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Aim A thorough analysis of multiple primary cancers (MPC) could provide important information as to the pathogenesis of human malignancies. Analysis of MPC using clinical databases has been performed, but little has been done using autopsy cases. Therefore, in this study, we first retrospectively analyzed MPC associated with endometrial and ovarian cancers using the Japan Autopsy Annual Database. Methods The Japan Autopsy Annual Database from 2002 to 2010 was established by the Japanese Society of Pathology, Tokyo, Japan. Among the 164 211 autopsy cases registered, 9142 were cases of primary cancers. Results The patients with endometrial cancer-associated MPC did have a lower risk of harboring colorectal cancer (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.45-0.89) but had a higher risk of ovarian cancer (OR, 3.15; 95% CI, 2.11-4.71). Those with ovarian cancer-associated MPC had a lower risk of harboring gallbladder cancer including bile ductal cancer (OR, 0.47; 95% CI, 0.27-0.80) but a higher risk of harboring breast (OR, 1.69; 95% CI, 1.20-2.38) and endometrial cancers (OR, 3.48; 95% CI, 2.33-5.20). Conclusion Both endogenous and exogenous factors are associated with the incidence of MPC. Results of our present study based on Japanese Autopsy Base first demonstrated that female hormones had a strong influence on the incidence of MPC. This study also demonstrated that the analysis of MPC using an autopsy database could have advantages over clinical database analysis.

Dehydroepiandrosterone (DHEA) is an androgen secreted by the adrenal glands, but its binding affinity for the androgen receptor is very low. DHEA is transformed into androstenedione by 3β-hydroxysteroid dehydrogenase (HSD) and then into testosterone by 17β-HSD type 5, or into estrone by aromatase. DHEA is also converted into androstenediol by 17β-HSD type 1. Therefore, DHEA is considered to play an important role as a precursor hormone for sex steroid hormones. We performed a search for a protein having an amino acid sequence homology to the DHEA binding site of 17β-HSD type 1, and found that microtubule-associated protein 2 (MAP2) binds to DHEA (Laurine E et al., J Biol Chem. 2003). MAP2 expression is necessary for neurite extension and cessation of cell division. MAP2 is known to suppress migration and invasion and affect the assembly, stabilization, and bundling of microtubules in melanoma cells, but the function of MAP2 in endometrial cancer has not been clarified. In this study, we investigated the expression of MAP2 and its association with DHEA in order to clarify the direct non-receptor action of DHEA in endometrial cancer. We employed frozen and formalin-fixed paraffin-embedded (FFPE) tissues of 35 endometrial cancer tissues (G1, n=12; G2, n=10; G3, n=9; Serous, n=4). Hormone concentrations were measured by liquid chromatograph-tandem mass spectrometer from the frozen sample, and immunohistochemistry of MAP2 was performed using FFPE tissues. We also examined MAP2 immunoreactivity using 59 normal endometrial tissues (proliferative phase, n=33; secretory phase, n=26) of FFPE tissue microarray slides. MAP2 immunoreactivity was found in the cytoplasm of endometrial cancer cells, and the MAP2-positive rate was significantly higher in type 1 (G1 and G2) than in type 2 (G2 and G3). The cell proliferation marker Ki-67 index was significantly lower in the MAP2-positive group. MAP2 was also detected in the glandular epithelial cells of the normal endometrium. The MAP2-positive rate was lower in the proliferative phase than in the secretory phase. Furthermore, the concentration of DHEA in the cancer tissue was significantly higher in the MAP2-positive group than in the MAP2-negative group. MAP2 is known to act on the stability of microtubules and is thought to be involved in the suppression of proliferation and infiltration in cancer cells. It was suggested that DHEA is involved in the stabilization of MAP2 and suppresses the progression of cancer in a hormone receptor-independent manner.

T cells in the tumor microenvironment, or tumor-infiltrating lymphocytes (TILs), have been recognized to play a critical role in tumor immunity. TILs are heterogeneously defined, and different T cell subsets have various effects. The properties of some T cell markers, such as CD3, CD4, CD8, and forkhead box P3 (FOXP3), are poor prognostic factors in several types of cancers. The effects of sex steroid hormones on T cell function in inflammation are known, and estrogen and androgen regulate the secretion of cytokines to enhance and attenuate, respectively, the immune response. While intratumoral estrogen and androgen synthesis plays an important role in the progression of cancer cells in hormone-dependent cancers, the relationship between intratumoral hormone levels and TIL subtypes is unclear. In this study, we examined the correlation between intratumoral hormone concentrations and expression scores of TIL markers in endometrial cancer. We employed frozen and formalin-fixed paraffin-embedded (FFPE) tissues of 19 endometrial cancer tissues (G1, n=6; G2, n=5; G3, n=6; Serous, n=2). Hormone concentrations were measured by LC-MC/MS from the frozen sample, and immunohistochemistry of T cell markers was performed using FFPE tissues. The five T cell markers examined in this study were CD3 (total T cells), CD4 (helper T cells), CD8 (cytotoxic T cells), FOXP3 (regulatory T cells), and thymocyte selection-associated HMG box (TOX) (exhausted T cells). The number of intratumoral CD3 in an arbitrary two-field (magnification, ×200) was counted and used as the CD3 score. Similarly, the number of other markers was counted, and the ratio to CD3 was used as the score for each marker. A correlation was found between TOX and CD8 using correlation between markers. The median scores for CD3 and CD8 were significantly higher in type 1 (G1 and G2) than in type 2 (G3 and serous) (CD3, p=0.031; CD8, P=0.031). The CD4 score had a positive correlation with estrogen (estrone, r2=0.591; estradiol, r2=0.501) and androgen (dihydrotestosterone, r2=0.327) concentrations. There was a poor negative correlation between cortisol concentration and CD8 score (r2=0.203). Estrogen and androgen at the tumor in situ were considered to affect TILs, especially CD4 positive T cells. It is also suggested that cortisol acts on immunosuppression, even locally in the tumor. This study showed the potential of a combination of immunotherapy and hormone therapy in endometrial cancer. Citation Format: Yasuhiro Miki, Fuka Onuma, Kiyoshi Takagi, Erina Iwabuchi, Takashi Suzuki, Hironobu Sasano, Kiyoshi Ito. Correlation between T cell infiltration subtypes and intratumoral hormone levels in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 726.

Endometrial cancer is one of the most common female pelvic cancers and has been considered an androgen-related malignancy. Several studies have demonstrated the anti-cell proliferative effect of androgen on endometrial cancer cells; however, the mechanisms of the anti-cancer effect of androgen remain largely unclear. 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2), which catalyzes the conversion of E2 to E1, is known to be upregulated by androgen treatment in breast cancer cells. In this study, we therefore focused on the role of androgen on estrogen dependence in endometrial cancer. Dihydrotestosterone (DHT) was found to induce 17β-HSD2 mRNA and protein expression in HEC-1B endometrial cancer cells. DHT could also inhibit cell proliferation of HEC-1B when induced by estradiol treatment. In 19 endometrioid endometrial adenocarcinoma (EEA) tissues, intratumoral DHT concentration was measured by liquid chromatography/electrospray tandem mass spectrometry and was found to be significantly correlated with 17β-HSD2 immunohistochemical status. We further examined the correlations between 17β-HSD2 immunoreactivity and clinicopathological parameters in 53 EEA tissues. 17β-HSD2 status was inversely associated with the histological grade, clinical stage, and cell proliferation marker Ki-67, and positively correlated with progesterone receptor expression. 17β-HSD2 status tended to be positively associated with androgen receptor status. In 53 EEA cases, the 17β-HSD2-positive group tended to have better prognosis than that for the negative group with respect to progression-free survival and endometrial cancer-specific survival. These findings suggest that androgen suppresses the estrogen dependence of endometrial cancer through the induction of 17β-HSD2 in endometrial cancer.

This survey sought to determine Japanese gynecologists' attitudes concerning administering hormone replacement therapy (HRT) for patients after surgery for endometrial cancer (EC).Eight hundred and eighty-eight members of the Japanese Gynecologic Oncology Group (JGOG) were asked to respond to an anonymous questionnaire on the JGOG website. The survey asked whether or not HRT was to be administered when surgery was performed (including a hysterectomy and bilateral oophorectomy) to treat EC before or after menopause. If HRT was not to be administered, respondents were asked the reason why. Respondents were presented with the same hypothetical patients that were featured in a previous survey in Germany, and differences in the mindsets of Japanese and German physicians were compared.Responses from 363 individuals (response rate 40.9 %) were analyzed. Seventy-eight percent of physicians considered HRT for patients undergoing surgery before menopause. The most prevalent reason of refusal to prescribe HRT was the risk of EC recurrence. Forty-eight percent of physicians considered HRT for patients undergoing surgery after menopause. The most prevalent reasons of refusal of HRT were its limited benefit and the availability of alternative therapies. Sixty-five percent of Japanese physicians responded that they would administer HRT to patients with low risk of recurrence vs. 46 % of physicians in Germany (P0.0002). Forty-nine percent of Japanese physicians approved of prescribing HRT for patients with high risk of recurrence vs. 25 % of physicians in Germany (P0.0001).Many Japanese gynecologists have a favorable attitude toward prescribing HRT after treatment of EC.

Endometrial carcinoma is the most common malignancy found in the female genital tract, and its incidence, particularly that of the most common histological type, endometrioid endometrial carcinoma, has increased recently.1,2 The estimated 5-year overall survival for early-stage endometrial carcinoma is 82% but decreases remarkably to 67% for regional disease and 16% for distant disease.3 Although the majority of patients (approximately 83%) are diagnosed as having stage I or II disease, those with advanced-stage endometrial carcinoma or unfavorable pathological characteristics have poor prognosis.2 Therefore, it is important to evaluate the clinical and biological markers in patients with endometrial carcinoma to predict recurrence after surgery and to evaluate the indications of additional therapies appropriately. Corticotropin-releasing hormone (CRH) is a major regulator of the stress response to internal and external factors.4 The stress response is characterized by an activation of the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis.5 Corticotropin-releasing hormone is secreted by the paraventricular nucleus of the hypothalamus in response to stress and stimulates the anterior lobe of the pituitary gland to release adrenocorticotropic hormone through its interaction with CRH receptors 1 (CRHR1) and 2 (CRHR2).6 Adrenocorticotropic hormone in turn stimulates the adrenocortex to produce and secrete cortisol.6,7 The actions of CRH and its receptors are thought to play important roles in various stress-related disorders.8 Recent studies have demonstrated that CRH is present not only in the central nervous system but also in various peripheral organs.9 Corticotropin-releasing hormone mediates endocrine responses to stress by activating the HPA axis as well as via direct actions in the periphery.10,11 Of note, the expression of CRH and its receptors has also been reported in several types of carcinoma.12,13 Specifically, Miceli14 reported CRH, CRHR1, and CRHR2 immunoreactivity in endometrial carcinoma. Although stress is known to be a promoter of tumor growth,15 it remains unclear whether CRH, CRHR1, or CRHR2 immunoreactivity in endometrial carcinoma is a risk factor for poor prognosis. In this study, we tested the hypothesis that the expression of CRH, CRHR1, and CRHR2 in endometrial carcinoma is associated with poor prognosis.

Background: Radical hysterectomy is recommended for endometrial adenocarcinoma patients with suspected gross cervical involvement. However, the efficacy of operative procedure has not been confirmed. Methods: The patients with endometrial adenocarcinoma who had suspected gross cervical involvement and underwent hysterectomy between 1995 and 2009 at seven institutions were retrospectively analysed (Gynecologic Oncology Trial and Investigation Consortium of North Kanto: GOTIC-005). Primary endpoint was overall survival, and secondary endpoints were progression-free survival and adverse effects. Results: A total of 300 patients who underwent primary surgery were identified: 74 cases with radical hysterectomy (RH), 112 patients with modified radical hysterectomy (mRH), and 114 cases with simple hysterectomy (SH). Median age was 47 years, and median duration of follow-up was 47 months. There were no significant differences of age, performance status, body mass index, stage distribution, and adjuvant therapy among three groups. Multi-regression analysis revealed that age, grade, peritoneal cytology status, and lymph node involvement were identified as prognostic factors for OS; however, type of hysterectomy was not selected as independent prognostic factor for local recurrence-free survival, PFS, and OS. Additionally, patients treated with RH had longer operative time, higher rates of blood transfusion and severe urinary tract dysfunction. Conclusion: Type of hysterectomy was not identified as a prognostic factor in endometrial cancer patients with suspected gross cervical involvement. Perioperative and late adverse events were more frequent in patients treated with RH. The present study could not find any survival benefit from RH for endometrial cancer patients with suspected gross cervical involvement. Surgical treatment in these patients should be further evaluated in prospective clinical studies.

Uterine papillary serous carcinoma (UPSC) morphologically resembles ovarian serous carcinoma and is categorized as a type II endometrial cancer. UPSC comprises about 10% of all types of endometrial cancer and has an aggressive clinical course and a poor prognosis. The 14-3-3σ gene was originally discovered as a p53-inducible gene; its expression is induced by DNA damage in a p53-dependent manner, which leads to G2 arrest and repair of damaged DNA. Moreover, it has been reported that expression of 14-3-3σ is frequently lost in various types of human cancer, including ovarian cancer. We therefore examined the association between 14-3-3σ expression determined by immunohistochemistry and clinical outcomes of 51 patients with UPSC. UPSC was considered positive for 14-3-3σ when > 30% of tumor cells were stained with a specific antibody. Of these patients, 29 (58.7%) showed positive immunoreactivity for 14-3-3σ and 22 (41.3%) had decreased 14-3-3σ staining. Decreased immunoreactivity for 14-3-3σ was associated with stage (P = 0.001) and lymphovascular space involvement (P = 0.005). Moreover, decreased 14-3-3σ expression was an independent risk factor for reduced overall survival (P = 0.0416) in multivariate analysis. Direct bisulfite sequencing was performed to evaluate the methylation status of the 27 CpG islands in the promoter region and first exon of the 14-3-3σ gene. These CpG islands were hypermethylated in 30% of 14-3-3σ-positive UPSC and 80% of 14-3-3σ-negative UPSC, although the difference was not statistically significant. These findings suggest that decreased expression of immunoreactive 14-3-3σ may be a predictor of poor prognosis in patients with UPSC.

In situestrogen biosynthesis is considered to play pivotal roles in the development and progression of human endometrial carcinoma. However, the biological roles of androgen have remained virtually unknown. Various epidemiological studies have revealed that elevated serum androgen levels are generally associated with an increased risk of developing endometrial carcinoma; however, studies directly examining androgens in carcinoma tissues are relatively rare and reviews summarizing this information are scarce. Therefore, we summarized recent studies on androgens in endometrial carcinoma, especially focusing androgen actions andin situandrogen biosynthesis. Among the enzymes required for local biosynthesis of androgen, 17β-hydroxysteroid dehydrogenase type 5 (conversion from androstenedione to testosterone) and 5α-reductase (reduction of testosterone to dihydrotestosterone (DHT)) are the principal enzymes involved in the formation of biologically most potent androgen, DHT. Both enzymes and androgen receptor were expressed in endometrial carcinoma tissues, andin situproduction of DHT has been reported to exist in endometrial carcinoma tissues. However, testosterone is not only a precursor of DHT production, but also a precursor of estradiol synthesis, as a substrate of the aromatase enzyme. Therefore, aromatase could be another key enzyme serving as a negative regulator forin situproduction of DHT by reducing amounts of the precursor. In anin vitrostudy, DHT was reported to exert antiproliferative effects on endometrial carcinoma cells. Intracrine mechanisms of androgens, the downstream signals of AR, which are directly related to anticancer progression, and the clinical significance of DHT-AR pathway in the patients with endometrial carcinoma have, however, not been fully elucidated.

Nucleobindin 2 (NUCB2) is a multifunctional protein containing several functional domains, and associated with wide variety of biological process such as food intake and energy homeostasis. Recently, NUCB2 has been implicated in not only normal human tissues but also some kinds of human malignancies. However, its clinical and/or biological significance has largely remained unknown in endometrial carcinomas. We therefore immunolocalized NUCB2 protein in 87 endometrial carcinoma tissues and examined its clinical significance. NUCB2 immunoreactivity was detected in 19 out of 87 (22%) of endometrial carcinoma cases examined, and positively correlated with Ki67 labeling index, while there was no significant correlation between NUCB2 and stage, histological grade, and progesterone receptor status. Furthermore, NUCB2 immunoreactivity was significantly correlated with increased risk of recurrence and worse clinical outcome regardless of stage or histological grade. Subsequent multivariate analyses did reveal that NUCB2 immunoreactivity was an independent prognostic factor for both disease-free survival and endometrial cancer specific survival. In vitro experiments demonstrated that knockdown of NUCB2 using specific siRNA for NUCB2 significantly impaired cell proliferation and migration of the endometrial carcinoma cell lines, Ishikawa and Sawano cells, and that nesfatin-1 treatment significantly promoted cell proliferation and migration in Ishikawa cells. These findings possibly suggested that NUCB2 and/or nesfatin-1 had pivotal roles in the progression of endometrial carcinomas. Immunohistochemical NUCB2 status may therefore serve as a potent biomarker for endometrial carcinomas.

Objective: Dysregulation of Kelch-like erythroid cell-derived protein with CNC homology-associating protein (Keap)-nuclear factor E2-related factor 2 (Nrf2) homeostasis owing to oncogenic mutations or to endogenous alteration of protein expression levels is implicated in tumor resistance to adjuvant treatment. To understand the role of Keap1 and Nrf2 in endometrial cancer, we performed DNA sequencing of tumors and noted the relation of the DNA sequence with annotated clinicopathologic data. Methods: We sequenced the Keap1 and Nrf2 genes in 105 tumor specimens. Associations of genetic mutations and polymorphisms with the patients9 clinicopathologic characteristics were evaluated. Results: We detected 9 patients with Keap1 mutations and 3 patients with Nrf2 mutations. No patient had both Keap1 and Nrf2 mutations. We found 2 single nucleotide polymorphisms within the coding region of Keap1 - rs1048290 (c. 1413C>G) and rs11545829 (c. 1611C>T) that displayed high heterogeneity in our cohort. The c. 1413C>G polymorphism is significantly associated with progression-free survival by multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.036-0.69; P = 0.014). The presence of Keap1 or Nrf2 mutations and c. 1611C>T are not associated with the clinical outcome of the patients. Conclusions: Mutations impairing Keap1-Nrf2 interaction are relatively common in endometrial cancer (12 [11.4%] of 105). Keap1 single nucleotide polymorphism rs1048290 may be a novel independent prognostic marker for patients with endometrial cancer receiving adjuvant treatment. Therefore, genotyping patients for this Keap1 polymorphism will help identify patient subgroups more likely to benefit from standard adjuvant therapy.

Endometrial carcinoma and possibly ovarian carcinoma are considered "estrogen-dependent tumors" in human gynecological malignancies. In endometrial carcinoma, the enzymes responsible for intratumoral estrogen metabolism and biosynthesis are different from those in human breast carcinoma, although both of them are considered "estrogen-dependent malignancies". Specific and effective endocrine treatment of endometrial carcinoma should be explored, although progestin agents have been widely used for a long time. Aromatase inhibitors, the most effective endocrine agents of breast carcinoma, retinoids, metabolites of vitamin A, and synthetic peroxisome proliferator-activated receptor (PPAR) gamma ligands, used for the treatment of insulin resistance in type II diabetes mellitus, may be the important candidates for possible endocrine treatment of endometrial carcinoma. In ovarian carcinoma, several clinical studies recently demonstrated that aromatase inhibitors had some therapeutic activity against recurrent ovarian carcinoma. However, at least at this juncture, further studies should be required to establish an aromatase inhibitor treatment as one form of endocrine therapy of ovarian carcinoma in future.

Relaxin is known to play an important role in animal pregnancies, including those of humans. It is suggested that relaxin induces aggressive cell growth and invasiveness in several types of cancer, including endometrial cancer. However, the mechanisms of relaxin remain largely unclear. In this study, we examined the effects of relaxin 2 (RLN2), the major circulating relaxin in humans, on human endometrial carcinoma cell lines. RLN2 treatment induced invasion in HEC-1B and Ishikawa cells. RLN2-induced cell invasion was significantly decreased by transfection of relaxin receptor 1 (RXFP1) siRNAs. The &beta, catenin inhibitor, XAV939, also significantly inhibited the RLN2-induced cell invasions. Both a decrease of cadherin expression and an increase of &beta, catenin phosphorylation were observed in response to the RLN2 treatment in HEC-1B and Ishikawa cells. We then examined RLN2 and RXFP1 expression in 80 human endometrioid endometrial carcinoma tissues. RLN2 immunoreactivity was detected in the human endometrial carcinoma cells and had a correlative tendency with histological grade and RXFP1. These results suggest that adherens junctions in cancer cells are weakened by the breakdown of the cadherin/catenin complex, which is induced by &beta, catenin phosphorylation via RLN2/RXFP1 signaling.

To investigate the association between green tea consumption and the risk of endometrial cancer restricted to endometrial endometrioid adenocarcinoma (EEA) using a case-control design in Japan.The cases were 152 patients with histopathologically diagnosed EEA, and the controls were 285 healthy women who were matched for age and area of residence with individual cases. The subjects completed a questionnaire regarding health-related lifestyle and reproductive history, and a food frequency questionnaire. Odds ratios (ORs) of EEA for frequency of green tea consumption were calculated by conditional logistic regression analysis.We observed a significant inverse association between green tea consumption and the risk of EEA with a dose-response relationship. The multivariate-adjusted OR of EEA was 0.77 (95% CI: 0.37-1.58) for those in the second quartile of green tea consumption (5-6 cups/week-1 cup/day), 0.61 (0.30-1.23) in the third quartile (2-3 cups/day), and 0.33 (0.15-0.75) in the highest quartile (or = 4 cups/day), as referenced with those in the lowest quartile (or = 4 cups/week; p for trend = 0.007). This inverse association was consistently observed regardless of the presence or absence of factors such as obesity and menopause.Green tea consumption may be associated with a lower risk of EEA.

We have previously reported on vasohibin as a novel endothelium-derived vascular endothelial growth factor (VEGF)-inducible inhibitor of angiogenesis. The aim of our present study was to define the role of vasohibin in endometrioid endometrial adenocarcinoma. We collected 78 sections of endometrial carcinoma for assessment using immunohistochemistry. Twenty-seven were well differentiated (G1), 25 were moderately differentiated (G2), and 26 were poorly differentiated endometrioid adenocarcinomas (G3). We also included 12 sections of normal cyclic endometria, six of which were in the proliferative phase and six were in the secretory phase. We investigated the expression of vasohibin, and compared it to VEGF receptor-2 (VEGFR-2: KDR/flk-1), CD34, Ki-67, VEGF-A, and D2-40 (as a lymphatic vessel marker). We assessed the ratio of vasohibin- and VEGFR-2-positive vessels in the stroma of endometrial carcinoma. Immunohistochemical assessment was classified as negative or positive based on staining intensity. Vasohibin was selectively expressed on vascular endothelial cells in both cyclic endometria and endometrial carcinomas. Vasohibin was highly expressed in the normal functional endmetrium of the secretory phase, especially in the spiral artery, and was highly expressed in all grades of endometrioid adenocarcinomas. The stromal endothelial cells in G3 expressed vasohibin and VEGFR-2 more frequently than these in G1. In endometrioid adenocarcinomas, there was a significant correlation between the expression percentage of vasohibin and that of VEGFR-2 (P < 0.0001, r(2) = 0.591). This is the first study to elucidate the correlation between expression of vasohibin in the stromal endothelial cells and that of VEGFR-2 in human carcinomas.

The retinoids (vitamin A and its biologically active derivatives) are essential for the health and survival of the individual. Several studies have reported a strong rationale for the use of retinoids in cancer treatment and chemoprevention. It has been discovered that expression of retinoic acid receptor (RAR) beta is frequently silenced in epithelial carcinogenesis, which has led to the hypothesis that RAR beta could act as a tumor suppressor. However, the status of RAR beta in human endometrial carcinoma has not been examined. In the present study, we initially studied the effects of retinoic acid on cell proliferation and the expression of RAR alpha, RAR beta, and RAR gamma using AM580 (a RAR-specific agonist) in the Ishikawa endometrial cancer cell line. We also examined the expression of RAR in human eutopic endometrium (30 cases), endometrial hyperplasia (28 cases), and endometrial carcinoma (103 cases) using immunohistochemistry. Finally, we correlated these findings with the clinicopathological parameters. In vitro, cell growth was inhibited and RAR beta and RAR gamma mRNA was significantly induced by AM580, compared with vehicle controls, whereas RAR alpha mRNA was significantly attenuated by AM580, compared with vehicle. RAR beta was detected predominantly in endometrial hyperplasia, compared with endometrial carcinoma. No statistically significant correlation was obtained between the expression of any other RAR subtypes and clinicopathological parameters in human endometrial carcinoma. The results of our study demonstrate that AM580 inhibits cell growth and induces RAR beta mRNA expression in the Ishikawa cell line, and the expression level of RAR beta in endometrial carcinoma is significantly lower than that in endometrial hyperplasia. AM580 might therefore be considered as a potential treatment for endometrial carcinoma.

Total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) have been performed as a standard surgical treatment for endometrial cancer. Many studies have reported on issues such as whether retroperitoneal lymphadenectomy should also be performed with TAH+BSO, to what extent lymphadenectomy should be performed when TAH+BSO is performed, and in what type of patients should lymphadenectomy be performed. These issues have been actively discussed, but there has not been any consensus. In this review article, the benefits of retroperitoneal lymphadenectomy in the initial surgical treatment for endometrial cancer will be discussed in terms of patients with pelvic lymphadenectomy and those with paraaortic (PA) lymphadenectomy. From the previous data, the establishment of TAH+BSO plus pelvic lymphadenectomy as the standard surgical treatment for endometrial cancer is thought to be reasonable. In this situation, is there benefit in performing PA lymphadenectomy? A discussion will be provided by separating the diagnostic significance from the therapeutic significance of this treatment. At present, there are no established treatments for PA-lymph node-positive patients that can be recommended more than the adjuvant therapies that are already performed at various institutions. A scientific basis that clearly indicates the therapeutic effect of PA lymphadenectomy does not exist at the present time. Despite performing thorough PA lymphadenectomy, the route of progression to extrauterine sites cannot be completely controlled. The standard surgical procedure for endometrial cancer is TAH+BSO+pelvic lymphadenectomy, which is considered necessary and sufficient. At present, the addition of PA lymphadenectomy for endometrial cancer can be regarded as only an investigated protocol.

Objective. We investigated the utility of sentinel lymph node (SLN) mapping for the detection of endometrial carcinoma micrometastases. We reevaluated the accuracy of our SLN detection procedure, this time combining step-serial section with cytokeratin immunostaining. Patients and methods. Between March 2002 and March 2005, consecutive patients undergoing laparotomy (total abdominal hysterectomy, bilateral salpingo-oophorectomy, total pelvic lymphadenectomy and para-aortic lymphadenectomy to the level of renal veins) with SLN biopsy for endometrial cancer at Tohoku University Hospital were enrolled in this study. Excluded were patients in whom lymph node metastases were detected by routine histological examination or those without detectable SLNs. All surgically removed lymph nodes, including SLNs, were examined histopathologically by immunohistochemistry staining with an anti-cytokeratin antibody (AE1/AE3) combined with step-serial sectioning at 200–500 μm intervals. Results. Four of seventy-four SLNs (5%) obtained from 20 patients had micrometastases or isolated tumor cells (ITC). In contrast, only 4 of the 1350 non-SLNs obtained from 20 patients (0.3%) had detectable micrometastases. The micrometastases were detected in the external iliac basin (two cases) and in the para-aortic area (two cases). The isolated tumor cell was detected in the external iliac basin (one case). Conclusion. SLNs detected by our method had micrometastases more frequently than did non-SLNs. Easy detection of micrometastases by immunostaining is only possible with step-serial sectioning of the SLNs.

SLC22A16 is one of newly isolated organic cation transporters, which is responsible for uptake and transport of adriamycin into cells. Adriamycin is one of the key drugs for treatment of endometrial cancer. Therefore, we examined expression of SLC22A16 in human endometrium and its disorders. Protein and mRNA expression levels of SLC22A16 were examined in 124 endometrial cancer specimens, 25 normal endometrial tissue samples (15 in proliferative phase, 10 in secretory phase), and 7 endometrial cancer cell lines using immunohistochemical analysis and reverse transcription-polymerase chain reaction. Changes in SLC22A16 mRNA expression level after progesterone exposure were also examined. Immunohistochemical analysis showed that SLC22A16 protein was highly expressed in endometrium during the normal secretory phase, but its level was significantly reduced in the proliferative phase. SLC22A16 protein was detected in 59 of 124 (48%) endometrial cancer specimens and 3 of 7 (43%) endometrial cancer cell lines. The mRNA levels measured by quantitative reverse transcription-polymerase chain reaction were comparable with levels of protein expression. Furthermore, SLC22A16 mRNA levels were increased in endometrial cancer cell lines in the presence of progesterone. In conclusion, SLC22A16 is expressed in various endometrial tissues. Its expression level is high during the secretory phase and may be regulated by progesterone. Our findings also suggest that it may be possible to use progestins to increase the response of endometrioid endometrial carcinoma with SLC22A16 expression to adriamycin-based chemotherapeutic regimens.

Endometrial carcinoma is one of the most common female pelvic malignancies. It is well known that uterine endometrial cell proliferation is under the control of both estrogen and progesterone. In this review, results of the recent studies on the biosynthesis and action of estrogen and progestin in normal endometrium and its disorders will be summarized and the new aspects of hormonal therapies in the patients with endometrial carcinoma will be discussed including its future prospectives. We reported that the enzymes responsible for intratumoral estrogen metabolism and biosynthesis are markedly different between human breast and endometrial carcinoma, although both of them are considered "estrogen-dependent malignancies". In addition, the biological significance of Progesterone receptor (PR) isoforms is considered to differ between endometrial and breast carcinomas. Clinical data concerning Hormone replacement therapy (HRT) and estrogen-dependent cancer risk also support these findings. These basic and clinical findings help to understand the biology and provide the new knowledge for prevention, diagnosis and treatment of human endomerial carcinoma. Specific endocrine treatment of endometrial carcinoma should be explored in future, although aromatase inhibitors are the most effective endocrine treatments of estrogen-responsive breast carcinoma. Retinoid, metabolities of vitamin A, and synthetic peroxisome proliferator-activated receptor (PPAR) gamma ligands, which have been used for the treatment of insulin resistance in type II diabetes mellitus, may be the important candidates as drugs not only for prevention but also for possible endocrine treatment of endometrial carcinoma.

Purpose: We examined expression of 14-3-3σ, a regulator of cell proliferation, and evaluated its clinical significance in endometrioid endometrial carcinoma. Experimental Design: One hundred three endometrioid endometrial adenocarcinoma cases were examined using immunohistochemistry with archival specimens. We correlated this finding with various clinicopathologic variables, including the status of estrogen receptor, progesterone receptor, and MIB-1 (Ki-57). Results: 14-3-3σ Immunoreactivity was detected in 78 of 103 (75.3%) of carcinoma cases. No statistically significant correlation was detected between status of 14-3-3σ and any of clinicopathologic variables examined. There was, however, a statistically significant correlation between loss of 14-3-3σ expression and adverse clinical outcome of the patients (P = 0.0007). In the early stages of cancer (stages I and II), 14-3-3σ immunoreactivity was absent in 5 of 10 (50.0%) patients who showed recurrence during follow-up, whereas its absence was detected in only 13 of 68 (19.1%) disease-free patients in the same period. In addition, 14-3-3σ immunoreactivity was absent in 4 of 5 (80.0%) patients who died, whereas its absence was detected in only 14 of 73 (19.2%) patients who had lived during the same period. Patients whose tumors were negative for 14-3-3σ were at much greater risk to develop recurrent and/or mortal disease (P = 0.0372 and 0.0067). In multivariate analysis using the Cox proportional hazards model, absence of 14-3-3σ turned out to be statistically independent risk factor in disease-free survival and overall survival even in patients with early-stage disease (P = 0.0321 and 0.0191). Conclusions: Results of our study showed that loss or absence of 14-3-3σ determined by immunohistochemistry may be an important tool to identify endometrial carcinoma cases at high risk of recurrence and/or death, who are otherwise not detected by current clinical and pathologic evaluation, especially in the early stages of the disease. In addition, results of 14-3-3σ immunohistochemistry in the early stage of endometrial carcinoma could contribute to planning postoperative follow-up and adjuvant therapy.

Objective . The purpose of this study was to examine the feasibility of sentinel lymph node (SLN) detection in patients with endometrial cancer using preoperative lymphoscintigraphy and an intraoperative gamma probe. Patients and methods . Between June 2001 and January 2003, 28 consecutive patients with endometrial cancer who were scheduled for total abdominal hysterectomy, bilateral salpingo-oophorectomy, total pelvic lymphadenectomy, and paraaortic lymphadenectomy at Tohoku University School of Medicine underwent sentinel lymph node detection. On the day before surgery, preoperative lymphoscintigraphy was performed by injection of 99m-Technetium ( 99m Tc)-labeled phytate into the endometrium during hysteroscopy. At the time of surgery, a gamma-detecting probe was used to locate radioactive lymph nodes. Results . At least one sentinel node was detected in each of 23 of the 28 patients (82%). The mean number of sentinel nodes detected was 3.1 (range, 1–9). Sentinel nodes could be identified in 21 of 22 patients (95%) whose tumor did not invade more than halfway into the myometrium. Eighteen patients had radioactive nodes in the paraaortic area. Most patients had a sentinel node in one of the following three sites: paraaortic, external iliac, and obturator. The sensitivity and specificity for detecting lymph node metastases were both 100%. Conclusion . The combination of preoperative lymphoscintigraphy with intraoperative gamma probe detection may be useful in identifying sentinel nodes in early-stage endometrial cancer.

It is very important to examine the influence of inhibition of in situ estrogen production on the pathobiology of human sex steroid-dependent tumors in order to understand the clinical effects of aromatase inhibitors. We have examined the biological changes before and after aromatase inhibitor treatment in vitro (endometrial and ovarian cancer) and in vivo (breast cancer). First, we analyzed these changes using histoculture of 15 human endometrial cancers and 9 ovarian cancers. Five of the fifteen endometrial cancers and four of the nine ovarian cancers demonstrated decreased [3H]thymidine uptake or Ki67 labeling index after 14alpha-hydroxy-4-androstene-3,6,17-trione (NKS01) treatment. In ovarian cancer cases, the responsive cases tended to be associated with higher aromatase and estrogen receptor alpha (ER) expression compared with the other cases but this was not seen in the endometrial cancer cases. There were no changes in ER and aromatase expression before and after NKS01 treatment in either ovarian or endometrial cancer cases. We then studied the same primary human breast tumors before and after aminoglutethimide (AMG, n=3) and 4-hydroxyandrostenedione (4-OHA, n=3) treatment. Tumor aromatase activity increased in 3 cases and decreased or was unchanged in 3 cases but aromatase immunoreactivity in stroma and adipocytes was unaltered in 5 cases. There were no changes in the ER labeling index before or after treatment. Five of the six cases including the responsive cases tended to be associated with decreased cell proliferation or Ki67 expression and increased apoptosis when examined by the TUNEL method. These results indicate that aromatase inhibitors may exert their effects on human breast and other cancers through decreasing proliferation and increasing apoptosis, possibly without altering ER status.

Objective The aim of the present study was to clarify the most effective combination of injected tracer types and injection sites in order to detect sentinel lymph nodes (SLNs) in early endometrial cancer. Patients and methods The study included 100 consecutive patients with endometrial cancer treated at Tohoku University Hospital between June 2001 and December 2012. The procedure for SLN identification entailed either radioisotope (RI) injection into the endometrium during hysteroscopy (55 cases) or direct RI injection into the uterine cervix (45 cases). A combination of blue dye injected into the uterine cervix or uterine body intraoperatively in addition to preoperative RI injection occurred in 69 of 100 cases. All detected SLNs were recorded according to the individual tracer and the resultant staging from this method was compared to the final pathology of lymph node metastases including para-aortic nodes. Results SLN detection rate was highest (96%) by cervical RI injection; however, no SLNs were detected in para-aortic area. Para-aortic SLNs were detected only by hysteroscopic RI injection (56%). All cases with pelvic lymph node metastases were detected by pelvic SLN biopsy. Isolated positive para-aortic lymph nodes were detected in 3 patients. Bilateral SLN detection rate was high (96%; 26 of 27 cases) by cervical RI injection combined with dye. Conclusion RI injection into the uterine cervix is highly sensitive in detection of SLN metastasis in early stage endometrial cancer. It is a useful and safe modality when combined with blue dye injection into the uterine body.

Dietary patterns can be associated with development of endometrial carcinoma in postmenopausal • women. Daily iso fl avone intake may be associated with a reduced risk of endometrial cancer development • in postmenopausal women. Moderate degrees of daily coffee consumption may be associated with a reduced risk of endome• trial cancer development in postmenopausal women. Protective roles of a daily high intake of vegetable or fruit in endometrial cancer development in • postmenopausal women are reasonably considered dubious. Possible roles of daily dietary patterns in endometrial cancer risk in menopausal women will be • discussed from the standpoints of estrogenic actions. No associations between dietary patterns and risks of ovarian cancer development have been • detected in postmenopausal women.

Endometrial cancer (EC) is the most prevalent gynecologic malignancy in Japan. Atypical endometrial hyperplasia (AEH) is viewed as the premalignant lesion of EC, however it is often difficult to distinguish EC from AEH. The rate of concurrent EC in women diagnosed preoperatively with AEH based on endometrial biopsy was reported as 17-52%. Although hysteroscopic inspection and total curettage are considered as useful methods to make diagnosis of endometrial lesions, there is no report using this combined method to discriminate EC from AEH. The purpose of this study was to examine whether hysteroscopic inspection and total curettage improve the prevalence of EC among women diagnosed preoperatively with AEH. We reviewed 22 patients who underwent hysteroscopic inspection and total curettage and were diagnosed with AEH before undergoing hysterectomy between November 2001 and May 2011. The diagnosis made with the hysterectomy specimens revealed AEH in 10 patients (45.5%), endometrial hyperplasia without atypia in 3 (13.6%), and endometrioid adenocarcinoma, the most common type of EC, in 9 (40.9%). Endometrioid adenocarcinoma included 7 patients without myometrial invasion (31.8%) and 2 patients with superficial myometrial invasion (9.1%). There was no hysteroscopic finding that was specific for EC or AEH. In conclusion, about 41% of women who underwent hysterectomy under a diagnosis of AEH were found to have coexisting adenocarcinoma, although the prevalence of EC among those women was similar to that in earlier reports with endometrial biopsy. Accordingly, we must be careful in planning the therapeutic strategy for women with a preoperative diagnosis of AEH.

Endometrial serous adenocarcinoma (ESC) is aggressive and carries a poor prognosis. p53 is frequently mutated in ESC. microRNAs (miRNAs) are a direct p53 target and have been implicated in cancer cell behavior. In this study, we compared miRNA expression levels in ESC with the levels in endometrial endometrioid adenocarcinoma (EEC) and normal endometria. Six miRNAs were identified as having aberrant down-regulation specific to ESC with miR-34b being most pronounced. miR-34b was found to have promoter hypermethylation, which when reversed, restored miR-34b expression in the cell lines treated with 5-aza-2' deoxycytidine (DAC). Ectopic expression of miR-34b in turn inhibited cell growth, migration and most notably invasion. Our findings suggest a relationship among p53 mutation, miR-34b promoter methylation and tumor cell behavior. These effects are likely mediated by the downstream target of miR-34b, the proto-oncogene mesenchymal-epithelial transition factor (MET), a known prognostic factor in endometrial carcinomas. The expression of MET was reduced following the restoration of miR-34b in cell lines. In summary, our data suggest that miR-34b plays a role in the molecular pathogenesis of endometrial cancer.

Endometrial carcinoma is one of the most common gynecologic malignancies in Japan and its incidence has increased recently. Although surgery is the cornerstone of the management of patients with endometrial cancer, there is significant variation in Japan with regard to the type of hysterectomy employed. Additionally, it remains controversial whether full nodal staging is required in all patients. Furthermore, adjuvant therapy differs between Japan and Western countries. To delineate clearly the standard of care for endometrial cancer treatment in Japan, the guidelines for the treatment of endometrial cancer were published in 2006 and revised in 2009. The 2009 edition included topics not addressed in the previous edition including the treatment of mesenchymal tumors, for example leiomyosarcoma, and sections covering the treatment of serous and clear-cell adenocarcinoma. These guidelines are composed of nine chapters and include nine algorithms. The guidelines also contain fifty-one clinical questions (CQs) and each CQ consists of recommendations, background, explanations, and references. The treatment recommendations herein are tailored to reflect current Japanese clinical practice and ensure equitable care for all Japanese women diagnosed with endometrial cancer.

During recent decades, the incidence of gynecologic cancers, i.e., cancers of the cervix, endometrium and ovary, has increased in Japan. However, risk factors of gynecologic cancers have not been fully clarified in Japan. To investigate common and site-specific risk factors among gynecologic cancers, we conducted a hospital-based case-control study. The cases, i.e., 151 cervical, 103 endometrial and 141 ovarian cancer cases and the controls (n = 2016) were selected from female patients aged 30 and over, who were admitted to a single hospital in Miyagi Prefecture from 1997 to 2003. Information on reproductive factors, exogenous hormone use, and lifestyles including smoking was collected using a self-administered questionnaire. Smoking was significantly associated with an increased risk of cervical cancer. A dose-response relationship with the number of cigarettes per day was also observed (p for trend = 0.004). Older age at menarche was associated with a decreased risk of endometrial and ovarian cancers. For these cancers, the decreased risk was detected with increasing parity number (endometrium, p for trend = 0.0001; ovary, p = 0.0002). There was no significant association between exogenous hormone use and gynecologic cancer risk. The results indicate that smoking is a major risk factor of cervical cancer. In addition, hormonal factors, which are related to early onset of menarche and low parity, are common risk factors for endometrial and ovarian cancers. The increase in female smokers and the decrease in fertility rate may contribute to the increase in gynecologic cancer incidence in Japan.

This study examined the association between coffee consumption and the risk of endometrial endometrioid adenocarcinoma (EEA) in Japan by a case-control design. The cases consisted of 107 women less than 80 years of age from two medical centers who had been histopathologically diagnosed to have EEA. The controls, selected from the participants of a cancer-screening program, were 214 women, with two controls selected for each case (matched for age and for area of residence). A self-administered questionnaire containing questions to determine dietary and beverage consumption, as well as reproductive history, was distributed to the cases and controls. Conditional logistic regression analysis was used to estimate the odds ratio (OR) of EEA for three levels of coffee consumption with adjustment for potential confounding factors. The multivariate-adjusted OR of EEA for individuals in the highest tertile of coffee consumption (2 to 3 cups or more/day) was 0.4 [95% confidence interval (CI), 0.2-0.9], and that of cases in the intermediate tertile (5 to 6 times/week-1 cup/day) was 0.6 (95% CI, 0.3-1.2), relative to the individuals in the lowest tertile of coffee consumption (3 to 4 times or less/week) (P for trend=0.014). The above association was observed in postmenopausal women (P for trend=0.016), but not in premenopausal women (P for trend=0.90). This study thus revealed an inverse dose-response relationship between coffee consumption and the risk of EEA, and its strong association in postmenopausal women but not in premenopausal women.

Aims: The aims of this study were to evaluate the factors affecting prognosis in patients with uterine sarcomas and to demonstrate that carcinosarcoma bears a similarity to high-grade endometrial carcinoma in terms of its prognosis and clinicopathological parameters. Methods: In June 2004, 17 Japanese institutions received questionnaires regarding uterine sarcomas. Study patients had uterine sarcomas initially treated at each institution between January 1990 and May 2004. Survival analyses and comparisons were performed by univariate methods. Patient data of 921 cases of endometrial adenocarcinoma were also analyzed and compared to the data with the uterine sarcomas. Results: One hundred twenty-one patients with uterine sarcomas were identified who met study eligibility criteria. In uterine sarcomas, carcinosarcoma had a worse prognosis than other sarcomas, but the difference was not significant (p = 0.302). In carcinosarcoma, significant differences were observed with age (p = 0.0388), stage (p < 0.01) and surgical procedure (with or without pelvic lymphadenectomy, p = 0.0316). In carcinosarcoma and G3 adenocarcinoma, no significant difference was identified with regard to overall survival in univariate (p = 0.191) and multivariate (p = 0.168) analyses. Conclusion: Our results demonstrate that the clinical behavior of carcinosarcoma strongly resembles that of G3 endometrial adenocarcinoma, setting it apart from other ‘pure’ uterine sarcomas.

The incidence of endometrial cancer is rapidly increasing in Japan. Although the risk factors in European populations have been well described, there are few epidemiologic studies regarding risk factors for endometrial cancer in Japanese women. This hospital-based case-control study among Japanese women was carried out from 1998 to 2000. The cases were selected from women with endometrial cancer (n =155), and the controls selected from women attending the university gynecological outpatient clinic for cervical cancer screening (n = 96). Subjects were interviewed to ascertain breast feeding practices, contraceptive usage, as well as potential risk factors for endometrial cancer. We observed a lower risk of endometrial cancer associated with oral contraceptive (OC) and a higher risk associated with higher body mass index (BMI), and older ages at first and last delivery. Gravidity reduced odds ratio (OR) for endometerial cancer to 0.34 (95% confidence interval [CI] 0.13-0.92). Compared with parous women who had never breastfed, the multivariate OR for women with a history of breastfeeding was 0.37 (95% CI, 0.17-0.82). Additionally, a greater lapse of time since breastfeeding increased OR for endometrial cancer by over three times. In conclusion, the present study has indicated that breastfeeding reduces the risk of endometrial cancer in Japanese women.

Androgen metabolism and actions are considered to play a very important role in the development and progression of the normal human endometrium and its disorders. Details regarding androgen actions in these tissues, however, have not been well studied. We first immunolocalized the androgen receptor (AR) and 5alpha-reductases, which catalyze the conversion of testosterone to the bioactive and potent androgen, 5alpha-dihydrotestesterone (DHT), in 18 normal cycling human endometria, 27 endometrial hyperplasia and 46 endometrioid endometrial adenocarcinomas. We also examined the mRNA expression of AR and 5alpha-reductases in 7 cases of endometrioid endometrial adenocarcinomas using reverse transcription polymerase chain reaction (RT-PCR). In the normal human endometrium, AR was immunolocalized predominantly in stromal cells of the proliferative phase of the menstrual cycle and in epithelial cells of the secretory phase, whereas 5alpha-reductase types 1 and 2 immunoreactivities were detected in the cytoplasm of epithelial cells but not in stromal cells throughout all phases of the menstrual cycle. In endometrial hyperplasia, the median labeling index (LI) for AR was 48.1%, whereas positive immunostaining for 5alpha-reductase Type 1 and Type 2 was detected in only 1 case. In endometrial carcinoma, AR immunoreactivity was detected in the nuclei of carcinoma cells and the number of positive cases was 39/44 (88.6%). Median LI for AR was 36.1%. Immunoreactivity for 5alpha-reductase Type 1 and Type 2 was detected in the cytoplasm of carcinoma cells and the number of positive cases was 37/44 cases (84.1%) and 34/44 (77.3%) for 5alpha-reductase Types 1 and 2, respectively. A significant positive correlation was detected between 5alpha-reductase Type 1 and Type 2 immunoreactivity (p < 0.001). AR LI was not correlated with the presence or absence of Type 1 and Type 2 5alpha-reductases. Results from our RT-PCR studies were consistent with those of immunohistochemistry. These results suggest that DHT may play more important roles than testosterone in the regulation of androgen action in endometrial cancer and normal human endometrium, especially in the secretory phase, in which both AR and 5alpha-reductase are increased. Androgenic actions may be also regulated predominantly by serum testosterone and not by DHT in endometrial hyperplasia because of the absence of 5alpha-reductases in the site of its actions.

Mutations involving the K-ras proto-oncogene are believed to play an important role in the mechanism of tumorigenesis for many human cancers and occur in 10-30% of endometrial carcinomas. In the present study 221 cases of endometrioid endometrial carcinoma obtained from Japanese patients with average follow-up of 41 months were examined for point mutations in codon 12 of K-ras through use of the polymerase chain reaction. In 103 cases lymph node dissection had been performed. K-ras mutations were significantly associated with the presence of lymph node metastases (P0.04). Since endometrial carcinoma in premenopausal women generally behaves less aggressively than tumors of similar histologic grade arising in postmenopausal patients, we evaluated the effect of K-ras mutation on outcome in patients stratified into three different age categories (53 years, premenopausal; 54-59 years, perimenopausal;60 years, postmenopausal). In the postmenopausal age group (60 years), the presence of K-ras mutations was statistically significantly associated with patients who died or experienced recurrence (41.2% vs 13.0%; P0.03). This was related to a dramatic (greater than eightfold; P = 0.011) increase in the likelihood of adverse outcome between the premenopausal and postmenopausal states for patients whose tumors contained mutant K-ras. These findings point to a possible role for K-ras activation in the mechanism(s) responsible for more aggressive clinical behavior of endometrioid endometrial cancer that is observed in postmenopausal patients.

Recent scientific and technical advances hold promise of providing new insight into understanding the molecular pathogenesis of malignant neoplasia. The tools of molecular biology as well as its basic knowledge are now being introduced into the fields of clinical medicine and diagnostic pathology. A growing awareness is developing that newly discovered oncogenes and tumor-suppressor genes may provide important new avenues for stratifying patients into different risk groups. This, in turn, can contribute to the development of new methods for detecting cancer and for identifying genetic susceptibility and/or predisposition to cancer, as well as for improving predictions of clinical outcome and providing avenues for new therapies. Gynecological malignancies are no exception.

Background: Constitutive activation and increased expression of Nrf2 as a result of oncogenic mutations or other endogenous factors that cause derepression of Nrf2 by its cytosolic inhibitor, Keap1, contribute to tumor resistance to adjuvant treatment. As endometrial cancer generally has a lower response rate to adjuvant treatment, Keap1 and Nrf2 genes were sequenced to investigate their roles in endometrial cancer. Materials and Methods: Tumor specimens from 105 individuals with endometrioid endometrial adenocarcinoma (Type I endometrial cancer) were sequenced. The specimens comprised 44 well-differentiated (FIGO grade 1), 38 moderately differentiated (FIGO grade 2) and 23 poorly differentiated (FIGO grade 3) tumors. Statistical analyses using the Fisher's exact test, Pearson's Chi-square test and Cox proportional hazards model were used to investigate the association of genetic mutations and haplotypes with patients’ annotated clinicopathologic characteristics. Results: A total of ten novel Keap1 mutations were found in nine individuals, and two novel Nrf2 mutations were found in three individuals. One patient had two simultaneous Keap1 mutations, whereas two patients had the same type of Nrf2 genetic mutation. Two single nucleotide polymorphisms, rs1048290 and rs11545829 were found in high frequency in the present cohort. The non-synonymous genetic mutations and rs11545829 were not associated with patients’ clinicopathologic characteristics. In the adjuvant treatment subgroup, the rs1048290 c.1413C/G genotype was significantly associated with a better progression-free survival (hazard ratio, 0.25; 95% confidence interval [CI], 0.068 to 0.94; P=0.041). On multivariate analysis, rs1048290 was an independent prognostic factor for progression-free survival (hazard ratio, 0.16; 95% CI, 0.036 to 0.69; P=0.014). Conclusion: Keap1 single nucleotide polymorphism rs1048290 may be a potential biomarker that enables individualized therapy using cytotoxic adjuvant treatment in endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 316. doi:10.1158/1538-7445.AM2011-316