Abstract 3273: Estrogen contributes to bevacizumab resistance in xenograft models of non-small cell lung cancer (NSCLC)
Authors: Saigal Babita , Herynk Mathew H , Cascone Tina , Nilsson Monique , Khajavi Mehrdad , Saintigny Pierre , Heymach John V. 
Published: June 2012

Previous studies have established that there are differences in the oncogenic pathways activated in women and men with NSCLC and that women with hormonal replacement therapy have significantly decreased survival. Furthermore, in the ECOG4599 study comparing chemotherapy with or without the VEGF inhibitor bevacizumab (BV), overall survival benefit was seen in men but not women. Together these studies suggest that estrogen (E2) may contribute to cancer progression and response to antiangiogenic therapy. The mechanism(s) by which this may occur is not well understood, although it has been previously reported that E2 increases the secretion of Vascular Endothelial Growth Factor (VEGF) in vitro, that the vast majority of NSCLC express estrogen receptors (ER), and that estrogen stimulates the growth of NSCLC xenografts in nude mice. To evaluate whether E2 promotes the growth of NSCLC and resistance to antiangiogenic therapy, we tested the impact of E2 on response to BV in murine models of NSCLC. Briefly, overiectomized nude female mice were primed with an extended release pellet of estradiol-17ß. Mice were then subcutaneously injected with HCC827 lung cancer cells and randomized when tumor volume reached 200-250mm3. Tumor progression was defined when tumor volume reached 1000mm3 in size. Mice were treated with BV in the presence or absence of E2 and were sacrificed at progression. We observed prolonged survival in the BV alone group compared to the BV+E2 group (median survival more than 200 days for BV vs. 56 days for the BV+E2 group p=0.006). In addition, the combination of BV+E2 group had a significantly improved survival compared with vehicle+E2 (56 days vs. 26 days, p &lt; 0.0001). Furthermore, in absence of E2, a trend towards a decrease in MVD was observed in BV vs Vehicle (11 vs 20, t-Test, p=0.08); in the presence of E2, by contrast, no significant changes in vascular density were observed between BV+E2 vs Vehicle+E2 (24.8 vs 21.75, t-Test, p=0.37). To investigate the contribution of estrogen signaling pathway in response to BV, a similar study was performed with the addition of the ER antagonist, fulvestrant (F). The addition of F to BV+E2 significantly prolonged the median survival compared with BV + E2 (88 days in F+BV+E2 group vs. 47 days in BV+E2, p=0.007). This was accompanied with significant reduction of MVD compared with BV+E2 (BV+F+E2 (12.77) vs BV+E2(22.12), t-Test, p = 0.03). No difference in survival was observed in F+E2 vs. Control+E2 (p=0.159) or F+E2 vs. BV+E2 (p=0.3). Conclusions: Our findings indicate that in a preclinical model of NSCLC, estrogen promoted resistance to anti-VEGF therapy and increased tumor microvesssel density. The addition of the ER antagonist fulvestrant was able to block the E2-induced BV resistance. These data suggest that estrogen blockade merits further investigation as a potential therapeutic strategy to mitigate resistance to antiVEGF therapy in women with NSCLC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3273. doi:10.1158/1538-7445.AM2011-3273