SAN FRANCISCO, CA USA (UroToday.com) - In this session Dr. Thomas Powles addressed genetic changes seen after the application of targeted therapy and the implications these changes have on the development of resistance.
He began by reviewing in vitro studies demonstrating FGF-2 as a potential mechanism for the development of VEGF resistance. He pointed out however that, despite these findings the GOLD study, a phase III trial of dovitinib (an FGF-2 inhibitor) use in VEGF resistant disease showed no improvement when compared to sorafenib, emphasizing the genetic heterogeneity that is likely responsible for conferring resistance.
He discussed data that illustrated the heterogeneity of metastatic disease in RCC, with individual metastatic sites behaving independent of one another in response to systemic therapies, with some sites being responsive and others resistant. In examination of tumor tissue through biopsies obtained prior to and after the administration of targeted therapies, he explained that instead of seeing decreasing heterogeneity as one would expect with the disappearance of sensitive clones and the predominance of resistant clones, his group found increasing tumoral heterogeneity in post-treatment biopsies. This increased heterogeneity correlated with an increase in tumor aggressiveness. Despite this development of increased heterogeneity after targeted therapy, there were some consistent amplifications and losses seen, including in VHL and CAIX. Dr. Powles focused on CAIX and showed data that demonstrated an association between CAIX loss and resistance to sunitinib therapy.
He then talked about the multiple pathways likely exist to the development of a resistant clone, and as the application of targeted therapy blocks several of these pathways, the tumor likely responds by utilizing other pathways -- thus resulting in the increased heterogeneity seen. He noted that as a result, tumor heterogeneity should differ significantly over time and cautioned that, as a result, a single historical tumor biopsy likely does not provide much insight into tumor biology or the presence of different biomarkers. Tumors must be followed over time to gain more information regarding developing pathways to resistance. He concluded by presenting new data from Nature on utilizing sequential circulating tumor DNA for real time tumor assessment, which may, in the future, obviate the need for tissue biopsy to obtain information on tumor changes over time.
Highlights of a presentation by Thomas Powles, MBBS, MRCP, MD at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
Barts Cancer Institute, London England
GU Cancers Symposium 2014, VEGF resistance, dovitinib, GOLD study, sunitinib