Abstract Purpose: Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second-line chemotherapy with a response rate >13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent EEC. Patients and Methods: A Simon two-stage design was employed. Women with ≤2 prior chemotherapy regimens for recurrence were eligible. Pretreatment biopsy was required, followed by everolimus 10 mg orally, letrozole 2.5 mg orally, and metformin 500 mg orally twice a day on a 4-week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity. Results: Sixty-two patients were enrolled. Median age was 62 years (40–77) with 401 cycles completed, median of 6 cycles (1–31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received >12 cycles. Median follow-up was 17.9 months (2–47). Median progression-free survival was 5.7 [95% confidence interval (CI), 3.0–8.1] and OS was 19.6 months (95% CI, 14.2–26.3). Positive progesterone receptor expression was associated with CB (89.5% vs. 27.3%, P = 0.001). Conclusions: Everolimus, letrozole, and metformin resulted in 50% CB and 28% OR in women with recurrent EEC. Progesterone receptor–positive tumors may have better response; validation studies are needed. See related commentary by Madariaga et al., p. 523

Letrozole

Everolimus

Single Center

10.1158/1078-0432.ccr-19-0471

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Citations (71)

Uterine papillary serous carcinoma (UPSC): a single institution review of 129 cases

Gynecologic Oncology (2003)

Brian M. Slomovitz Thomas W. Burke Patricia J. Eifel Lois M. Ramondetta Elvio G. Silva

10.1016/j.ygyno.2003.08.018

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Citations (343)

Beyond BRAF V600

Alan Siroy Genevieve M. Boland Denái R. Milton Jason Roszik Silva Frankian

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Citations (86)

Abstract 4182: Overexpression of Mig-6 suppresses endometrial cancer development and progression in ablation of Pten mice

Cancer Research (2012)

Tae Hoon Kim Hong Im Kim Michael J. Large Russell R. Broaddus John P. Lydon

Abstract Endometrial cancer is the most common gynecological cancer. Estrogen-dependent endometrioid carcinoma is the most common type of endometrial cancer. In previous studies, we have identified mitogen-inducible gene 6 (Mig-6) as a downstream target of Progesterone Receptor (Pgr) action in the uterus. Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and estrogen-induced endometrial cancer. These results suggest that Mig-6 act as a tumor suppressor in endometrial cancer. To assess the effects of the overexpression Mig-6 and the PTEN/PI3K/AKT signaling pathways on uterine tumorigenesis, mice with Pten floxed (Ptenf/f) and LoxP-STOP-LoxP Mig-6 (R26Mig-6LSL) were bred to the PRCre mouse model to generate ablation of Pten and overexpression of Mig-6 in the uterus (PRcre+ R26Mig-6LSL Ptenf/f). PRcre+ R26Mig-6LSL Ptenf/f showed significantly increased survival time compared to PRcre/+ Ptenf/f mice. Double mutant mice showed significantly decreased uterine weight compared to PRcre/+Ptenf/f at 3 months of age. Gross morphology at 3 months of age showed that double mutant mice dramatically retarded the development of endometrial cancer compared to ablation of Pten alone. Histological analysis showed that endometrial adenocarcinoma with invasion into the myometrium was observed in the PRcre/+Ptenf/f mice at 3 months of age. However, double mutant mice did not develop endometrial cancer. Immunohistochemstry analysis showed significantly increased apoptosis and decreased proliferation at epithelial cells in PRcre+ R26Mig-6LSL Ptenf/f mice compared to PRcre/+ Ptenf/f mice at 3 months of age. The expression of pERK1/2 was significantly decreased in PRcre+ R26Mig-6LSL Ptenf/f mice compared to PRcre/+ Ptenf/f mice at 2 and 3 months of age. The expression of Pgr and its tartget genes was significantly increased in PRcre+ R26Mig-6LSL Ptenf/f mice compare to PRcre/+ Ptenf/f mice. However, the expression of Estrogen Receptor ≤ (Esr1) and its target genes was significantly decreased. The ability of Mig-6 to repress cancer development indicates that it exerts a tumor suppressor function in endometrial cancer. These results will contribute to the understanding of the molecular mechanism of tumorigenesis and to the development of therapeutic approaches for endometrial cancer.(Supported by NIH, R01 HD057873) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4182. doi:1538-7445.AM2012-4182

10.1158/1538-7445.am2012-4182

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Data from Hotspot Mutation Panel Testing Reveals Clonal Evolution in a Study of 265 Paired Primary and Metastatic Tumors

Rashmi S. Goswami Keyur P. Patel Rajesh R. Singh Funda Meric‐Bernstam Scott Kopetz

<div>AbstractPurpose: We used a clinical next-generation sequencing (NGS) hotspot mutation panel to investigate clonal evolution in paired primary and metastatic tumors.Experimental Design: A total of 265 primary and metastatic tumor pairs were sequenced using a 46-gene cancer mutation panel capable of detecting one or more single-nucleotide variants as well as small insertions/deletions. Mutations were tabulated together with tumor type and percentage, mutational variant frequency, time interval between onset of primary tumor and metastasis, and neoadjuvant therapy status.Results: Of note, 227 of 265 (85.7%) tumor metastasis pairs showed identical mutation calls. Of the tumor pairs with identical mutation calls, 160 (60.4%) possessed defining somatic mutation signatures and 67 (25.3%) did not exhibit any somatic mutations. There were 38 (14.3%) cases that showed at least one novel mutation call between the primary and metastasis. Metastases were almost two times more likely to show novel mutations (n = 20, 7.5%) than primary tumors (n = 12, 4.5%). TP53 was the most common additionally mutated gene in metastatic lesions, followed by PIK3CA and SMAD4. PIK3CA mutations were more often associated with metastasis in colon carcinoma samples.Conclusions: Clinical NGS hotspot panels can be useful in analyzing clonal evolution within tumors as well as in determining subclonal mutations that can expand in future metastases. PIK3CA, SMAD4, and TP53 are most often involved in clonal divergence, providing potential targets that may help guide the clinical management of tumor progression or metastases. Clin Cancer Res; 21(11); 2644–51. ©2015 AACR.</div>

Mutation frequency

Primary tumor

10.1158/1078-0432.c.6523914

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Phase II trial of imatinib mesylate in patients with recurrent platinum- and taxane-resistant epithelial ovarian and primary peritoneal cancers

Gynecologic Oncology (2005)

Robert L. Coleman Russell R. Broaddus Diane C. Bodurka Judith K. Wolf Thomas W. Burke

Imatinib Mesylate

Tolerability

Taxane

10.1016/j.ygyno.2005.09.041

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Citations (102)

The synergistic effect of Mig-6 and Pten ablation on endometrial cancer development and progression

Oncogene (2010)

Tae Hyun Kim Heather L. Franco Sung Yun Jung Jun Qin Russell R. Broaddus

10.1038/onc.2010.126

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Citations (55)

A prospective evaluation of universal tumor testing strategies for Lynch syndrome in endometrial cancer.

Journal of Clinical Oncology (2014)

Kari L. Ring Amanda Bruegl Brittany Batte Molly S. Daniels Mark F. Munsell

5512 Background: Screening for Lynch Syndrome (LS) in endometrial cancer (EC) has traditionally been based on early age at diagnosis and family history. Universal tumor testing has been proposed given poor sensitivity of referral criteria and low referral rates. While immunohistochemistry (IHC) is cost effective and widely available, no prospective evaluation of concordance between screening strategies has been completed in EC to define the optimal approach. Our objective was to perform a prospective, population-based evaluation of universal tumor testing in EC to evaluate concordance between microsatellite instability (MSI) and IHC. Methods: MSI and IHC for expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) were performed prospectively on all EC undergoing surgical staging from August 2012 to August 2013 (n=184). PCR-based MLH1 methylation analysis was performed on tumors with IHC loss of MLH1. Results: Forty-five tumors (24.9%) were MSI-H and 50 tumors (27.2%) had loss of ≥1 MMR protein on IHC. Overall concordance between MSI analysis and IHC was 93.9% (CI 89.4 – 96.9); however, 11 patients (6.1%) had discordant tumor studies. One of 45 MSI-H tumors (2.2%) had intact IHC for all 4 proteins and demonstrated MLH1 methylation. Five of 50 tumors (10.0%) with loss of ≥1 MMR protein on IHC were MS-stable (MSS). Three of these 5 tumors had heterogeneous loss of MLH1 and PMS2 and 1 tumor had complete loss of expression of MLH1 and PMS2. All 4 tumors had MLH1 methylation and presumed sporadic. One MSS tumor had isolated MSH6 loss and a confirmed germline mutation in MSH6. Five tumors (2.8%) were MSI-L, 4 of which had intact IHC. Of these 4, 2 had no germline mutation detected in MSH6, 1 had a variant of unknown significance (VUS) in MSH6, and one did not undergo germline testing. One MSI-L tumor had loss of MLH1 and PMS2, with MLH1 methylation. Conclusions: Overall concordance between MSI and IHC was high in this prospective EC population. However, 6.1% of patients had discordant tumor studies and 2 of 5 patients without MLH1 methylation had a confirmed germline mutation or VUS. Heterogeneous loss of expression on IHC and MSI-L tumors present clinical caveats that are not well defined in EC and warrant further evaluation.

Lynch Syndrome

PMS2

MSH6

MLH1

Microsatellite Instability

MSH2

Concordance

10.1200/jco.2014.32.15_suppl.5512

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Citations (1)

Data from Omental Adipose Tissue–Derived Stromal Cells Promote Vascularization and Growth of Endometrial Tumors

Ann H. Klopp Yan Zhang Travis Solley Felipe Amaya‐Manzanares Frank C. Marini

<div>AbstractPurpose: Adipose tissue contains a population of tumor-tropic mesenchymal progenitors, termed adipose stromal cells (ASC), which engraft in neighboring tumors to form supportive tumor stroma. We hypothesized that intra-abdominal visceral adipose tissue may contain a uniquely tumor-promoting population of ASC to account for the relationship between excess visceral adipose tissue and mortality of intra-abdominal cancers.Experimental Design: To investigate this, we isolated and characterized ASC from intra-abdominal omental adipose tissue (O-ASC) and characterized their effects on endometrial cancer progression as compared with subcutaneous adipose-derived mesenchymal stromal cells (SC-ASC), bone marrow–derived mesenchymal stromal cells (BM-MSC), and lung fibroblasts. To model chronic recruitment of ASC by tumors, cells were injected metronomically into mice bearing Hec1a xenografts.Results: O-ASC expressed cell surface markers characteristic of BM-MSC and differentiated into mesenchymal lineages. Coculture with O-ASC increased endometrial cancer cell proliferation in vitro. Tumor tropism of O-ASC and SC-ASC for human Hec1a endometrial tumor xenografts was comparable, but O-ASC more potently promoted tumor growth. Compared with tumors in SC-ASC–injected mice, tumors in O-ASC–injected mice contained higher numbers of large tortuous desmin-positive blood vessels, which correlated with decreased central tumor necrosis and increased tumor cell proliferation. O-ASC exhibited enhanced motility as compared with SC-ASC in response to Hec1a-secreted factors.Conclusions: Visceral adipose tissue contains a population of multipotent MSCs that promote endometrial tumor growth more potently than MSCs from subcutaneous adipose tissue. We propose that O-ASCs recruited to tumors express specific factors that enhance tumor vascularization, promoting survival and proliferation of tumor cells. Clin Cancer Res; 18(3); 771–82. ©2011 AACR.</div>

10.1158/1078-0432.c.6519938.v1

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Loss of phosphatase and tensin homologue deleted on chromosome 10 and phosphorylation of mammalian target of rapamycin are associated with progesterone refractory endometrial hyperplasia

International Journal of Gynecological Cancer (2007)

Michael R. Milam Pamela T. Soliman Linda H. Chung K. Schmeler R. L. Bassett

The objective of our study was to evaluate the phosphatase and tensin homologue deleted on chromosome 10 (PTEN), p27, and mammalian target of rapamycin (mTOR) expressions in women with progesterone-responsive and refractory endometrial hyperplasia (EH) samples and to determine if these markers could be associated with response or used as potential targets for treatment. Thirty-eight matched pre- and posttreatment pairs of paraffin-embedded endometrial biopsies were obtained from patients with EH. Immunohistochemical analysis for PTEN, p27, and phospho-mTOR were performed on all samples. Median age at diagnosis was 49 years (20-79 years). Median treatment interval was 3 months (1-12 months). Sixteen patients (42.1%) had complete resolution of their hyperplasia (responders), and 22 (57.9%) had persistent hyperplasia (nonresponders) after treatment with progesterone. In the pretreatment samples, no markers were found to predict nonresponders. In posttreatment samples, loss of PTEN expression with phospho-mTOR expression was observed in more nonresponders than responders (40.9% vs 6.3%; P= 0.03). Phospho-mTOR overexpression was found in 63.6% of nonresponders. We found that persistent hyperplasia refractory to progesterone therapy was associated both with the loss of PTEN and with the loss of phosphorylation of mTOR. In select cases of non-responsive progesterone refractory EH, a rational target for treatment may involve the mTOR pathway.

Tensin

Endometrial hyperplasia

Refractory (planetary science)

10.1111/j.1525-1438.2007.00958.x

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Citations (23)