Using Genomic Variation to Distinguish Ovarian High-Grade Serous Carcinoma from Benign Fallopian Tubes.

The preoperative diagnosis of pelvic masses has been elusive to date. Methods for characterization such as CA-125 have had limited specificity. We hypothesize that genomic variation can be used to create prediction models which accurately distinguish high grade serous ovarian cancer (HGSC) from benign tissue. METHODS: In this retrospective, pilot study, we extracted DNA and RNA from HGSC specimens and from benign fallopian tubes. Then, we performed whole exome sequencing and RNA sequencing, and identified single nucleotide variants (SNV), copy number variants (CNV) and structural variants (SV). We used these variants to create prediction models to distinguish cancer from benign tissue. The models were then validated in independent datasets and with a machine learning platform. RESULTS: The prediction model with SNV had an AUC of 1.00 (95% CI 1.00-1.00). The models with CNV and SV had AUC of 0.87 and 0.73, respectively. Validated models also had excellent performances. CONCLUSIONS: Genomic variation of HGSC can be used to create prediction models which accurately discriminate cancer from benign tissue. Further refining of these models (early-stage samples, other tumor types) has the potential to lead to detection of ovarian cancer in blood with cell free DNA, even in early stage.

The role of minimally invasive gynecologic surgeons in the era of subspecialties: when to refer and consult.

PURPOSE OF REVIEW: Minimally invasive gynecologic surgery (MIGS) is a subspecialty focus of obstetrics and gynecology with focused expertise on complex benign gynecologic disorders. To date, no formal recommendations have been made in defining a referral system for MIGS. This article reviews the evidence regarding common disorders and procedures and their outcomes, and posits a basis for MIGS referral. RECENT FINDINGS: In instances where intraoperative and perioperative features may pose clinical challenges to the surgeon and ultimately the patient, the literature suggests the following scenarios may have adverse outcomes, and therefore, benefit from the skills of MIGS subspecialists: fibroids - at least five myomas, myoma size at least 9 cm, and suspected myoma weight at least 500 g; endometriosis - presence of endometrioma(s), suspected stage III/IV endometriosis, and requirement for advanced adjunct procedures; hysterectomy - uteri at least 250 g or 12 weeks estimated size, at least three prior laparotomies, obesity, and complex surgical history with suspected adhesive disease. SUMMARY: A referral system for MIGS subspecialists has proven benefits for both the gynecologic surgical community as well as the patients and their outcomes. This article provides evidence for collaboration with MIGS especially as it relates to leiomyomatous uteri, endometriosis, and complex hysterectomies.

Interval debulking surgery is not worth the wait: a National Cancer Database study comparing primary cytoreductive surgery versus neoadjuvant chemotherapy.

OBJECTIVE: In previous studies, neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to primary cytoreductive surgery as initial treatment for advanced epithelial ovarian cancer. Our study aimed to compare surgical and survival outcomes between the two treatments in a large national database. METHODS: Data were extracted from the National Cancer Database from January 2004 to December 2015. Patients with FIGO (International Federation of Gynecologists and Obstetricians) stage III-IV epithelial ovarian cancer and known sequence of treatment were included: primary cytoreductive (surgery=26 717 and neoadjuvant chemotherapy=9885). Tubal and primary peritoneal cancer diagnostic codes were not included. Residual disease after treatment was defined based on recorded data: R0 defined as microscopic or no residual disease; R1 defined as macroscopic residual disease. Multivariate Cox proportional HR was used for survival analysis. Multivariate logistic regression analysis was utilized to compare mortality between groups. Outcomes were adjusted for significant covariates. Validation was performed using propensity score matching of significant covariates. RESULTS: A total of 36 602 patients were included in the analysis. Patients who underwent primary cytoreductive surgery had better survival than those treated with neoadjuvant chemotherapy followed by interval surgery, after adjusting for age, co-morbidities, stage, and residual disease (p<0.001). Primary cytoreductive surgery patients with R0 disease had best median survival (62.6 months, 95% CI 60.5-64.5). Neoadjuvant chemotherapy patients with R1 disease had worst median survival (29.5 months, 95% CI 28.4-31.9). There were small survival differences between primary cytoreductive surgery with R1 (38.9 months) and neoadjuvant chemotherapy with R0 (41.8 months) (HR 0.93, 95% CI 0.87 to 1.0), after adjusting for age, co-morbidities, grade, histology, and stage. Neoadjuvant chemotherapy had 3.5 times higher 30-day mortality after surgery than primary cytoreductive surgery (95% CI 2.46 to 5.64). The 90-day mortality was higher for neoadjuvant chemotherapy in multivariate analysis (HR 1.31, 95% CI 1.06 to 1.61) but similar to primary cytoreductive surgery after excluding high-risk patients. CONCLUSIONS: Most patients with advanced epithelial ovarian cancer may benefit from primary cytoreductive surgery. Patients treated with neoadjuvant chemotherapy should be those with co-morbidities unfit for surgery.

Differential DNA methylation in high-grade serous ovarian cancer (HGSOC) is associated with tumor behavior.

The epigenome offers an additional facet of cancer that can help categorize patients into those at risk of disease, recurrence, or treatment failure. We conducted a retrospective, nested, case-control study of advanced and recurrent high-grade serous ovarian cancer (HGSOC) patients in which we assessed epigenome-wide association using Illumina methylationEPIC arrays to characterize DNA methylation status and RNAseq to evaluate gene expression. Comparing HGSOC tumors with normal fallopian tube tissues we observe global hypomethylation but with skewing towards hypermethylation when interrogating gene promoters. In total, 5,852 gene interrogating probes revealed significantly different methylation. Within HGSOC, 57 probes highlighting 17 genes displayed significant differential DNA methylation between primary and recurrent disease. Between optimal vs suboptimal surgical outcomes 99 probes displayed significantly different methylation but only 29 genes showed an inverse correlation between methylation status and gene expression. Overall, differentially methylated genes point to several pathways including RAS as well as hippo signaling in normal vs primary HGSOC; valine, leucine, and isoleucine degradation and endocytosis in primary vs recurrent HGSOC; and pathways containing immune driver genes in optimal vs suboptimal surgical outcomes. Thus, differential DNA methylation identified numerous genes that could serve as potential biomarkers and/or therapeutic targets in HGSOC.

High stathmin expression is a marker for poor clinical outcome in endometrial cancer: An NRG oncology group/gynecologic oncology group study.

OBJECTIVE: Gynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin. METHODS: We analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer. RESULTS: We first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin. CONCLUSIONS: Our findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.

Placenta-Specific Protein 1 Expression in Human Papillomavirus 16/18-Positive Cervical Cancers Is Associated With Tumor Histology.

OBJECTIVE: Expression of the trophoblast-specific gene placenta-specific protein 1 (PLAC1) has been detected in a wide variety of cancers. However, to date, PLAC1 expression has not been shown in cervical cancer. We have carried out a preliminary study that shows for the first time that PLAC1 is expressed in cervical cancers. METHODS: A total of 16 primary cervical tumors were obtained from patients shown to be human papillomavirus (HPV) 16/18 positive. Total cellular RNA, genomic DNA, and total protein were purified from each tumor. These materials were then used to determine PLAC1 expression, TP53 mutation status, and p53 expression. RESULTS: The PLAC1 expression was demonstrated in all 16 primary cervical tumors. The highest levels of expression were found in the more aggressive squamous and adenosquamous histologic types compared with adenocarcinomas. Moreover, the proportion of total PLAC1 message coming from the P1 promoter, also termed the distal or cancer promoter, was significantly greater in the more aggressive squamous and adenosquamous histologic types compared with adenocarcinomas. Finally, in spite of all 16 tumors being HPV-16/18 positive, 3 of 8 squamous cell cancers and 2 of 5 adenocarcinomas expressed wild-type p53 protein. Consistent with the recently shown suppression of the PLAC1P1 promoter by wild-type p53, these p53 positive tumors displayed among the lowest P1-specific PLAC1 expression levels. CONCLUSIONS: The PLAC1 expression has been demonstrated for the first time in cervical cancers. This preliminary study has further revealed a complex relationship between PLAC1 expression, cervical cancer histologic type, p53, and HPV type that requires further investigation.

p53 mutation status is a primary determinant of placenta-specific protein 1 expression in serous ovarian cancers.

Placenta-specific protein 1 (PLAC1) expression is co-opted in numerous human cancers. As a consequence of PLAC1 expression, tumor cells exhibit enhanced proliferation and invasiveness. This characteristic is associated with increased aggressiveness and worse patient outcomes. Recently, the presence of the tumor suppressor p53 was shown in vitro to inhibit PLAC1 transcription by compromising the P1, or distal/cancer, promoter. We sought to determine if this phenomenon occurs in primary patient tumors as well. Furthermore, we wanted to know if p53 mutation influenced PLAC1 expression as compared with wild-type. We chose to study serous ovarian tumors as they are well known to have a high rate of p53 mutation. We report herein that the phenomenon of PLAC1 transcription repression does occur in serous ovarian carcinomas but only when TP53 is wild-type. We find that mutant or absent p53 protein de-represses PLAC1 transcription. We further propose that the inability of mutant p53 to repress PLAC1 transcription is due to the fact that the altered TP53 protein is unable to occupy a putative p53 binding site in the PLAC1 P1 promoter thus allowing transcription to occur. Finally, we show that PLAC1 transcript number is significantly negatively correlated with patient survival in our samples. Thus, we suggest that characterizing tumors for TP53 mutation status, p53 protein status and PLAC1 transcription could be used to predict likely prognosis and inform treatment options in patients diagnosed with serous ovarian cancer.

Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182.

Altered expression of cullin-5 (CUL5), a member of the cullin-RING E3 ubiquitin ligase family, has been implicated in a number of types of cancers including breast, cervical and hepatocellular cancers. In the present study, we found that CUL5 expression was significantly decreased in both endometrioid and serous endometrial adenocarcinomas with the more aggressive serous type displaying a higher reduction (-4.3-fold) than the less aggressive endometrioid type (-2.9-fold). Overexpression of CUL5 mRNA and protein in Ishikawa H endometrial cancer cells resulted in decreased cell proliferation and in a reduction in CUL5-RING E3 ligase downstream clients JAK2 and FAS-L. Finally, we demonstrated for the first time that CUL5 is a direct target of miR-182 that we previously showed to be significantly overexpressed in endometrial adenocarcinomas and we provided evidence that increased miR-182 expression is, at least in part, a result of demethylation of its upstream promoter. These data suggest a cascade in which miR-182 expression is epigenetically increased leading to decreased CUL5 expression and increased cellular proliferation. The final step in the cascade may be operating through a decrease in ubiquitination of pro-growth CUL5 ubiquitin ligase clients. This cascade offers a series of potential interventional steps involving epigenetic modification, miRNA and/or gene targeting and ubiquitination.

Downregulation of FOXO1 mRNA levels predicts treatment failure in patients with endometrial pathology conservatively managed with progestin-containing intrauterine devices.

OBJECTIVE: To examine hormone receptor expression levels and downstream gene activation in pre-treatment and post-treatment biopsies in a cohort of patients with endometrial pathology who were being conservatively managed with a progestin-containing intrauterine device (IUD). A molecular signature of treatment failure is proposed. METHODS: A retrospective analysis of pre- and post-treatment biopsy specimens from 10 women treated with progestin-containing IUD for complex atypical hyperplasia (CAH) or grade 1 endometrioid adenocarcinoma was performed. Expression of estrogen receptor (ER), progesterone receptor (PR) and PR target genes was examined by immunohistochemistry (IHC) and quantitative RT-PCR. RESULTS: The mean treatment duration was 14.3 months. Four CAH patients had stable disease or regressed after treatment, and four progressed to endometrioid adenocarcinoma. Both patients with an initial diagnosis of endometrioid adenocarcinoma regressed to CAH or no disease. In general, hormone receptor levels diminished post-treatment compared to pre-treatment biopsies; however, we noted unexpected higher expression of the B isoform of PR (PRB) as well as ER in those patients who progressed to frank cancer. There was a trend towards a non-nuclear cytoplasmic location of PRB in these patients. Importantly, the differentiating impact of PR signaling, as determined by the expression of the progestin-controlled tumor suppressor FOXO1, was lost in individuals who progressed on therapy. CONCLUSIONS: FOXO1 mRNA levels may serve as a biomarker for response to therapy and an indicator of PR function in patients being conservatively managed with a progestin-containing IUD.

A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: Cediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer. PATIENTS AND METHODS: Eligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]). RESULTS: Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall survival (OS) 12.5 months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD. CONCLUSION: Cediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity.

Genetic Deficiency of Mtdh Gene in Mice Causes Male Infertility via Impaired Spermatogenesis and Alterations in the Expression of Small Non-coding RNAs.

Increased expression of metadherin (MTDH, also known as AEG-1 and 3D3/LYRIC) has been associated with drug resistance, metastasis, and angiogenesis in a variety of cancers. However, the specific mechanisms through which MTDH is involved in these processes remain unclear. To uncover these mechanisms, we generated Mtdh knock-out mice via a targeted disruption of exon 3. Homozygous Mtdh knock-out mice are viable, but males are infertile. The homozygous male mice present with massive loss of spermatozoa as a consequence of meiotic failure. Accumulation of γ-H2AX in spermatocytes of homozygous Mtdh knock-out mice confirms an increase in unrepaired DNA breaks. We also examined expression of the DNA repair protein Rad18, which is regulated by MTDH at the post-transcriptional level. In testes from Mtdh exon 3-deficient mice, Rad18 foci were increased in the lumina of the seminiferous tubules. The Piwi-interacting RNA (piRNA)-interacting protein Mili was expressed at high levels in testes from Mtdh knock-out mice. Accordingly, genome-wide small RNA deep sequencing demonstrated altered expression of piRNAs in the testes of Mtdh knock-out mice as compared with wild type mice. In addition, we observed significantly reduced expression of microRNAs (miRNAs) including miR-16 and miR-19b, which are known to be significantly reduced in the semen of infertile men. In sum, our observations indicate a crucial role for MTDH in male fertility and the DNA repair mechanisms required for normal spermatogenesis.

Robotic surgery in supermorbidly obese patients with endometrial cancer.

OBJECTIVE: Morbid obesity is a known risk factor for the development of endometrial cancer. Several studies have demonstrated the overall feasibility of robotic-assisted surgical staging for endometrial cancer as well as the benefits of robotics compared with laparotomy. However, there have been few reports that have evaluated robotic surgery for endometrial cancer in the supermorbidly obese population (body mass index [BMI], ≥50 kg/m(2)). We sought to evaluate safety, feasibility, and outcomes for supermorbidly obese patients who undergo robotic surgery for endometrial cancer, compared with patients with lower body mass indices. STUDY DESIGN: We performed a retrospective chart review of 168 patients with suspected early-stage endometrial adenocarcinoma who underwent robotic surgery for the management of their disease. Analysis of variance and univariate logistic regression were used to compare patient characteristics and surgical variables across all body weights. Cox proportional hazard regression was used to determine the impact of body weight on recurrence-free and overall survival. RESULTS: The mean BMI of our cohort was 40.9 kg/m(2). Median follow up was 31 months. Fifty-six patients, 30% of which had grade 2 or 3 tumors, were supermorbidly obese with a BMI of ≥50 kg/m(2) (mean, 56.3 kg/m(2)). A comparison between the supermorbidly obese and lower-weight patients demonstrated no differences in terms of length of hospital stay, blood loss, complication rates, numbers of pelvic and paraaortic lymph nodes retrieved, or recurrence and survival. There was a correlation between BMI and conversion to an open procedure, in which the odds of conversion increased with increasing BMI (P = .02). CONCLUSION: Offering robotic surgery to supermorbidly obese patients with endometrial cancer is a safe and feasible surgical management option. When compared with patients with a lower BMI, the supermorbidly obese patient had a similar outcome, length of hospital stay, blood loss, complications, and numbers of lymph nodes retrieved.

Systematic dissection of the mechanisms underlying progesterone receptor downregulation in endometrial cancer.

UNLABELLED: Progesterone, acting through its receptor, PR (progesterone receptor), is the natural inhibitor of uterine endometrial carcinogenesis by inducing differentiation. PR is downregulated in more advanced cases of endometrial cancer, thereby limiting the effectiveness of hormonal therapy. Our objective was to understand and reverse the mechanisms underlying loss of PR expression in order to improve therapeutic outcomes. Using endometrial cancer cell lines and data from The Cancer Genome Atlas, our findings demonstrate that PR expression is downregulated at four distinct levels. In well-differentiated cancers, ligand-induced receptor activation and downregulation are intact. miRNAs mediate fine tuning of PR levels. As differentiation is lost, PR silencing is primarily at the epigenetic level. Initially, recruitment of the polycomb repressor complex 2 to the PR promoter suppresses transcription. Subsequently, DNA methylation prevents PR expression. Appropriate epigenetic modulators reverse these mechanisms. These data provide a rationale for combining epigenetic modulators with progestins as a therapeutic strategy for endometrial cancer. SIGNIFICANCE: Traditional hormonal therapy for women with endometrial cancer can be molecularly enhanced by combining progestins with epigenetic modulators, thereby increasing progesterone receptor expression and significantly improving treatment efficacy.

Placenta-specific protein 1: a potential key to many oncofetal-placental OB/GYN research questions.

Placenta-specific protein 1 (PLAC1) is a secreted protein found in trophoblasts. Several reports implicate a central role for PLAC1 in establishment and maintenance of the placenta. In addition to placentae PLAC1 is expressed in a variety of solids including breast, endometrial, and ovarian cancers. In order to show that PLAC1 is potentially relevant to a number of research questions in OB/GYN, we report on PLAC1 expression in a selected panel that includes two choriocarcinoma cell lines, normal placental tissues, and endometrial and ovarian tumors. We report for the first time that PLAC1 is also expressed in human fetal tissues. PLAC1 is transcriptionally heterogeneous with one promoter (P1) generating two transcripts with alternately spliced 5' UTRs and the other promoter (P2) generating a third transcript. Placental tissues favor P2 transcripts, while P1 is favored in most of the other cells. Mechanisms determining multiple PLAC1 transcripts and promoter preferences are as yet unknown, but it is clear that this protein is likely to be important in a variety of phenomena relevant to both gynecologic oncology and maternal-fetal medicine.

Intra-operative frozen section results reliably predict final pathology in endometrial cancer.

OBJECTIVES: Typically, complete surgical staging is necessary for patients with high-risk endometrial cancer. However, patients with low-risk disease may be able to avoid lymphadenectomy and its associated morbidity. We sought to evaluate the agreement rates between the intra-operative frozen sections (FSs) and the final paraffin sections (PSs) at our institution, and to determine if this was a reliable method for guiding our intra-operative decision-making with regard to the necessity of lymphadenectomy. MATERIALS AND METHODS: 116 patients with a pre-operative diagnosis of endometrioid adenocarcinoma of the uterus or complex atypical hyperplasia (CAH) underwent surgery at our institution. Demographic data, as well as information on stage, grade, histology and depth of invasion determined at FS and on PS were collected. Cohen's kappa statistic was used to assess the agreement rate between FS and final PS with regard to depth of invasion, grade, and histology. RESULTS: Our correlation rate between FS and final PS for histologic subtype, grade, and depth of myometrial invasion was 97.5%, 88%, and 98.2% respectively. Seven cases identified as complex atypical hyperplasia on FS were later determined to be cancerous on final PS, resulting in two patients being undertreated. CONCLUSIONS: Our results support the use of FS analysis as a means to guide intra-operative decisions regarding lymphadenectomy. Determination of histologic subtype, depth of invasion and grade is reliable at our institution, and demonstrates high concordance rates between FS and PS. These factors should be used to guide intra-operative decision-making regarding the necessity of a lymphadenectomy in patients with endometrial cancer.

Comprehensive profiling of EGFR/HER receptors for personalized treatment of gynecologic cancers.

The primary gynecologic cancers include cancers of the endometrium, ovary, and cervix. Worldwide, cervical cancer is the most common gynecologic cancer, whereas endometrial cancer is the most common in the US. Ovarian cancer is the fifth most deadly cancer in women, with 5-year survival rates for advanced disease at only 27 %. As such, there is an urgent need for reliable screening tools and novel targeted therapeutic regimens for these malignancies. The epidermal growth factor receptor (EGFR)/human EGFR (HER) family of receptors has been associated with the development and progression of many solid tumors. Despite clear roles for these receptors in other cancers, the expression of HER family members in gynecologic cancers and their relationship with disease stage, grade, and response to treatment remain controversial. In this review, we describe the existing evidence for the use of HER family members as diagnostic and prognostic indicators as well as their potential as therapeutic targets in gynecologic cancers.

Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study.

OBJECTIVES: To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma. BACKGROUND: Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy. METHODS: We performed a randomized phase II trial of intravenous temsirolimus 25mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma. RESULTS: There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded. CONCLUSIONS: Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.

The estrogen receptor joins other cancer biomarkers as a predictor of outcome.

Endometrial cancer, the most common gynecologic malignancy in the United States, is on the rise, and survival is worse today than 40 years ago. In order to improve the outcomes, better biomarkers that direct the choice of therapy are urgently needed. In this review, we explore the estrogen receptor as the most studied biomarker and the best predictor for response for endometrial cancer reported to date.