The anti-angiogenic agent bevacizumab (BEV) is one of the most effective forms of biologic therapy developed thus far for cervical cancer (CC). However, response is variable, BEV is expensive, and significant toxicity may occur. Given the projected increase in the global burden of cancer and limited health care resources, it is imperative that research be conducted to define patients that will truly benefit from expensive therapies. The development of an angiogenic biomarker to direct the use of BEV could maximize benefit, as well as minimize toxicity and cost. My collaborator, Dr. Andrew Nixon, and his team at Duke have developed a protein-based plasma multiplex array (angioma) that consists of 26 growth factors and cytokines involved in angiogenesis and inflammation. We propose to evaluate our most promising biomarker, interleukin-6 (IL-6), which has demonstrated predictive efficacy for BEV in other solid tumors, in women with advanced metastatic CC enrolled on the Gynecologic Oncology Group (GOG) 240. Our primary aim is to determine if IL-6 levels can be utilized to direct BEV therapy for women with CC. The pivotal phase III GOG-0240, a 2x2 bifactorial placebo- controlled trial of taxane-based chemotherapy with and without BEV is the ideal platform to assess biomarkers.
Our specific aims will determine if (a) baseline IL-6 is predictive of BEV benefit based on survival outcomes, (b) other angiome biomarkers are predictive and/or prognostic of survival outcomes in women with advanced CC and c) angiome biomarker change is associated with outcome and response. Plasma samples at baseline and pre-cycle 2 from GOG-0240 will be analyzed in Dr. Nixon?s laboratory using several multiplex systems including technology from Quanterix Corporation, MesoScaleDiscovery, and Protein Simple (R&D Systems). Statistical analyses will be performed to identify and validate biomarkers of interest. Kaplan-Meier plots and log-rank tests will compare treatment groups. Our ultimate goal is to improve the outcome for women with CC by rationally directing BEV therapy; minimizing toxicity and cost; and identifying novel targets to develop future anti-angiogenic therapies. We anticipate that our research will help to harmonize analyses across other malignancies, which will be critical for understanding if IL-6 and other candidate biomarkers predictive of BEV efficacy are, or are not, disease specific.
IL-6 has a crucial role in the tumor microenvironment, a may represent a key intersection between tumor angiogenesis signaling pathways, immune response, and the inflammatory response in cancer. This project will determine if the IL-6 biomarker that can guide the use of anti-angiogenic agents in cervical cancer patients. The successful completion of this project could alter the paradigm for the use of bevacizumab as well as other anti-angiogenic agents in cervical cancer; allow for rational and potentially cost-effective delivery of therapy; develop the foundation to evaluate biomarkers to direct anti-angiogenic and immunotherapy; and harmonize biomarker analyses across other malignancies.
