## 10 Estrogen-Related Receptors and Non-Small Cell Lung Cancer
### Progress of Clinical Trials on Estrogen-Targeting-Driven Non-Small Cell Lung Cancer Treatment  
Table 2 enlists the to-date progress of clinical trials aimed at the NSCLC treatment through targeting the estrogen-regulated signaling pathways and regulatory activities. Three of the described attempts have used a combinatorial approach, employing EGFR inhibitors, gefitinib or erlotinib, in combination with the estrogen-inhibiting compound fulvestrant. Since these studies correspond to different phases, the results do not present an unbiased picture to compare. For instance, a phase I clinical trial of gefitinib with fulvestrant exhibited a good safety profile with significant anti-tumor response in female sufferers having recurrent-stage NSCLC, irrespective of the therapies received. Three of the examined twenty patients in this study developed partial responses with a 15% response rate, 12-week median progression-free survival and a 38.5-week median overall survival. A striking observation corresponded to a longer overall survival in patients expressing ER\(\beta\) to a higher extent, 65.5 weeks against the 21 weeks for low-ER\(\beta\)-expressing tumors [143]. This was the first clinical trial of estrogen in NSCLC, the results of which were published in 2009, demonstrating safety and potential efficacy. Another of these studies was conducted at a phase II level, which found the clinical benefit rate (comprising partial responders and those with stable disease) to be higher amongst the sufferers treated with erlotinib and fulvestrant rather than erlotinib alone. This trend was specifically observed for the patients having EGFR wild configured tumors [144], albeit the third study (a phase II clinical trial) using this combination also observed a better response for the combinatorial mode but was restricted to NSCLC sufferers with EGFR wild configurations [184]. A far-sighted concluding generalization was made in the first of these attempts, wherein other than the feasibility of fulvestrant and erlotinib combined, no reliability was anticipated without knowing about the EGFR status. Thereby, administering erlotinib and fulvestrant in combination is indeed not suitable with respect to an unselected sufferer population [202]. Two studies focused on tuning hormonal response (estrogens via exemestane) in combination with immune checkpoint inhibitors (ICIs) and chemotherapeutic drugs (pemetrexed disodium and carboplatin), on both occasions in postmenopausal women [145; 146]. A third configuration comprised of co-delivering EGFR and aromatase inhibitors, namely, gefitinib and anastrazole, taking encouragement from their synergistic response toward suppressed proliferation and apoptotic induction in NSCLC cell lines [149]. Amongst the remaining four attempts, three worked on optimizing the dosage extent of chemotherapeutic drugs (paclitaxel poliglumex with carboplatin, xenutzumab with abemaciclib and nintedanib with ethinyl estradiol and levonorgestrel) with or without hormonal therapies. The paclitaxel poliglumex co-delivery with carboplatin was a phase III study screened in \(>\)25 pg\(\cdot\)mL\({}^{-1}\) estradiol possessing female NSCLC sufferers [146] while the other two trials were phase I studies conducted irrespective of tumor stages with the xenutzumab-abemaciclib combination in the optional togetherness of hormonal replacement therapy (in progress) [145; 147]. The remaining study analyzed the efficacy of entinostat pharmacokinetics with respect to specific food intake. This attempt co-delivered entinostat with erlotinib (an EGFR inhibitor) and exemestane (an anti-estrogen) to screen the pharmacokinetic distribution of entinostat, but no results have been published so far for this study. Of note, entinostat is a benzamide histone deacetylase inhibitor and is being screened for anticancer efficacy via multiple clinical trials.