Effect of Aromatase Inhibition on Functional Gene Modules in Estrogen Receptor–Positive Breast Cancer and Their Relationship with Antiproliferative Response

Abstract

Purpose: To investigate potential associations between gene modules representing key biologic processes and response to aromatase inhibitors (AI) in estrogen receptor-positive (ER þ ) breast cancer.Patients and Methods: Paired gene expression and Ki67 protein expression were available from 69 postmenopausal women with ER þ early breast cancer, at baseline and 2 weeks post-anastrozole treatment, in the presurgical setting. Functional gene modules (n ¼ 26) were retrieved from published studies and their module scores were computed before and after elimination of proliferation-associated genes (PAG). Ki67 and module scores were assessed at baseline and 2 weeks post-anastrozole. Unsupervised clustering was used to assess associations between modules and Ki67. Results: Proliferation-based modules were highly correlated with Ki67 expression both pretreatment and on-treatment. At baseline with and without PAGs, Ki67 expression was significantly inversely correlated with ERG, ESR1.2, SET, and PIK3CA modules. Modules measuring estrogen signaling strongly predicted antiproliferative response to therapy with and without PAGs. Baseline expression of insulin-like growth factor-1 (IGF-I) module predicted a poor change in Ki67-implicating genes within the module as involved in de novo resistance to AIs. High expression of Immune.2.STAT1 module pretreatment predicted poor antiproliferative response to therapy. A significant association between estrogen-regulated genes modules (ESR1, ESR1-2, SET, and ERG) was evident post AI.Conclusions: Multiple processes and pathways are affected by AI treatment in ER þ breast cancer.Modules closely associated with ESR1 expression were predictive of good antiproliferative response to AIs, but modules representing immune activity and IGF-I/MAPK were predictive of poor Ki67 response, supporting their therapeutic targeting in combination with AIs.

Prediction of Response to Aromatase Inhibitors in Breast Cancer

“…For example, Miller et al [142] studied RNA expression in sequential biopsies taken before and after two weeks of neoadjuvant treatment with letrozole. The effects of 2-weeks preoperative treatment with either anastrozole or letrozole have also been examined [35,122,143]. Molecular responses detected in the studies were consistent.…”

“…In a similar study employing anastrozole pretreatment. Gao et al [143] also found that multiple processes and pathways were affected by the AI treatment. Modules closely associated with ESR1 expression were predictive of good antiproliferative response to AIs, whereas modules representing immune activity and IGF-I/MAPK were predictive of poor Ki67 response, supporting their therapeutic targeting in combination with AIs.…”

The kinome associated with estrogen receptor-positive status in human breast cancer

“…In ERC breast cancer, gene signatures that are based on proliferation often strongly correlate with Ki67 expression (Gao et al 2014), a well-known marker of proliferation. Furthermore, in ERC breast tumors in particular, it is Ki67 and not pCR that is the early correlative endpoint for predicting efficacy of both hormonal therapy or chemotherapy in ERC breast cancer (Yerushalmi et al 2010, Dowsett et al 2011, von Minckwitz et al 2012, Gao et al 2014.…”

“…Furthermore, in ERC breast tumors in particular, it is Ki67 and not pCR that is the early correlative endpoint for predicting efficacy of both hormonal therapy or chemotherapy in ERC breast cancer (Yerushalmi et al 2010, Dowsett et al 2011, von Minckwitz et al 2012, Gao et al 2014. Recently, using Yes (Wei et al 2014) neoadjuvant antiestrogen therapy (particularly AIs), it was observed that decreased detection of survival pathway activation markers (e.g.…”

Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay

“…Aromatase inhibitors (AIs) are continuously being developed that have considerable clinical impact on the production of estrogen among post-menopausal women and thereby on breast cancer [10,11] . Currently, AIs are classified into two subtypes: steroidal and non-steroidal.…”