Different Transcriptional Responses to Fulvestrant and Estrogen Deprivation in ER-Positive Breast Cancer

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In a study reported in Clinical Cancer Research, Patani and colleagues investigated whether distinct transcriptional responses were associated with the reported increased effectiveness of the estrogen receptor (ER) antagonist fulvestrant (Faslodex) over the aromatase inhibitor anastrozole in ER-positive breast cancer.

Global gene-expression profiles from ERα-positive breast cancers before and during neoadjuvant treatment with fulvestrant (n = 22) or anastrozole (n = 81) and corresponding in vitro models were compared. The overall transcriptional response to fulvestrant and estrogen deprivation with anastrozole was correlated (r = .61 in presurgical studies, r = .87 in vitro), with the response involving downregulation of genes associated with estrogen regulation and proliferation. The transcriptional response to fulvestrant was of greater magnitude (slope = 0.62 in presurgical studies, 0.63 in vitro).

The investigators identified 28 genes and 40 Gene Ontology consortium categories affected differentially by fulvestrant vs anastrozole. These included 17 fulvestrant-specific genes, including CAV1/2, SNAI2, and NRP1, that were associated with ERα, androgen receptor, and TP53 in a network regulating cell cycle, death, survival, and tumor morphology. In addition, 18 genes responding differently to fulvestrant predicted antiproliferative response to fulvestrant but not anastrozole. The transcriptional effects of lower-dose fulvestrant treatment were correlated with those of higher-dose treatment but occurred at a lesser magnitude (ratio = 0.29).

The investigators concluded, “The transcriptional response to fulvestrant has much in common with estrogen deprivation, but is stronger with distinctions potentially attributable to arrest of estrogen-independent ERα activity and involvement of [androgen receptor] signaling. Genes responding differently to fulvestrant may have predictive utility. These data are consistent with the clinical efficacy of fulvestrant versus anastrozole and higher dosing regimens.” ■

Patani N, et al: Clin Cancer Res 20:3962-3973, 2014.