Cellular mechanism of hormone action
Intracellular Steroid Hormone Receptor Signaling PathwayA few breakthroughs have been accomplished for the treatment of ovarian cancer, the most deadly gynecologic carcinoma, in the current era of targeted oncologic treatment. The estrogen receptor was the first target of testosteron medikamente nebenwirkungen treatments with the introduction of tamoxifen four decades ago in breast cancer therapeutics. Attempts to duplicate the success of hormonal therapies in ovarian cancer steroid hormone receptor v 8 1 with mixed results, which may be due to an inferior degree of hormone dependency in this cancer. Alternatively, this may be due to the failure to anabol steroid price identify the subsets of ovarian cancer with hormone sensitivity. This article reviews the expression of hormone receptors by ovarian cancer cells, the prognostic value of these expressions, and their predictive capacity for response to hormonal agents. The possible ways ahead are briefly discussed.
Regulation of Intracellular Steroid Hormone Receptor Signaling
A few breakthroughs have been accomplished for the treatment of ovarian cancer, the most deadly gynecologic carcinoma, in the current era of targeted oncologic treatment.
The estrogen receptor was the first target of such treatments with the introduction of tamoxifen four decades ago in breast cancer therapeutics. Attempts to duplicate the success of hormonal therapies in ovarian cancer met with mixed results, which may be due to an inferior degree of hormone dependency in this cancer. Alternatively, this may be due to the failure to clearly identify the subsets of ovarian cancer with hormone sensitivity.
This article reviews the expression of hormone receptors by ovarian cancer cells, the prognostic value of these expressions, and their predictive capacity for response to hormonal agents. The possible ways ahead are briefly discussed. The receptors for estrogen and progesterone hormones have a well-established prognostic and treatment-predictive role in breast cancer, but, although they have been studied in ovarian cancer, their role in that disease is less well defined.
A clear benefit has not been established in several small clinical trials evaluating the role of hormone-blocking treatments in ovarian cancer, despite the fact that clinicians treating the disease often encounter positive outcomes with these treatments.
Indeed, most studies usually involve only a few dozen patients, including all ovarian cancer subtypes, and some studies do not take into account the expression of the hormone receptors in tumor cells. This expression has been of paramount importance for confirming the value of hormonal treatments in breast cancer.
In breast cancer, additional genomic markers are currently available to further characterize antihormone treatment sensitivity in estrogen receptor ER -positive cancers, and therapeutic algorithms have advanced to rely on these markers in addition to the expression of the hormone receptors. Failure to stratify patients with the aid of treatment-predictive factors may significantly impede the ability to discern the benefits of specific anticancer treatments, and this has become even more critical in the present environment of targeted treatments.
This article discusses current data on the expression of various important hormone receptors as a basis to evaluate hormone treatments for ovarian cancer in the second line or beyond setting. It will further explore ways when these treatments become optimized in the future based on predictive markers and their pathogenic implications. The largest study examining ER expression was reported by the Ovarian Tumor Tissue Analysis Consortium and included ovarian cancer patients with various epithelial histologies.
The study also found that ER positivity across subtypes was associated with a better prognosis with a hazard ratio of 0. When progesterone receptor PR positivity was taken additionally into account, tumors positive for both receptors had even better disease-specific survival with a hazard ratio of 0. A series of stage III and IV serous ovarian carcinomas evaluated ER and PR expression taking into consideration the differences with the age of the patient at presentation.
Although no prognostic role of ER and PR was found in the entire cohort, a trend toward a better prognosis of ER- and PR-positive tumors was observed in younger patients.
An adverse prognostic value for ER-positive tumors was also reported in another series of 96 optimally cytoreduced serous ovarian cystadenocarcinomas. The worse survival of ER-positive patients was due to late deaths, after three years from surgery. Different cutoff points, antibodies used, and techniques as well as different populations studied may explain the variable results in these studies. Of interest is that the only study examining serous cystadenocarcinomas found a reverse influence of ER expression in survival.
This observation argues for the importance of patient selection in therapeutic trials, given that different prognostic implications of a marker may also underline the variability in the value of treatments targeting the marker. Human GPER1 is a completely different protein from the two estrogen nuclear receptors and mediates the effects of estrogens through signaling from the membranes of the endoplasmic reticulum. GPER1 was expressed in both the mRNA and protein level in approximately one-third of ovarian cancers, but no prognostic association was found.
PR is the prototypic ER target gene, and in breast cancer, its prognostic role has been proposed to be due to the information it may provide regarding functional ER competence. Progesterone Receptor PR expression and prognostic value in serous ovarian carcinoma. The previously discussed Danish study examined the expression of PR, in addition to ER, in ovarian cancer patients according to histologic subtype.
PR positivity conferred a better disease-specific survival with a hazard ratio of 0. As previously mentioned, combined ER and PR positivity conferred an even better disease-specific survival. PR-positive tumors had a better prognosis and better 2-year and 5-year survival than negative cases, while ER was not prognostic.
In a series of 96 patients with stage III ovarian cystadenocarcinomas who underwent optimal cytoreduction and postoperative chemotherapy, PR status essayed by a biochemical method instead of IHC was not prognostic for survival. PR expression at the mRNA level was examined in a study of both normal and neoplastic human surface ovarian epithelium. GnRH is another target of estrogen signaling. GnRH affects ovarian cancer cells both indirectly by stimulating production of FSH and LH in the hypophysis, which then stimulate estrogen and progesterone production in the ovaries and directly as the majority of ovarian cancer cell lines and ovarian cancers express the GnRH receptor.
Having established the presence of hormone receptors in ovarian cancer, the next step to advance a therapeutic role involves confirmation of their involvement in pathogenesis, which implies dependence of cancer cells to their signaling. In vitro and in vivo models may inform these points. Activation of GPER1 is also involved in signaling in ovarian cancer cells. The invasion and motility promotion effect was traced in this cell line model to an upregulation of metalloproteinase MMP-9 induced by GPER1 activation.
GnRH analogs and antagonists have an inhibitory effect in human xenograft ovarian cancer cell models in nude mice. GnRH receptor on the surface of human ovarian cancer cells signals through a phosphotyrosine phosphatase to down-regulate receptor tyrosine kinases activity and also through JunD to inhibit cell cycle. Overall, these data pinpoint to several possible avenues to further explore the development of clinical hormonal therapies in ovarian cancer, guided by the effects seen in ovarian cancer preclinical models.
A number of studies have examined the role of hormonal therapies in ovarian cancer and have been reviewed. The focus will also be on studies that include receptors expression and published in full. Most experience exists with tamoxifen and aromatase inhibitors, while only a few studies examined fulvestrant or GnRH analogs. All studies are small phase II or retrospective series, include, at best, a few dozen patients with pretreated ovarian cancer and tend to encompass all epithelial histologies.
Several have not examined receptor expression as an inclusion criterion, and some have been published only in abstract form but not in full. From these studies, some clinically useful evidence can be extracted.
Most reports on aromatase inhibitors use letrozole. In an open-labeled nonrandomized study of 60 relapsed ovarian cancer patients, letrozole 2. Patients with higher ER expression had a higher response compared with those with intermediate expression. The same was true for aromatase inhibitors versus tamoxifen. The ER downregulator fulvestrant was evaluated in a phase II trial of ovarian cancer patients who had received multiple previous chemotherapies.
Based on these results and given the advanced disease status of these patients and lack of other treatment options, fulvestrant may represent a useful and well-tolerated drug, if this study is replicated. An interesting case report of a year-old woman with ER- and PR-positive heavily pretreated with chemotherapy serous ovarian carcinoma illustrates the concept of using multiple lines of hormonal treatment.
PR-targeting agents have also been studied in small phase II studies in ovarian cancer. Medroxyprogesterone is a progestin with androgenic activity in addition to progestogen activity, which has been used clinically as a contraceptive.
Studies have suggested that women using medroxyprogesterone contraceptives may have a decreased incidence of epithelial ovarian cancer. Patients in this study were all pretreated with chemotherapy, and most had two or three lines of treatment.
A phase II study of 26 chemotherapy pretreated ovarian cancer patients examined the combination of monthly goserelin with tamoxifen. Another therapeutic concept takes an advantage of the expression of various receptors by tumor cells to target chemotherapeutic cytotoxic drugs to these cells by using ligands of the receptors conjugated to cytotoxic chemotherapeutics. One such compound conjugates the GnRH agonist zoptarelin with doxorubicin.
This drug was examined in a phase II trial of 42 platinum refractory or resistant ovarian cancer patients with mostly serous histology. The median OS was 53 weeks, and the toxicity profile was acceptable with a few grade 3 and 4 toxicities.
The authors conclude that the conjugate is a candidate for further development. A recently reported randomized trial of patients with ovarian cancer studied adjuvant hormone replacement therapy for a planned five years in women diagnosed with epithelial ovarian cancers within the previous nine months. Fifty-three of the 72 patients who received therapy in the treatment arm had an estrogen-alone preparation, while 19 patients received estrogens combined with norgestrel. Concomitant treatments were not reported, but the median hormone therapy duration in the treatment arm was 1.
The study showed a better overall and relapse-free survival in the replacement group. As a result of the variability of stage, histologies, and replacement treatment, as well as the unknown variable of concomitant treatments, the study is minimally helpful in informing the question of the value of hormone replacement as a therapeutic manipulation in ovarian cancer and serous histology in particular.
At this point, hormone replacement could be considered for menopause symptom relief in early stage disease if no other hormone manipulation as an anticancer therapy is planned. Effective treatments are needed for patients with ovarian cancer, especially in the second line and beyond, as well as the platinum refractory setting. Significant progress has been made in cancer therapeutics over the past several years with the introduction of targeted therapies that take advantage of the improved understanding of cancer biology.
This unfortunately has not been the case in ovarian cancer where the only targeted treatment currently shown to produce a benefit is the Vascular Endothelial Growth Factor VEGF monoclonal antibody bevacizumab in the platinum-resistant recurrent setting. Ovarian cancer arising also in an endocrine organ could be another target of this type of treatment.
Experience gained from breast cancer, where hormone treatments comprise the backbone of systemic therapy for ER-positive carcinomas, and also from endometrial carcinomas, where similar hormonal treatments have been used in the second-line metastatic setting, 81 could direct further development of these treatments in ovarian cancer. Evaluation of ER expression has been instrumental in guiding ER-directed treatments in breast cancer and should be taken into consideration for further development of these treatments in ovarian cancer.
In addition, there is a need to better target specific subsets of the disease based on histologies and genetic profiles instead of treating all ovarian cancers as a uniform disease, which is clear that it is not. Standardization of the evaluation of their expression in the clinic is a prerequisite for their full exploitation as previously learned from the ER use in breast cancer.
Eventually, one can envisage the use of a panel of well-standardized expressions of several hormone receptors to guide treatment of well-characterized ovarian cancer subsets as the optimal mean of obtaining the full potential of hormonal treatments. Development of a test based on the expression of a panel of estrogen-responsive genes correlating with the response to endocrine therapies could be an alternative or complementary strategy. An additional problem in cancer treatment with targeted agents consists of changes of the expression of the target with disease evolution.
This is a well-documented issue in breast cancer and could be a cause of treatment failure with hormonal agents in ovarian cancer if receptor expression changes. Information on this aspect of individual tumor biology would be of interest for treatment planning and use of sequential treatments addressing parts of the cancer with differing biologies.
Tumor heterogeneity, either primary or secondary to treatment pressure, may relate to the presence or acquisition of molecular lesions leading to tumor resistance.
Lesions commonly present in serous ovarian cancers have been characterized in whole-genome studies. Finally, development of combinations of hormonal treatments with other targeted agents is another therapeutic pathway to consider. Here again breast cancer leads the way with the introduction of combinations of hormonal therapies with mTOR or cyclin D inhibitors and the hope is that ovarian cancer could follow the paradigm.
William Chi-shing Cho, Editor in Chief. Six peer reviewers contributed to the peer review report. Author discloses no external funding sources. Author discloses no potential conflicts of interest. Paper subject to independent expert blind peer review. All editorial decisions made by independent academic editor. Upon submission manuscript was subject to anti-plagiarism scanning.
Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties.
Wrote the first draft of the manuscript: Developed the structure and arguments for the paper:
The Role of Gonadotropin-Releasing Hormone in Cancer Cell Proliferation and Metastasis
Clark JH, Peck EJ () Steroidhormone receptors: Basic principles and measurement. In: O'Nolley BW, Birnboumer L (eds) Receptor and hormone action, vol 1. J Steroid Biochem 8: Ferland L, Fernand L, Kelly PA, Raymond V () Interactions between hypothalamic and peripheral hormones in the control. Oncogene – J Clin Endocrinol Metab – RM Evans ( ) The steroid and thyroid hormone receptor superfamily. Raven, New York Giguere V, Hollenberg SM, Rosenfeld MG, Evans RM () Functional Proc Natl Acad Sci USA – 1 1 Mangelsdorf DJ, Thummel C, Beato M. () The DNAbinding protein HMG-1 enhances progesterone receptor binding to its target Orti E, Bodwell JE, Munck A () Phosphorylation of steroid hormone receptors. Baillieres Clin Endocrinol Metab – Pedersen SB, Jonler M, EMBO J – Picard D, Kumar V, Chambon P, Yamamoto KR.