Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis.

Lancet. 2009 Jan 10;373(9658):137-46

Authors: , Blake P, Swart AM, Orton J, Kitchener H, Whelan T, Lukka H, Eisenhauer E, Bacon M, Tu D, Parmar MK, Amos C, Murray C, Qian W

BACKGROUND: Early endometrial cancer with low-risk pathological features can be successfully treated by surgery alone. External beam radiotherapy added to surgery has been investigated in several small trials, which have mainly included women at intermediate risk of recurrence. In these trials, postoperative radiotherapy has been shown to reduce the risk of isolated local recurrence but there is no evidence that it improves recurrence-free or overall survival. We report the findings from the ASTEC and EN.5 trials, which investigated adjuvant external beam radiotherapy in women with early-stage disease and pathological features suggestive of intermediate or high risk of recurrence and death from endometrial cancer.

Current treatment of metastatic endometrial cancer.

Cancer Control. 2009 Jan;16(1):38-45

Authors: Temkin SM, Fleming G

BACKGROUND: Endometrial cancer is the most common gynecologic malignancy. The majority of patients have disease confined to the uterus and have an excellent overall prognosis. However, subgroups of patients have advanced primary disease or recurrences following primary treatment.

CYP1A1, SULT1A1, and SULT1E1 polymorphisms are risk factors for endometrial cancer susceptibility.

Cancer. 2008 May 1;112(9):1964-73

Authors: Hirata H, Hinoda Y, Okayama N, Suehiro Y, Kawamoto K, Kikuno N, Rabban JT, Chen LM, Dahiya R

BACKGROUND: In estrogen biosynthetic pathways, many enzymes are important for metabolism, detoxification, and bioavailability. Polymorphisms in these genes may have an effect on the enzymes' function. For example, higher expression and activation of biosynthetic enzymes and lower expression and activation of conjugation enzymes may lead to high toxicity or carcinogenesis. The authors hypothesized that single nucleotide polymorphisms (single nucleotide polymorphisms) of CYP1A1, CYP1A2, CYP1B1, CYP17, SULT1A1, SULT1E1, and SHBG genes may be risk factors for endometrial cancer.

Gonadotropin-releasing hormone (GnRH)-I and GnRH-II induce cell growth inhibition in human endometrial cancer cells: Involvement of integrin beta3 and focal adhesion kinase.

Reprod Biol Endocrinol. 2009 Aug 5;7(1):81

Authors: Park DW, Choi KC, Maccalman CD, Leung PC

ABSTRACT:

Endometrial carcinoma is the most common neoplasm of the female genital tract, accounting for nearly one half of all gynecologic cancers in the Western world. Although intensive research on pathological phenomena of endometrial cancer is currently going on, but exact cause and biological aspects of this disease are not well described yet. In addition to well-documented roles of gonadotropin-releasing hormone (GnRH) in hypopituitary ovarian (HPO) axis, the agonistic or antagonistic analogs (or both) of GnRH have been shown to inhibit the proliferation of a variety of human gynecologic cancers. Thus, in the present study, we further examined the possibility that GnRH induces integrin beta3 and activation of focal adhesion kinase (FAK) through mitogen-activated protein kinases (MAPKs), ERK1/2 and p38, to inhibit the growth of HEC1A endometrial cancer cell line. As a result, both GnRH-I and GnRH-II resulted in a significant increase in integrin beta3 expression and evoked the activation of FAK in a time-dependent manner in these cells. In addition, these analogs induced an activation of ERK1/2 and p38 MAPK in a time-dependent manner as downstream pathways of FAK. It appears that GnRH-II has much greater effect on the activation of FAK, ERK1/2 and p38 compared to GnRH-I in these cells. Further, we demonstrated that the growth inhibition of HEC1A cells by GnRH-I or GnRH-II is involved in the activation of integrin-FAK and ERK1/2 and p38 MAPK pathways. Taken together, these results suggest that GnRH may be involved in the inhibition of endometrial cancer cell growth via activation of integrin beta3 and FAK as a direct effect. This knowledge could contribute to a better understanding of the mechanisms implicated in the therapeutic action of GnRH and its biomedical application for the treatment against endometrial cancer. P

MID: 19656390 [PubMed - as supplied by publisher]

Read Full Article pubmed: endometrial cancer

Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease.

Proc Natl Acad Sci U S A. 2009 May 26;106(21):8677-82

Authors: Jeong JW, Lee HS, Lee KY, White LD, Broaddus RR, Zhang YW, Vande Woude GF, Giudice LC, Young SL, Lessey BA, Tsai SY, Lydon JP, DeMayo FJ

Normal endometrial function requires a balance of progesterone (P4) and estrogen (E2) effects. An imbalance caused by increased E2 action and/or decreased P4 action can result in abnormal endometrial proliferation and, ultimately, endometrial adenocarcinoma, the fourth most common cancer in women. We have identified mitogen-inducible gene 6 (Mig-6) as a downstream target of progesterone receptor (PR) and steroid receptor coactivator (SRC-1) action in the uterus. Here, we demonstrate that absence of Mig-6 in mice results in the inability of P4 to inhibit E2-induced uterine weight gain and E2-responsive target genes expression. At 5 months of age, the absence of Mig-6 results in endometrial hyperplasia. Ovariectomized Mig-6(d/d) mice exhibit this hyperplastic phenotype in the presence of E2 and P4 but not without ovarian hormone. Ovariectomized Mig-6(d/d) mice treated with E2 developed invasive endometrioid-type endometrial adenocarcinoma. Importantly, the observation that endometrial carcinomas from women have a significant reduction in MIG-6 expression provides compelling support for an important growth regulatory role for Mig-6 in the uterus of both humans and mice. This demonstrates the Mig-6 is a critical regulator of the response of the endometrium to E2 in regulating tissue homeostasis. Since Mig-6 is regulated by both PR and SRC-1, this identifies a PR, SRC-1, Mig-6 regulatory pathway that is critical in the suppression of endometrial cancer.

PMID: 19439667 [PubMed - indexed for MEDLINE]

Read Full Article pubmed: cancer endometrial

Silencing of heat shock protein 70 expression enhances radiotherapy efficacy and inhibits cell invasion in endometrial cancer cell line.

Croat Med J. 2009 Apr;50(2):143-50

Authors: Du XL, Jiang T, Wen ZQ, Gao R, Cui M, Wang F AIM: To investigate the role of heat shock proteins 70 (HSP70) in radiosensitivity and invasiveness of endometrial cancer in vitro.

METHODS: HSP70 expression was silenced in relatively radioresistant, well-differentiated human endometrial cancer cell line ISK, using small interference RNA method, or by HSP70 overexpression after transfecting a HSP70-expressing vector. The effect of HSP70 on ISK cell line response to irradiation was evaluated. The surviving fraction was measured using colony-formation assay. Apoptosis was detected by flow cytometry and HSP70 expression was determined by quantitative real-time polymerase chain reaction, western-blot, and/or immunocytochemistry. Cell invasiveness was measured using transwell invasion assay.

RESULTS: HSP70 silencing caused a significant increase in irradiation-induced cell killing in comparison with control cells, with an enhancement factor of 1.27, and in the percentage of apoptotic cells (14.22% vs 6.74%, P = 0.021). After 4 Gy irradiation, mean +/- standard deviation survival fraction in ISK cells was reduced to 0.32 +/- 0.04 in comparison with control values but in ISK/siRNA-HSP70 cells the survival fraction was higher and amounted to 0.51 +/- 0.08 (P = 0.026). Silencing HSP70 significantly inhibited cell invasion before and after irradiation (106 +/- 19 vs 219 +/- 18 and 119 +/- 16 vs 256 +/- 31, P = 0.007). On the contrary, ectopic overexpression of HSP70 attenuated irradiation-induced apoptosis (7.15% vs 4.08%, P = 0.043) and induced more ISK/HSP70 cells invaded through the filters than mock-infected cells before and after irradiation (274 +/- 21 vs 194 +/- 16 before irradiation, and 298 +/- 24 vs 227 +/- 19 after irradiation, respectively, P = 0.032).

CONCLUSION: Disruption of HSP70-induced cytoprotection during irradiation enhances therapeutic effect of irradiation, which makes HSP70 a promising target in the research of endometrial cancer.

PMID: 19399947 [PubMed - indexed for MEDLINE]

Read Full Article pubmed: cancer endometrial

Race disparities between black and white women in the incidence, treatment, and prognosis of endometrial cancer.

Cancer Control. 2009 Jan;16(1):53-6

Authors: Allard JE, Maxwell GL

BACKGROUND: Uterine cancer is the most common gynecologic malignancy in the United States, with an estimated 40,100 new cases and 7,470 deaths occurring in 2008. Although the incidence of endometrial cancer is lower among black women compared with white women, the proportion of cancer-related deaths among blacks is higher and has continued to rise over the past two decades.

The molecular biology of endometrial cancers and the implications for pathogenesis, classification, and targeted therapies.

Cancer Control. 2009 Jan;16(1):8-13

Authors: Bansal N, Yendluri V, Wenham RM

BACKGROUND: Understanding and identifying molecular biology and genetics of endometrial cancer are central to the development of novel therapies. This article reviews the molecular basis for genesis of endometrial cancer with regard to pathogenesis, classification, and implications for targeted therapies.

The role of comprehensive surgical staging in patients with endometrial cancer.

Cancer Control. 2009 Jan;16(1):23-9 ;  Authors: Frederick PJ, Straughn JM

BACKGROUND: The cornerstone of the management of patients with endometrial cancer is hysterectomy. Since 1988, the role of lymphadenectomy for patients with endometrial cancer has been debated. Patients who undergo pelvic and para-aortic lymphadenectomy are more likely to be accurately staged and are less likely to receive adjuvant radiation therapy.

The use of minimally invasive surgery for endometrial cancer.

Cancer Control. 2009 Jan;16(1):30-7 Authors: Humphrey MM, Apte SM

BACKGROUND: Endometrial cancer is the most common gynecologic malignancy in the United States. Surgical staging is an integral component in the treatment of this disease. Minimally invasive surgical techniques have been utilized with increasing frequency in its management.

Will patients benefit from regionalization of gynecologic cancer care?

PLoS One. 2009;4(1):e4049

Authors: Brookfield KF, Cheung MC, Yang R, Byrne MM, Koniaris LG

OBJECTIVE: Patient chances for cure and palliation for a variety of malignancies may be greatly affected by the care provided by a treating hospital. We sought to determine the effect of volume and teaching status on patient outcomes for five gynecologic malignancies: endometrial, cervical, ovarian and vulvar carcinoma and uterine sarcoma.