Nobuyuki Susumu

Characteristics of endometrial cancer progressed to extrauterine lesions following fertility preserving medroxyprogesterone acetate therapy for young endometrial cancer patients

Medroxyprogesterone acetate (MPA) is an effective fertility-preserving treatment for early endometrial cancer and atypical endometrial hyperplasia (AEH), and rarely leads to the development of extrauterine lesions (ELs). We aimed to clarify the characteristics of patients who developed ELs post-MPA therapy. We analyzed the clinicopathological factors and prognoses of 319 patients with endometrioid carcinoma grade 1 (EMG1) and AEH treated with MPA at our institution. All patients underwent imaging before MPA treatment to rule out ELs. Seven patients (2.2%) with EMG1 showed EL after MPA treatment. Two patients developed EL during the initial treatment, 2 during repeated treatment, and 3 during follow-up. Two patients had peritoneal dissemination, 3 had regional lymph node metastasis, 1 had distant metastasis at the Virchow lymph node, and 1 had ovarian metastasis. ELs were diagnosed using imaging tests in 6 patients and elevated tumor markers in 3 (overlapping) patients. One patient was diagnosed with ELs pathologically after hysterectomy. Upon EL diagnosis, patients underwent standard treatment, including hysterectomy and chemotherapy, that was followed by a diagnosis of EMG1 for 5, EMG2 for 1, and EMG3 for 1 patient. One patient died 15 months after start of therapy and another died 119 months post-treatment initiation, while the others have been survived. Only 2.2% of all patients developed ELs post-MPA treatment, but some cases were fatal. It is essential to conduct imaging tests and screen for tumor markers during and after MPA treatment regularly and also when cancer progression is suspected.

A phase II trial evaluating the efficacy and safety of repeated high dose medroxyprogesterone acetate (MPA) therapy for patients with recurrent early-stage endometrial cancer or atypical endometrial hyperplasia: Japanese Gynecologic Oncology Group study (JGOG2051/KGOG2031, REMPA trial)

Fertility preserving therapy using medroxyprogesterone acetate (MPA) is an important option for young patients with endometrial cancer or atypical endometrial hyperplasia (AEH). However, the effectiveness and feasibility of repeated MPA therapy for patients with intrauterine recurrence following initial MPA therapy is controversial. Only a few single-institution retrospective studies have been conducted on repeated MPA therapy, therefore, multicenter prospective studies for repeated MPA therapy are highly needed. The aim of this study is to assess whether repeated MPA therapy is effective and feasible for patients with intrauterine recurrence following initial MPA therapy. This is a prospective, single-arm, a multicenter phase II trial on repeated MPA therapy for intrauterine recurrence following fertility-preserving therapy for AEH or stage IA (the International Federation of Gynecology and Obstetrics [FIGO] 2008) non-myoinvasive endometrioid carcinoma grade 1. Patients are treated with oral MPA (500-600 mg/day). Pathologically assessment via dilation and curettage will be performed every 2 months until complete response. The major inclusion criteria are 1) intrauterine recurrence of AEH or stage IA (FIGO 2008) endometrioid carcinoma grade 1 without myometrial invasion or extrauterine spread confirmed by imaging tests after complete remission with the previous MPA therapy. 2) The number of recurrences should be up to twice. 3) histologically diagnosed as AEH or endometrioid carcinoma grade 1, 4) 20-42 years of age, and 5) strong desire and consent for fertility-sparing treatment. The primary endpoint is 2-year recurrence-free survival rate. A total of 115 patients will be enrolled from multiple institutions in Japan and Korea within 4 years and followed up for 2 years. Japan Registry of Clinical Trials Identifier: jRCTs031200256.

Prognostication of early-onset endometrioid endometrial cancer based on genome-wide DNA methylation profiles

The aim of this study was to establish criteria that would indicate whether fertility preservation therapy would likely be safe for patients aged 40 years or less with endometrioid endometrial cancer based on their DNA methylation profile. Forty-nine fresh-frozen tissue samples from patients with endometrial cancer from an initial cohort and 31 formalin-fixed paraffin-embedded tissue samples from a second cohort were subjected to genome-wide DNA methylation analysis using the Infinium MethylationEPIC BeadChip. Epigenomic clustering of early-onset endometrial cancer was correlated with the widely used recurrence risk classification. Genes showing differences in DNA methylation levels between the low-recurrence-risk category and intermediate- and high-risk categories were accumulated in pathways related to fibroblast growth factor and nuclear factor-κB signaling. DNA hypomethylation and overexpression of DNA methylation diagnostics criteria using up to 6 of 8 CpG sites for

Prognostic Biomarker of Fertility‐Preserving Hormonal Therapy Based on Multigene Panel Testing for Endometrial Cancer

ABSTRACT In this study, we identified prognostic biomarkers that predict treatment outcome in patients receiving fertility‐preserving high‐dose medroxyprogesterone acetate (MPA) therapy through comprehensive multigene panel testing. A total of 38 patients (20 atypical endometrial hyperplasia and 18 stage IA G1 without myometrial invasion) who received first‐line MPA therapy were enrolled. Genomic DNA was extracted from formalin‐fixed paraffin‐embedded samples, and PleSSision‐Rapid multigene panel testing was performed. Of the 38 patients, 31 (82%) achieved complete response (CR), 2 (5%) had stable disease (SD), and 5 (13%) had progressive disease (PD) following initial treatment. The median duration to achieve tumor disappearance was 7 months (range: 4–14 months). Following initial treatment, 25 of 32 patients (78%) experienced recurrence, with a median recurrence‐free survival (RFS) of 21 months (range: 2–84 months). The most frequently observed actionable gene mutations were PTEN (68.4%), CTNNB1 (55.2%), and PIK3CA (33.3%). Patients harboring PTEN mutations in EMG1 required a significantly longer duration to achieve tumor disappearance ( p  = 0.011). In addition, the presence of PIK3CA mutations in AEH was significantly associated with shorter RFS ( p  = 0.048). Molecular classification identified 34 patients (89%) with no specific molecular profile (NSMP), 1 patient (3%) with POLE mutation, and 3 patients (8%) with deficient mismatch repair (d‐MMR). Most patients undergoing MPA therapy were classified as having NSMP. Genetic alterations, specifically mutations in PTEN and PIK3CA , were significantly associated with treatment outcomes, highlighting their potential as prognostic biomarkers.

Prognostic significance of para-aortic node metastasis in endometrial cancer: Japanese Gynecologic Oncology Group Study JGOG2043 post hoc analysis

This study aimed to assess the prognostic significance of para-aortic lymphadenectomy (PALX) and para-aortic lymph node metastasis in endometrial cancer (EC) patients at risk of post-operative recurrence. Japanese Gynecologic Oncology Group (JGOG) 2043 was a randomized controlled trial assessing the efficacy of adjuvant chemotherapy in EC patients at risk for post-operative recurrence. A retrospective analysis included patients who underwent pelvic lymphadenectomy (PLX) alone or both PLX and PALX in JGOG2043. Data on positive lymph nodes and other clinicopathological risk factors were collected. PLX and PALX were performed on 402 patients, while PLX alone was conducted on 250 patients. Evaluating the effect of PALX on survival was challenging through a comparison of the outcomes of the 2 cohorts since PALX was predominantly administered to higher-risk patients. Patients with 2 or more metastases in para-aortic nodes exhibited significantly poorer overall survival than those with no or 1 metastasis, respectively (p<0.001, p=0.031). Multivariate analysis revealed that 2 or more metastases in para-aortic nodes is independent risk factors for disease-free survival (hazard ratio [HR]=1.72; 95% confidence interval [CI]=1.10-2.72; p=0.019) and are marginally significant for overall survival (HR=1.58; 95% CI=0.92-2.72; p=0.096) compared to no or a single metastasis. The clinical relevance of PALX was challenging to evaluate in the JGOG2043 cohort; however, the presence of 2 or more para-aortic node metastases was identified as an independent unfavorable prognostic factor in EC patients at risk of recurrence.

Prognostic impact of the number of resected pelvic nodes in endometrial cancer: Japanese Gynecologic Oncology Group Study JGOG2043 post hoc analysis

This study aimed to determine whether the number of resected pelvic lymph nodes (PLNs) affects the prognosis of endometrial cancer (EC) patients at post-operative risk of recurrence. JGOG2043 was a randomized controlled trial to assess the efficacy of three chemotherapeutic regimens as adjuvant therapy in EC patients with post-operative recurrent risk. A retrospective analysis was conducted on 250 patients who underwent pelvic lymphadenectomy alone in JGOG2043. The number of resected and positive nodes and other clinicopathologic risk factors for survival were retrieved. There were 83 patients in the group with less than 20 PLNs removed (group A), while 167 patients had 20 or more PLNs removed (group B). There was no significant difference in patients' backgrounds between the two groups, and the rate of lymph node metastasis was not significantly different. There was a trend toward fewer pelvic recurrences in group B compared with group A (3.5% vs. 9.6%; p=0.050). Although Kaplan-Meier analysis showed no statistically significant difference in survival rates between the two groups (5-year overall survival [OS]=90.3% vs. 84.3%; p=0.199), multivariate analysis revealed that resection of 20 or more nodes is one of the independent prognostic factors (hazard ratio=0.49; 95% confidence interval=0.24-0.99; p=0.048), as well as surgical stage, high-risk histology, and advanced age for OS. Resection of 20 or more PLNs was associated with improved pelvic control and better survival outcomes in EC patients at risk of recurrence who underwent pelvic lymphadenectomy alone and were treated with adjuvant chemotherapy.