Fertility-preserving treatment with progestin, and pathological criteria to predict responses, in young women with endometrial cancer

Yamazawa, Koji; Hirai, Makiko; Fujito, Atsuya; Nishi, Hirokata; Terauchi, Fumitoshi; Ishikura, Hiroshi; Shozu, Makio; Isaka, Keiichi

doi:10.1093/humrep/dem088

Cited by 137 publications

(100 citation statements)

References 19 publications

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“…These conflicting clinical findings may be because of tumor heterogeneity, resulting from genetic alterations in addition to PTEN loss. The expression of PR in endometrial cancer specimens correlates with a positive response to progesterone therapy (25,37). In our in vivo model, differential expression of epithelial PR was observed in AKT vs. PTEN-initiated tumors.…”

Section: Discussionmentioning

confidence: 61%

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Memarzadeh¹,

Zong

Janzen³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial-specific activation of the PI3-kinase pathway is the most common genetic alteration in type I endometrial cancer. In the majority of these tumors, PTEN expression is lost in the epithelium but maintained in tumor stroma. Currently reported PTEN knockout mouse models initiate type I endometrial cancer concomitant with loss of PTEN in both uterine epithelium and stroma. Consequently, the biologic outcome of selectively activating the PI3-kinase pathway in the endometrial epithelium remains unknown. To address this question, we established a malleable in vivo endometrial regeneration system from dissociated murine uterine epithelium and stroma. Regenerated endometrial glands responded to pharmacologic variations in hormonal milieu similar to the native endometrium. Cellautonomous activation of the PI3-kinase pathway via biallelic loss of PTEN or activation of AKT in adult uterine epithelia in this model was sufficient to initiate endometrial carcinoma. AKT-initiated tumors were serially transplantable, demonstrating permanent genetic changes in uterine epithelia. Immunohistochemistry confirmed loss of PTEN or activation of AKT in regenerated hyperplastic glands that were surrounded by wild-type stroma. We demonstrate that cell-autonomous activation of the PI3-kinase pathway is sufficient for the initiation of endometrial carcinoma in naive adult uterine epithelia. This in vivo model provides an ideal platform for testing the response of endometrial carcinoma to targeted therapy against this common genetic alteration.tissue regeneration model | progesterone receptor | uterine cancer E ndometrial cancer, the most common gynecologic cancer in the United States (1), is a hormonally regulated tumor arising from epithelial cells lining the uterine cavity. Effective targeted therapy is unavailable, partly because of lack of knowledge regarding basic biologic pathways and cellular compartments that can initiate this malignancy. Women diagnosed with endometrial cancer are treated in a similar manner irrespective of the heterogeneity of this disease, with surgery or combinations of radiation and chemotherapy. Although endometrial cancer can be cured in early stages, side effects associated with the current therapy can have lifelong debilitating effects on some patients. The majority of women diagnosed with late-stage or metastatic disease die, despite undergoing radical treatments.Endometrial cancer can be divided into two distinct subtypes (2). Type I tumors occur in younger patients exposed to high levels of estrogen unopposed by progesterone. They are typically localized with better response to hormonal therapy. Type II tumors occur in older patients independent of hormonal status. These tumors are more invasive, have a greater propensity for metastatic spread, and are refractory to hormonal treatment. Activation of distinct biologic pathways has been reported in type I vs. type II cancers. Type I tumors are associated with activation of the PI3-kinase pathway, activating mutations of KRAS, mutant β-catenin, an...

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Section: Discussionmentioning

confidence: 61%

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Memarzadeh¹,

Zong

Janzen³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Studies at various institutions have reported the results of fertility-sparing treatment for EC using progesterone preparations (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). However, as the number of cases have been low, the efficacy of such treatment has yet to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Fertility-sparing treatment using medroxyprogesterone acetate for endometrial carcinoma

et al. 2012

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Abstract. The purpose of this study was to present the results of fertility-sparing treatment using medroxyprogesterone acetate (MPA) for endometrial carcinoma (EC), and to clarify patient characteristics by investigating patient background factors. A total of 59 patients with EC, who received MPA as fertility-sparing therapy at two institutions over a 21-year period between 1987 and 2008, were studied retrospectively. Patients were administered oral MPA at 400-600 mg/day for 16-24 weeks as long as they responded. Endometrial tissue was assessed twice, at 8-12 weeks (during treatment) and shortly after treatment. The overall complete response (CR) rate was 71%. A total of 22 (52%) of 42 responders later developed relapse. A total of 19 cases became pregnant, and 25 infants were born. Eighty percent of recurrences occurred within 2 years. For stages Ⅰa and Ⅰb-Ⅱa (FIGO, 1988), initial CR rates were 80.0 and 42.9%, respectively (p<0.01), demonstrating a significant difference. Total hysterectomy was performed for 26 patients (44%) due to recurrence or failure to respond to the initial treatment. Among these 26 patients, postoperative stages were more advanced in 10 patients (38%). The grade advanced (became more poorly differentiated) postoperatively in 2 patients (8%). Premenopausal females with EC can be treated successfully with MPA, however patients should be informed of the risks and limitations of this conservative treatment. IntroductionIn Western countries, endometrial carcinoma (EC) is the most common type of malignant tumor in the field of gynecology (1,2). A state of persistent high estrogen, as observed with ovulation disorders and obesity, is considered a risk factor (3-5). The standard treatments for EC are total hysterectomy and bilateral adnexectomy.EC is a disease that frequently affects perimenopausal females, however approximately 10% of affected females are ≤40 years old, and the incidence in young females has recently been on the increase (6). As in Western countries, the number of ≤40-year-old females with EC in Japan is on the rise (7). Thus, the number of patients who select to undergo fertilitysparing treatment is growing.Studies at various institutions have reported the results of fertility-sparing treatment for EC using progesterone preparations (8-17). However, as the number of cases have been low, the efficacy of such treatment has yet to be clarified. Furthermore, few studies have closely described the clinical background of young females with early-stage EC wishing to undergo fertility-sparing treatment.The present study investigated the effects of treatment, prognosis, pregnancy status and other factors, in order to demonstrate the therapeutic outcomes of current fertility-sparing treatment. Furthermore, patient background factors were investigated to elucidate the characteristics of the patient group. Patients and methods Patients.A total of 59 patients with EC who underwent fertilitysparing treatment, at either the Jichi Medical University Hospital or the Kitasato University Hospit...

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“…These cases were mostly thought to be independent primary or concurrent ovarian endometrioid adenocarcinoma based on histological findings showing that both lesions were very early stage and were rarely confirmed by a heterozygous pattern at the human androgen receptor gene locus. It is of note that Huang et al found similar microscopic patterns, immunohistochemical profiles, and DNA ploidy in a small ovarian lesion of 2×2 mm 2 compared to a primary endometrial lesion [9,11,[14][15][16].…”

Section: Discussionmentioning

confidence: 86%

“…Cases in which extrauterine metastasis occurred during conservative therapy, such as those reported by Imai et al and Ota et al, were also excluded because such cases can be treated by standard surgery. Thus, 13 cases of extrauterine recurrence after temporary remission are listed in Table 2 [3,[8][9][10][11][12][13][14]. Six of these cases had ovarian lesions as the extrauterine site.…”

Section: Discussionmentioning

confidence: 99%

Relapse as Advanced Carcinosarcoma Following Uterus-Preserving Therapy in a Patient with Early-Staged and Grade 1 Endometrioid Adenocarcinoma: A Case Report and Review of the Literature

Takeshita¹

2014

Gynecol Obstet (sunnyvale)

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Fertility-sparing treatment with high-dose progestin is now used in many young patients with early stage, grade 1 endometrioid adenocarcinoma. The response rate of this therapy is quite good, but the relapse rate is relatively high. If the site of recurrence is limited to the uterus, this may be treated with additional hormone therapy or hysterectomy. We recently experienced a case of a 30-year-old primigravida patient in whom intraperitoneal dissemination of carcinosarcoma occurred during follow-up after apparent complete remission of early-stage grade 1 endometrioid adenocarcinoma. We report the case as an example of a rare high-grade histology tumor that relapsed in an extrauterine site after primary remission had been achieved with high-dose progestin therapy. In a review of the literature through a MEDLINE search, we found 13 articles describing relapse in an extrauterine site, including 6 ovarian metastases, 4 retroperitoneal lymph node metastases, and 3 metastases to organs other than the ovary. Early stage, well-differentiated endometrioid adenocarcinoma of the uterine corpus is generally considered to have a good prognosis, but counseling of patients regarding life decisions is important, with provision of sufficient information on the possibility of extrauterine progression or disseminated recurrence.

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Fertility-preserving treatment with progestin, and pathological criteria to predict responses, in young women with endometrial cancer

Abstract: Patients with an initial PR can obtain CR after further treatment, and the PgR may be useful in predicting CR to fertility-preserving treatment in young women with endometrial cancer.

Cited by 137 publications

References 19 publications

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Fertility-sparing treatment using medroxyprogesterone acetate for endometrial carcinoma

Relapse as Advanced Carcinosarcoma Following Uterus-Preserving Therapy in a Patient with Early-Staged and Grade 1 Endometrioid Adenocarcinoma: A Case Report and Review of the Literature

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