New insights on the role of hormonal therapy in ovarian cancer

Abstract

Ovarian cancer (OVCA) is the most lethal gynecological malignancy. It is often diagnosed in advanced stages and despite therapy, 70% relapse within 2 years with incurable disease. Regimens with clinical benefit and minimal toxicity are urgently needed. More effective hormonal therapies would be appealing in this setting. Estrogens (E2) are implicated in the etiology of OVCA. Estrogens drive proliferation and anti-estrogens inhibit ovarian cancer growth in vitro and in vivo. Despite estrogen receptor (ER) expression in 67% of OVCAs, small anti-estrogen therapy trials have been disappointing and the benefit of hormonal therapy has not been systematically studied in large well-designed trials. OVCAs often manifest de novo anti-estrogen resistance and those that initially respond invariably develop resistance. Estrogens stimulate ovarian cancer progression by transcriptional activation and cross talk between liganded ER and mitogenic pathways, both of which drive cell cycle progression. Estrogen deprivation and estrogen receptor (ER) blockade cause cell cycle arrest in susceptible OVCAs by increasing the cell cycle inhibitor, p27. This review summarizes and discusses scientific and epidemiological evidence supporting estrogen’s role in ovarian carcinogenesis, provides an overview of clinical trials of ER blockade and aromatase inhibitors in OVCA and reviews potential causes of antiestrogen resistance. Anti-estrogen resistance was recently shown to be reversed by dual ER and Src signaling blockade. Blocking cross-talk between ER and constitutively activated kinase pathways may improve anti-estrogen therapeutic efficacy in OVCA, as has been demonstrated in other cancers. Novel strategies to improve benefit from anti-estrogens by combining them with targeted therapies are reviewed.

Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma

“…Cross-talk of downstream of estrogen receptor and other receptor tyrosine kinase (RTK) may also explain the possibility that estrogen receptor expression itself was not associated with survival outcome in HGSOC [12]. In this cross-talk mechanism, regulation of tumor growth by the ER-pathway could be activated by another type of RTK signaling that is commonly seen in other types of hormonal sensitive malignancies such as breast and endometrial cancer [30,31].…”

“…HGSOC, the most common histologic subtype of ovarian cancer and known to have aggressive tumor biology, expresses estrogen receptor in 60-85% of the samples [7,8]. Estrogen replacement therapy has been related to increased ovarian cancer incidence and mortality related to disease [9][10][11][12]. In particular, this increased risk of ovarian cancer with estrogen use was seen for serous histology [13,14].…”

Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma

“…HGSOC, the most common histologic subtype of ovarian cancer and known to have aggressive tumor biology, expresses estrogen receptor in 60-85% of the samples [7,8]. Estrogen replacement therapy has been related to increased ovarian cancer incidence and mortality related to disease [9-12]. In particular, this increased risk of ovarian cancer with estrogen use was seen for serous histology [13,14].…”

Activation of estrogen receptor α by estradiol and cisplatin induces platinum-resistance in ovarian cancer cells

“…The clinical response rate of tamoxifen (a selective estrogen receptor modulator) for recurrent ovarian cancer was 48%. 37 Furthermore, combination therapy with first line chemotherapeutic agents and tamoxifen did not improve the efficacy of the cytotoxic agents in ovarian cancer patients. 38 However, the limitation of previous clinical studies is that ERa expression was not investigated.…”