prior VEGFR targeted therapy (Sharpe, 2013). Tissue biomarkers in RCC are usually evaluated in the primary tumors, which may not accurately reflect expression in the metastases that are the target of systemic therapy. We report the comparison of MET expression in a series of ccRCCs and their metastases. Methods: Formalin-fixed paraffinembedded tissue blocks from 31 primary ccRCCs and corresponding metastases were retrieved. Multiple areas of the primary tumors, including areas of predominant and highest Fuhrman nuclear grade, were selected for analysis. Immunohistochemistry was performed on four micron-thick tumor sections using a previously validated anti-MET monoclonal antibody (MET4, provided by Dr. Vande
Woude at Van Andel Research Institute) at 1:250 dilution. Membranous expression in tumor cells was quantified using a combined score calculated by multiplying the percentage of positive tumor cells with the predominant membranous staining intensity [1 + to 3+]. Results: Of the 31 ccRCC included in the study, 28 primary tumors and metastases pairs were assessable for MET staining. Furthermore, 17 cases out of 28 (61%) were analyzed in different areas of the primary tumor to investigate potential tumor heterogeneity in MET staining. The median combined score in primary tumors was 17.8 (range: 0–150) while the median combined score in metastatic sites was 60.0 (range: 0–180), P = 0.001. High level of heterogeneity for MET staining was observed within primary tumors with absolute difference of the combined scores between two areas of the same primary ranging from 0 to 115 and an absolute median difference of the combined scores of 20. MET expression in primary tumors was significantly associated with higher Fuhrman nuclear grade (P = 0.006). Conclusions: MET expression displays heterogeneity within the primary tumors and is significantly higher in metastatic sites compared to primary lesions. Accurate assessment of MET expression as predictive biomarker for MET inhibitors may potentially require analysis of metastatic lesions. Ongoing clinical trials (METEOR, NCT01865747; CABOSUN, NCT01835158) will further address the use of MET inhibition Analysis of a larger patient cohort is ongoing to confirm these findings.
© 2014 The Authors BJU International © 2014 BJU International | 114, Supplement 4, 1–18
An alternative titration schedule of axitinib in metastatic renal cell carcinoma Vyshak Alva, Laura S. Wood, Paul Elson, Allison Martin, Jennifer Beach, Jorge A. Garcia, Brian I. Rini Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH
Background: Titration of axitinib for metastatic renal cell carcinoma (mRCC) is currently based on tolerance with escalation from 5 to 7 to 10 mg p.o. BID. However, not all patients (pts) who undergo dose escalation require a higher dose for response, nor do all patients tolerate the increased dose levels. An alternative titrating strategy was employed based on radiographic response, tolerance and using non-standard dosing. Methods: In this retrospective analysis of mRCC, axitinib was initiated at 5 mg BID. Response was assessed with CT scans at 6 weeks after each dosing change. Patients with response by MASS criteria and acceptable AEs (
BJUI
Abstracts
Differential expression of MET between primary and metastatic sites in clear cell Renal Cell Carcinomas (ccRCCs) Laurence Albiges1, Guillermo De Velasco1, André P. Fay1, Marcella Caella1, Ingrid Carvo1, Jiaxi Song1, Elizabeth M. Genega1, Mamta Gupta1, Rupal S. Bhatt1, David F. McDermott1, Michael B. Atkins2, George F. Vande Woude3, Toni K. Choueiri1, Sabina Signoretti1 1 Kidney Cancer Program, Dana-Farber/ Harvard Cancer Center, Boston, MA, USA; 2 Georgetown-Lombardi Comprehensive Cancer Center, DC, USA; 3Van Andel Research Institute, MI, USA
Background: Targeting MET with Tyrosine Kinase Inhibitors is currently actively being evaluated in ccRCC. MET expression has been correlated with worse prognosis in ccRCC (Gibney, 2013), but its value as a predictive biomarker remains unknown. Furthermore, some reports suggest that MET expression can be induced by prior VEGFR targeted therapy (Sharpe, 2013). Tissue biomarkers in RCC are usually evaluated in the primary tumors, which may not accurately reflect expression in the metastases that are the target of systemic therapy. We report the comparison of MET expression in a series of ccRCCs and their metastases. Methods: Formalin-fixed paraffinembedded tissue blocks from 31 primary ccRCCs and corresponding metastases were retrieved. Multiple areas of the primary tumors, including areas of predominant and highest Fuhrman nuclear grade, were selected for analysis. Immunohistochemistry was performed on four micron-thick tumor sections using a previously validated anti-MET monoclonal antibody (MET4, provided by Dr. Vande
Woude at Van Andel Research Institute) at 1:250 dilution. Membranous expression in tumor cells was quantified using a combined score calculated by multiplying the percentage of positive tumor cells with the predominant membranous staining intensity [1 + to 3+]. Results: Of the 31 ccRCC included in the study, 28 primary tumors and metastases pairs were assessable for MET staining. Furthermore, 17 cases out of 28 (61%) were analyzed in different areas of the primary tumor to investigate potential tumor heterogeneity in MET staining. The median combined score in primary tumors was 17.8 (range: 0–150) while the median combined score in metastatic sites was 60.0 (range: 0–180), P = 0.001. High level of heterogeneity for MET staining was observed within primary tumors with absolute difference of the combined scores between two areas of the same primary ranging from 0 to 115 and an absolute median difference of the combined scores of 20. MET expression in primary tumors was significantly associated with higher Fuhrman nuclear grade (P = 0.006). Conclusions: MET expression displays heterogeneity within the primary tumors and is significantly higher in metastatic sites compared to primary lesions. Accurate assessment of MET expression as predictive biomarker for MET inhibitors may potentially require analysis of metastatic lesions. Ongoing clinical trials (METEOR, NCT01865747; CABOSUN, NCT01835158) will further address the use of MET inhibition Analysis of a larger patient cohort is ongoing to confirm these findings.
© 2014 The Authors BJU International © 2014 BJU International | 114, Supplement 4, 1–18
An alternative titration schedule of axitinib in metastatic renal cell carcinoma Vyshak Alva, Laura S. Wood, Paul Elson, Allison Martin, Jennifer Beach, Jorge A. Garcia, Brian I. Rini Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH
Background: Titration of axitinib for metastatic renal cell carcinoma (mRCC) is currently based on tolerance with escalation from 5 to 7 to 10 mg p.o. BID. However, not all patients (pts) who undergo dose escalation require a higher dose for response, nor do all patients tolerate the increased dose levels. An alternative titrating strategy was employed based on radiographic response, tolerance and using non-standard dosing. Methods: In this retrospective analysis of mRCC, axitinib was initiated at 5 mg BID. Response was assessed with CT scans at 6 weeks after each dosing change. Patients with response by MASS criteria and acceptable AEs (
