Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial

Janda, Monika; Robledo, Kristy; Gebski, Val; Armes, Jane E.; Alizart, Michelle; Cummings, Margaret C.; Chen, Chen; Leung, Yee; Sykes, Peter; McNally, Orla; Oehler, Martin K.; Walker, Graeme; Garrett, Andrea; Tang, Amy; Land, Russell; Nicklin, James L.; Chetty, Naven; Perrin, Lewis; Hoet, Greet; Sowden, Katherine; Eva, Lois; Tristram, Amanda; Obermair, Andreas

doi:10.1016/j.ygyno.2021.01.029

Cited by 59 publications

(63 citation statements)

References 51 publications

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“…Knowing the role of obesity-related biological pathways and mediators in the pathogenesis and prognosis of endometrioid endometrial malignancies offers new perspectives and therapeutic strategies that have not been explored to date. A combined approach, comprising aromatase inhibitors combined with antidiabetic, anti-inflammatory, and antioxidant drugs, plus progestins administered locally through an intrauterine device [ 66 ], may constitute a new targeted therapeutic approach, particularly in women that, by virtue of obesity, may also have an increased risk of surgical complications and, therefore, could not receive optimal surgery. The contribution of targeting these pathways in the context of adjuvant treatment is no less important, where the information available is limited and scarcely homogeneous.…”

Section: Discussionmentioning

confidence: 99%

Correlation of Leptin, Proinflammatory Cytokines and Oxidative Stress with Tumor Size and Disease Stage of Endometrioid (Type I) Endometrial Cancer and Review of the Underlying Mechanisms

Madeddu

Sanna

Gramignano³

et al. 2022

Cancers

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Endometrioid endometrial cancer is associated with increased BMI and obesity through multiple pathogenetic mechanisms involving hyperestrogenism, hyperinsulinemia, altered adipokine secretion, inflammation, and oxidative stress. In the present study, we aimed to investigate the correlation between BMI, leptin, the proinflammatory cytokines IL-6 and TNFα, reactive oxygen species (ROS), and the traditional prognostic factors T, G, N and M status among type I endometrioid and type II endometrial cancer patients. We enrolled 305 consecutive endometrial cancer patients prospectively. We found that BMI, leptin, and IL-6 significantly correlated with T status, N status, and M status among endometrioid type I endometrial cancer patients. Among type II endometrial cancer patients, BMI and leptin did not correlate with any of the prognostic parameters, whereas there was a positive correlation between IL-6 and the presence of distant metastases. In the multivariate regression analysis, BMI, leptin, and IL-6 were independent predictive variables of T, N, and M status in endometrioid type I endometrial cancer patients. Our study demonstrates that weight gain, adiposity-related adipokines, inflammation, and oxidative stress correlate with the prognostic factors of endometrioid endometrial cancer. Knowledge of the role of obesity-related biological pathways and mediators in the pathogenesis and prognosis of endometrioid endometrial malignancies may offer new perspectives on combined therapeutic strategies that have not been explored to date, both in the advanced disease and in the adjuvant setting.

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Section: Discussionmentioning

confidence: 99%

Correlation of Leptin, Proinflammatory Cytokines and Oxidative Stress with Tumor Size and Disease Stage of Endometrioid (Type I) Endometrial Cancer and Review of the Underlying Mechanisms

Madeddu

Sanna

Gramignano³

et al. 2022

Cancers

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“…The feMMe trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA. The methods and primary outcomes of this study have been previously described ( Janda et al, 2021 ). Qualitative interviews were conducted as part of long-term follow-up of women who participated in the feMMe trial to inform the translation of the trial interventions into clinical practice.…”

Section: Methodsmentioning

confidence: 99%

“…Only few clinical trials have evaluated the efficacy and oncologic safety of non-surgical treatment of EAC and EHA using levonorgestrel delivered by an intrauterine device (LNG-IUD) ( Hawkes et al, 2014 , Janda et al, 2021 , Kim et al, 2019 , Minig et al, 2011 , Westin et al, 2021 ), reporting pathological response rates ranging from 37% to 66% ( Janda et al, 2021 , Kim et al, 2019 , Minig et al, 2011 , Westin et al, 2021 ). One of these was the feMMe trial, a randomised controlled Phase II clinical trial that investigated the effectiveness of LNG-IUD for the treatment of EAC or EHA, with or without metformin or weight loss ( Janda et al, 2021 ). The feMMe trial enrolled 165 patients, 96 (58%) diagnosed with EAC and 69 (42%) diagnosed with EHA.…”

Section: Introductionmentioning

confidence: 99%

Patient experiences of conservative treatment for early stage endometrial cancer and endometrial hyperplasia with atypia using levonorgestrel intrauterine device: A qualitative study

O’Hara

Janda

McCarthy

et al. 2022

Gynecologic Oncology Reports

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“…12 The evidence base for the use of the LNG-IUS when treating EEC appears promising, with treatment in this setting yielding response rates between 52% and 67%. [13][14][15][16] Compared with oral progestogens, the LNG-IUS has a similar disease regression rate and is associated with fewer systemic adverse effects due to being placed locally in the uterus. 17 Still, the evidence appears that there is inconsistency in response when using the LNG-IUS for treatment of early-stage EC in some women making the unknown mechanisms of LNG resistance a critical obstacle for the conservative management of EC.…”

Section: Introductionmentioning

confidence: 99%

Characterisation of Levonorgestrel-Resistant Endometrial Cancer Cells

Dore¹,

Filoche²,

Danielson³

et al. 2021

CMAR

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Background: Endometrial cancer (EC) is the most common gynaecologic malignancy in the developed world, and incidence is increasing in premenopausal women. The levonorgestrel intrauterine system (LNG-IUS) is gaining traction as an alternative treatment for hyperplasia and early-stage EC for women who are unable to undergo surgery. Thirty to 60% of the women do not respond to this treatment, making the unknown mechanisms of levonorgestrel (LNG) resistance a critical obstacle for the conservative management of EC. This study aimed to characterise LNG-IUS treatment resistance in early-stage endometrial cancer in cell-line models. Methods: LNG-resistant endometrial cancer cell lines (MFE296 R and MFE319 R ) and cultures from three early stage endometrial cancer patients were developed. The behavioural profile of MFE296 R and MFE319 R was analysed using proliferation, adhesion, migration (wound healing and transwell) and invasion (spheroid) assays. LNG-sensitive cell lines (MFE296 S and MFE319 S ) were compared to LNG R cell lines (MFE296 R and MFE319 R ). A literature search was conducted to identify possible candidate biomarkers of LNG resistance. RT-qPCR was used to analyse the mRNA expression of 17 candidate biomarkers in MFE296 R and MFE319 R . mRNA expression of the top differentially expressed genes was measured using RT-qPCR in primary cultures. Results: LNG resistance did not affect proliferation or invasion in immortalised endometrial cancer cells. Transwell migration was significantly increased in MFE319 R cells (p=0.03). Cellular adhesion significantly decreased in both MFE296 R cells (p=0.012) and MFE319 R cells (p=0.04). mRNA expression of KLF4 and SATB2 was significantly amplified in MFE296 R and MFE319 R cells. mRNA expression of KLF4 was significantly upregulated LNG-resistant primary cell lines. Conclusion: LNG-resistant cells may have more oncogenic potential than their LNGsensitive counterparts. Significant changes in the mRNA expression of KLF4 and SATB2 of LNG-resistant cells is a promising preliminary result in biomarker discovery for guiding LNG-IUS treatment of early stage endometrial cancer.

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Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial

Cited by 59 publications

References 51 publications

Correlation of Leptin, Proinflammatory Cytokines and Oxidative Stress with Tumor Size and Disease Stage of Endometrioid (Type I) Endometrial Cancer and Review of the Underlying Mechanisms

Correlation of Leptin, Proinflammatory Cytokines and Oxidative Stress with Tumor Size and Disease Stage of Endometrioid (Type I) Endometrial Cancer and Review of the Underlying Mechanisms

Patient experiences of conservative treatment for early stage endometrial cancer and endometrial hyperplasia with atypia using levonorgestrel intrauterine device: A qualitative study

Characterisation of Levonorgestrel-Resistant Endometrial Cancer Cells

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