Abstract SY01-01: Endocrine resistance in metastatic breast cancer: Mechanisms and new therapeutic strategies
Authors: Schiff Rachel , Veeraraghavan Jamunarani , Fu Xiaoyong 
Published: August 2018

Abstract
Multiple lines of preclinical and clinical evidence suggest a continued, albeit altered, role of estrogen receptor (ER) in endocrine resistance, a major hurdle in the clinical management of ER+ breast cancer. In the recent years, several studies that explored the biology of ER in recurrent metastatic disease in patients and in endocrine-resistant preclinical models have uncovered various mechanisms underlying altered ER activity and endocrine resistance. Some of these mechanisms are observed to emerge under the pressure of chronic endocrine therapy, through selective clonal expansion, resulting in acquired resistance. Recurrent gain-of-function mutations in the ligand-binding and other domains of the ER encoding gene ESR1 have been identified in 20-50% of the patients with endocrine-resistant metastatic breast cancers. Tumor biopsies have long been useful in identifying various mutations, but circulating tumor DNA in patients with advanced disease is now also emerging as a clinically valuable resource enabling the noninvasive detection of ESR1 mutations. Most of the ESR1 mutations confer constitutive ligand-independent ER activity, causing resistance to estrogen deprivation (i.e., aromatase inhibitors) and reduced sensitivity to the selective ER modulator (SERM) tamoxifen and the selective ER downregulator (SERD) fulvestrant. Less frequent ESR1-related genomic alterations, including gene amplifications, rearrangements, and gain-of-function gene fusions identified mostly in patients with recurrent metastatic disease, represent additional mechanisms of acquired endocrine resistance. While the therapeutic value of newly developed orally bioavailable SERMs/SERDs such as GDC-0810 and GDC-0927 for patients with tumors harboring ESR1 mutations is yet to be clinically proven, we anticipate that ongoing studies will address this open question. Additionally, the recent clinically potent CDK4/6 inhibitor palbociclib, in combination with fulvestrant, has shown promising therapeutic efficacy against tumors harboring ESR1 mutations. Acquired amplification of the aromatase-encoding gene CYP19A1, recently reported in ~20% of aromatase inhibitor-treated relapsed patients, has also been linked to endocrine resistance due to increased aromatase activity and intratumoral estrogen levels.
Besides genomic alterations in ER, crosstalk between growth factor receptor (GFR) signaling pathways and ER can also mediate resistance by altering the activity of ER and its co-regulators, and as a result, the ER-dependent transcriptional program. In particular, the bidirectional crosstalk between ER and the HER family and other GFRs, including in ER+/HER2- tumors that harbor HER2 activating mutations and FGFR1 amplification in 10-15% of patients with ER+ breast cancer, has been implicated in endocrine resistance. Combined treatment with endocrine therapy plus inhibitors against pertinent GFRs or their downstream signaling components to circumvent resistance is currently under preclinical and clinical evaluation. Other factors that contribute to endocrine resistance are changes in ER-interacting/co-regulator proteins such as the ER co-activator SRC3, transcription factor complex AP-1, and the pioneer factor FOXA1. Most recently, a new smal- molecule inhibitor targeting SRC3 has been shown to inhibit the levels and/or transcriptional activity of the SRC family of coactivators and the growth of endocrine-naïve and resistant tumors in vivo.
Clinical findings and preclinical data from in vivo mouse xenograft models have shown that the endocrine-resistant tumors harbor increased AP-1 activity, which mediates a shift in the ER transcriptional program and promotes endocrine resistance and metastatic capabilities. Numerous preclinical findings have long suggested the crucial role of the ER pioneer factor FOXA1 in cancer development and progression. In breast cancer, we first reported that high levels of FOXA1, by gene amplification and/or overexpression, promote acquired endocrine resistance across multiple endocrine-resistant cell and xenograft mouse models. In the clinical setting, recent sequencing studies have reported FOXA1 genomic aberrations, including gene amplification, recurrent mutations, and overexpression via activating mutations in the promoter region, in about 10% of ER+ primary tumors, and enrichment in metastatic tumors. Further, in the metastatic setting, FOXA1 genetic aberrations and ESR1 mutations associated with aromatase inhibitor resistance appear to be mutually exclusive, suggesting the involvement of different mechanisms in high FOXA1-induced endocrine resistance and metastasis. Our new studies in acquired endocrine-resistant preclinical models suggest that FOXA1 gene amplification and/or overexpression results in a global enhancer and transcriptional reprogramming that activates key downstream transcription factors, including the hypoxia-induced factor HIF2α, and the prometastatic secretome. Our findings thus support the notion that, at least in a subset of patients with ER+ breast cancer, high levels or activity of FOXA1 are drivers of endocrine resistance and metastasis, presenting new therapeutic targets and novel therapeutic approaches along its reprogrammed transcriptional axis at both the regulatory and downstream effector levels.
These findings underscore the need for a more careful assessment of the genomic, epigenomic, and signaling landscape of recurrent lesions in order to devise more tailored therapies to effectively circumvent and/or prevent endocrine resistance and metastasis. In addition, a more complete suppression of the levels and activity of ER, its co-activators, and alternative survival pathways may prove to be a better therapeutic strategy in effectively combating endocrine resistance. Effective therapeutic strategies may include novel epigenomic approaches to inhibit gene expression and activity of ER and its co-activators, more potent SERDs, small-molecule inhibitors of SRC3 and other ER co-activators, signal transduction inhibitors that modulate levels and activity of ER and its co-activators, a new HIF2α small-molecule inhibitor currently under clinical evaluation in renal cell carcinoma, and development of drugs that specifically target the pioneer factor FOXA1.
Citation Format: Rachel Schiff, Jamunarani Veeraraghavan, Xiaoyong Fu. Endocrine resistance in metastatic breast cancer: Mechanisms and new therapeutic strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY01-01.