Phase 2 study of anastrozole in recurrent estrogen (ER)/progesterone (PR) positive endometrial cancer: The PARAGON trial – ANZGOG 0903

Mileshkin, Linda; Edmondson, Richard J.; O’Connell, Rachel; Sjoquist, Katrin Marie; Andrews, Jeffrey C; Jyothirmayi, R.; Beale, Philip; Bonaventura, Tony; Goh, Jeffrey C.; Hall, Marcia; Green, John; Lord, Rosemary; Amant, Frédéric; Alexander, Laura E. Crotty; Carty, Karen; Paul, James; Scurry, James; Millan, David; Nottley, Steven; Friedlander, Michael

doi:10.1016/j.ygyno.2019.05.007

Cited by 37 publications

(24 citation statements)

References 26 publications

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“…34,35 The response to tamoxifen and aromatase inhibitors was low in line with studies that show lower RR compared with progestins. 31,36,37 However, in this study, some centers exclusively used tamoxifen and aromatase inhibitors in PR-negative disease. Aside from its predictive relevance, PR IHC expression is also a strong prognostic marker potentially impacting response to hormonal therapy and outcome in cases with PR-negative disease.…”

Section: Commentmentioning

confidence: 98%

Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer

Weelden¹,

Lalisang

Bulten

et al. 2021

American Journal of Obstetrics and Gynecology

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BACKGROUND: Approximately 20% of women with endometrial cancer have advanced-stage disease or suffer from a recurrence. For these women, prognosis is poor, and palliative treatment options include hormonal therapy and chemotherapy. Lack of predictive biomarkers and suboptimal use of existing markers for response to hormonal therapy have resulted in overall limited efficacy. OBJECTIVE: This study aimed to improve the efficacy of hormonal therapy by relating immunohistochemical expression of estrogen and progesterone receptors and estrogen receptor pathway activity scores to response to hormonal therapy. STUDY DESIGN: Patients with advanced or recurrent endometrial cancer and available biopsies taken before the start of hormonal therapy were identified in 16 centers within the European Network for Individualized Treatment in Endometrial Cancer and the Dutch Gynecologic Oncology Group. Tumor tissue was analyzed for estrogen and progesterone receptor expressions and estrogen receptor pathway activity using a quantitative polymerase chain reactionebased messenger RNA model to measure the activity of estrogen receptorerelated target genes in tumor RNA. The primary endpoint was response rate defined as complete and partial response using the Response Evaluation Criteria in Solid Tumors. The secondary endpoints were clinical benefit rate and progression-free survival. RESULTS: Pretreatment biopsies with sufficient endometrial cancer tissue and complete response evaluation were available in 81 of 105 eligible cases. Here, 22 of 81 patients (27.2%) with a response had estrogen and progesterone receptor expressions of >50%, resulting in a response rate of 32.3% (95% confidence interval, 20.9e43.7) for an estrogen receptor expression of >50% and 50.0% (95% confidence interval, 35.2e64.8) for a progesterone receptor expression of >50%. Clinical benefit rate was 56.9% for an estrogen receptor expression of >50% (95% confidence interval, 44.9e68.9) and 75.0% (95% confidence interval, 62.2e87.8) for a progesterone receptor expression of >50%. The application of the estrogen receptor pathway test to cases with a progesterone receptor expression of >50% resulted in a response rate of 57.6% (95% confidence interval, 42.1e73.1). After 2 years of follow-up, 34.3% of cases (95% confidence interval, 20e48) with a progesterone receptor expression of >50% and 35.8% of cases (95% confidence interval, 20e52) with an estrogen receptor pathway activity score of >15 had not progressed. CONCLUSION: The prediction of response to hormonal treatment in endometrial cancer improves substantially with a 50% cutoff level for progesterone receptor immunohistochemical expression and by applying a sequential test algorithm using progesterone receptor immunohistochemical expression and estrogen receptor pathway activity scores. However, results need to be validated in the prospective Prediction of Response to Hormonal Therapy in Advanced and Recurrent Endometrial Cancer (PROMOTE) study.

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Section: Commentmentioning

confidence: 98%

Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer

Weelden¹,

Lalisang

Bulten

et al. 2021

American Journal of Obstetrics and Gynecology

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“…In the PARAGON trial a response rate of 7% and a clinical benefit rate of 44% was reported with anastrazole in a cohort of 82 patients with recurrent, receptor positive, endometrial carcinoma. 396 A single-arm phase II trial demonstrated a high response rate and clinical benefit rate with the combination of letrozole and everolimus. 397 Confirmation of hormone receptor status by biopsy should be considered at the time of recurrence because of a potential change in hormone receptor expression between primary tumor and recurrence.…”

Section: Systemic Treatment For Recurrent Diseasementioning

confidence: 99%

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma

Concin

Matías‐Guiu

Vergote

et al. 2020

Int J Gynecol Cancer

994

1,395

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A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.

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“…For example, in 40 women treated with exemestane, there was remission in 10% and lack of progression after 6 months in 35% of the patients (Lindemann et al 2014). The PARAGON trial, a phase 2 open label study using anastazole in 82 patients with ER and/or PR positive hormonal therapy naive metastatic endometrial cancer, reported clinical benefit in 44% of patients (Mileshkin et al 2019), although results from other trials have been disappointing and may have been influenced by obesity in the target population (van Weelden et al 2019). Some promising results have been reported following treatment of women with the rarer cancer low grade endometrial sarcoma with AIs (reviewed in Pannier et al 2019).…”

Section: Aromatase Inhibitorsmentioning

confidence: 99%

Androgens, oestrogens and endometrium: a fine balance between perfection and pathology

Gibson

Simitsidellis

Collins

et al. 2020

Journal of Endocrinology

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The endometrium is a complex multicellular tissue that is exquisitely sensitive to the actions of sex steroids synthesised in the ovary (endocrine system). Recent studies have highlighted a previously under-appreciated role for local (intracrine) metabolism in fine-tuning tissue function in both health and disease. In this review we have focused on the impact of oestrogens and androgens on endometrial function summarising data from studies on normal endometrial physiology and disorders including infertility, endometriosis and cancer. We consider the evidence that expression of enzymes including aromatase, sulphatase and AKR1C3 by endometrial cells plays an important role in tissue function, and malfunction, and discus results from studies using drugs targeting intracrine pathways to treat endometrial disorders. We summarise studies exploring the spatial and temporal expression of oestrogen receptors (ERalpha, ERbeta and GPER) and their role in mediating the impact of endogenous and synthetic ligands on cross-talk between vascular, immune, epithelial and stromal cells. There is a single androgen receptor and androgens play a key role in stromal-epithelial cross talk, scar-free healing of endometrium during menstruation and regulation of cell proliferation. The development of new receptor-selective drugs (SERMs, SARMs, SARDs) has reinvigorated interest in targeting receptor subtypes in treatment of disorders including endometriosis and endometrial cancer and some show promise as novel therapies. In summary, understanding the mechanisms regulated by sex steroids provides the platform for improved personalised treatment of endometrial disorders as well as novel insights into the impact of steroids on processes such as tissue repair and regeneration.

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Phase 2 study of anastrozole in recurrent estrogen (ER)/progesterone (PR) positive endometrial cancer: The PARAGON trial – ANZGOG 0903

Cited by 37 publications

References 26 publications

Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer

Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma

Androgens, oestrogens and endometrium: a fine balance between perfection and pathology

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