Askep Kanker Endometrium Pdf Software
Abstract
Objectives: Type II and other high-grade endometrial carcinomas may challenge conventional treatment due to recurrence and metastatic spread and therefore are a persistent clinical dilemma. Effective targeted therapy for these is a goal for clinicians and researchers alike.
Methods: An extensive review of the literature has been performed for obtaining an in-depth understanding of the clinicopathological characteristics, etiologic factors, and molecular profile of these subsets of endometrial carcinoma. Progress made with current and emerging biomarkers for prognosis assessment and therapeutic targeting has been summarized.
Results: There has been a significant increase in research on potential biomarkers of endometrial cancer, and beneficial targeted therapies have been identified.
Conclusions: Clinical trials are leading the charge for substantial gains toward personalized treatment of aggressive endometrial carcinoma subtypes.
Upon completion of this activity you will be able to:
describe the most common etiologic factors for endometrial carcinoma and correlate them with its different types.
recognize the aggressive variants of endometrial carcinoma and describe their histopathologic features.
list the most common molecular alteration in different types of endometrial carcinoma and correlate these with potential clinical applications and treatment outcome.
The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module.
The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.
Exam is located at www.ascp.org/ajcpcme.
Endometrial cancer is the fourth most common malignancy in women, representing 7% of all new cancer cases in the United States. A total of 10,170 women are estimated to die of endometrial cancer in 2015. The incidence of endometrial cancer increased by 2.4% per year from 2007 to 2011, and the death rate increased by 1.9% per year. The 5- and 10-year relative survival rate is 82% and 79%, respectively.1,2
Why Is Targeted Therapy Necessary?
A subgroup of patients with endometrial cancer does not respond to standard therapies, such as those with advanced stage disease or with recurrent endometrial cancer. The standard treatment modalities are associated with significant side effects.3‐6 In addition, many patients with endometrial cancer, particularly those with high-grade cancer, are of advanced age7 and often have comorbidities. These patient-related factors can make the treatment even more problematic and be associated with considerable treatment-related morbidity and mortality.
Chemotherapy resistance is another barrier to successful treatment. Resistance may be present before onset of therapy or may eventually develop shortly after treatment of recurrent adenocarcinoma. A number of important mechanisms of resistance have been identified. For example, deregulation of factors in the apoptotic pathways (such as p53, Fas/FasL, Bcl-2 family proteins, inhibitor of apoptosis proteins), survival pathways (phosphatidylinositol-3-kinase [PI3K]/AKT, MAPK), hormone receptor signaling pathways (progesterone receptor [PR]), and cyclooxygenase-2 and Her-2 have been identified as important pathogenetic mechanisms of chemotherapy resistance. Furthermore, the copresence of several activated mechanisms may suggest that chemotherapy resistance is a truly multifactorial phenomenon.8
These findings indicate that there is tremendous potential for improvement of treatment outcomes by allowing for individualization of therapy through the application of prognostic and predictive markers. A biomarker (or a panel of biomarkers) that could reliably predict good vs poor response to therapy in patients with endometrial cancer would have strong clinical utility. That might allow medical oncologists to treat the predicted “poor response to treatment” subset more aggressively and potentially avoid the costly and toxic treatments in the predicted “good prognosis” group, similar to what has been firmly established in the treatment of patients with breast cancer. This review article aims to highlight the histopathology of aggressive forms of endometrial cancer and addresses the most promising endometrial cancer biomarkers that have potential in therapeutic practice.
Types of Endometrial Cancer
The dualistic model of endometrial cancer is now widely accepted. Endometrial cancer is divided into two types: type I and type II. This model, proposed by Bokhman,9 is based on differences in endocrine and metabolic factors. It was postulated that the first pathogenetic type develops in women who have conditions associated with hyperestrogenism, such as obesity, anovulatory uterine bleeding, infertility, polycystic ovary syndrome, late menopause, and endometrial hyperplasia. This is the most common type of endometrial cancer (85%), and it is characterized by moderately differentiated morphology of the carcinoma, superficial invasion into the myometrium, and high sensitivity to progesterone; this type has a somewhat favorable prognosis. In contrast, the second type is not associated with endometrial hyperplasia, develops in the presence of atrophy, is poorly differentiated histologically with a tendency for deep invasion of the myometrium, and has a high frequency of metastatic spread. This type has a rather poor prognosis, especially in the elderly population.9
The validity of this model is supported by numerous studies. Type II endometrial cancer is diagnosed more often in elderly and nonwhite women who have a history of multiparity, tobacco smoking, and tamoxifen-treated breast carcinoma.7,10‐13 There is an overlap in the pathology between grade 3 type I endometrioid endometrial carcinoma (EEC) and type II nonendometrioid endometrial carcinoma (NEEC).
The Gynecologic Oncology Group (GOG) study 210 showed that the risk factors for grade 3 EEC are generally similar to type II cancers, although patients with grade 3 EEC usually have histories of breast cancer without tamoxifen exposure, while those with type II tumors are more frequently treated with tamoxifen.7,13 A recent report found that the two endometrial cancer types share many common etiological factors, and type II carcinoma is not completely estrogen independent. Parity, oral contraceptive use, tobacco smoking, age at onset of menarche, and diabetes mellitus type II are associated with both grade 3 EEC and type II NEEC. Body mass index, however, has a greater effect on type I tumors than on type II tumors. Risk factor patterns for high-grade endometrioid tumors and type II tumors are similar.7
Endometrioid Endometrial Carcinoma
Endometrioid endometrial carcinoma is classified as type I EC and accounts for 85% of cases. It is an estrogen-sensitive carcinoma that usually arises in the presence of endometrial hyperplasia. Such tumors tend to be biologically indolent with the exception of grade 3 EEC, which behaves aggressively.
As per the World Health Organization, endometrial carcinomas (ECs) are primarily graded based on their architecture14:
Grade 1: less than 5% nonsquamous or nonmorular solid growth pattern
Grade 2: 6% to 50% nonsquamous or nonmorular solid growth pattern
Grade 3: more than 50% nonsquamous or nonmorular solid growth pattern
Grade 1 EEC
The prototype of type 1 EC is endometrioid carcinoma Image 1A and Image 1B. There are three essential diagnostic criteria for carcinoma compared with endometrial hyperplasia: (1) a confluent glandular pattern in which individual glands, uninterrupted by stroma, merge and create a cribriform pattern; (2) an extensive papillary pattern; and (3) an irregular infiltration of glands associated with an altered fibroblastic stroma (desmoplastic stromal response).15,16
Endometrial carcinoma with poor prognostic features. A, International Federation of Gynecology and Obstetrics. Well-differentiated (FIGO) grade 1 endometrioid endometrial carcinoma with deep myometrial invasion (13/17 mm) (H&E, ×40). B, The tumor consists of confluent back-to-back glands without a solid component (H&E, ×400). C, FIGO grade 3 poorly differentiated endometrioid endometrial carcinoma with a predominant solid pattern and a near-total myometrial invasion (H&E, ×40). D, Lymphovascular invasion by carcinoma (H&E, ×200).
Endometrial carcinoma with poor prognostic features. A, International Federation of Gynecology and Obstetrics. Well-differentiated (FIGO) grade 1 endometrioid endometrial carcinoma with deep myometrial invasion (13/17 mm) (H&E, ×40). B, The tumor consists of confluent back-to-back glands without a solid component (H&E, ×400). C, FIGO grade 3 poorly differentiated endometrioid endometrial carcinoma with a predominant solid pattern and a near-total myometrial invasion (H&E, ×40). D, Lymphovascular invasion by carcinoma (H&E, ×200).
Grade 2 EEC
Grade 2 EEC is defined based on the amount of solid component of the carcinoma (6%-50%). The presence of grade 3 nuclei involving greater than 50% of the tumor is associated with more aggressive behavior and therefore justifies upgrading the tumor by one grade.
Grade 3 EEC
This is an architecturally solid tumor with at least focal gland formation. The solid component is usually arranged in large nests (Image IC), and it may also form trabeculae. Solid and gland-forming elements transition seamlessly within the tumor. The tumor cells in gland-forming areas are frequently columnar. There may be squamous and mucinous metaplasia, as well as secretory changes. The nuclear grade in both the solid and glandular components is usually 2 on a 3-point scale. Background hyperplasia is present in a minority of cases. International Federation of Gynecology and Obstetrics (FIGO) grade 3 EECs metastasize primarily to pelvic and para-aortic lymph nodes, pelvic tissues, and, occasionally, to abdominal organs and the lung. Extrauterine extension is generally correlated with deep myometrial invasion and lymphovascular invasion (Image 1D).12,17
Grade 3 EEC has an overlap with type II EC in both clinical behavior and prognosis. They share the some etiologic factors. Some studies suggest that grade 3 ECC more closely resembles type II NEEC than grades 1 to 2 ECC, arguing for the inclusion of grade 3 ECC into type II cancers.7,13 Grade 3 EEC also shares similar molecular alterations with both low-grade EEC and serous carcinoma.18 In addition, some ECs exhibit overlapping features of type I and type II cancer. This includes endometrial adenocarcinoma “with ambiguous features” and undifferentiated adenocarcinoma.12,17,19 They have an aggressive behavior.20
Serous Carcinoma
The prototype of type II endometrial adenocarcinoma is serous carcinoma (SC). These lesions were first described by Hendrickson et al21 in 1982 as a highly malignant subtype of EC. Patients with serous carcinoma are an average of 5 years older than those with endometrioid carcinoma. These tumors usually present with vaginal bleeding. Serous carcinoma accounts for less than 10% of endometrial malignancies, has a poor prognosis, and is usually seen in postmenopausal women with an atrophic endometrium. The spread of serous carcinoma is commonly intra-abdominal, in a manner resembling ovarian cancer.15
Intra-abdominal metastases occur early and are often present at diagnosis. Therefore, although it constitutes approximately 10% of all ECs, it causes a disproportionate number of deaths.16
Serous carcinoma is a papillary or glandular tumor, composed of partly dyshesive polygonal cells with high nuclear-to-cytoplasmic ratios and a high mitotic index (>10 mitotic figures per 10 high-power fields). Papillary architecture or slit-like spaces are almost always present, at least focally. Cell detachment, budding, and tufting are usually present, typically resulting in luminal borders that appear ruffled, in contrast to the linear, smooth contours of endometrioid carcinoma. The nuclei are classically defined as “high grade” Image 2A.12,17
Aggressive histopathologic variants of endometrial carcinoma and carcinosarcoma. A, Serous endometrial carcinoma with slit-like spaces, high nuclear grade, and “hobnail” appearance of nuclei (H&E, ×400). B, Solid variant of clear cell carcinoma (H&E, ×40). C, Solid variant of clear cell carcinoma showing nuclear pleomorphism, high nuclear/cytoplasmic ratio, and cytoplasmic clearing (H&E, ×400). D, Glandular architectural variant of clear cell carcinoma with psammoma bodies (H&E, ×100). E, Uterine carcinosarcoma with a serous carcinoma component and heterologous rhabdomyosarcoma component (H&E, ×100). F, Positive staining on an immunohistochemical stain for myogenin confirms the diagnosis of a rhabdomyosarcoma component in the carcinosarcoma (H&E, × 200).
Aggressive histopathologic variants of endometrial carcinoma and carcinosarcoma. A, Serous endometrial carcinoma with slit-like spaces, high nuclear grade, and “hobnail” appearance of nuclei (H&E, ×400). B, Solid variant of clear cell carcinoma (H&E, ×40). C, Solid variant of clear cell carcinoma showing nuclear pleomorphism, high nuclear/cytoplasmic ratio, and cytoplasmic clearing (H&E, ×400). D, Glandular architectural variant of clear cell carcinoma with psammoma bodies (H&E, ×100). E, Uterine carcinosarcoma with a serous carcinoma component and heterologous rhabdomyosarcoma component (H&E, ×100). F, Positive staining on an immunohistochemical stain for myogenin confirms the diagnosis of a rhabdomyosarcoma component in the carcinosarcoma (H&E, × 200).
Clear Cell Carcinoma
Endometrial clear cell carcinomas are rare. They show papillary, glandular, tubulocystic, and/or solid architecture. The tumor cells are polygonal and frequently contain clear cytoplasm. A variant containing eosinophilic cytoplasm has been termed the oxyphilic variant. Papillary areas have cells with intermediate nuclear-to-cytoplasmic ratios and round nuclei with prominent nucleoli. The predominant cell type lining glands and the papillae is hobnail or cuboidal. Solid areas may have a cobblestone appearance, composed of polygonal, clear cells with sharp cytoplasmic borders and a nucleolus. The stroma in clear cell carcinoma is distinctive, has inflammation, and is hyalinized and myxoid. Clear cell carcinomas usually have a mitotic index that is lower than that of serous carcinoma (60% of cases have a mitotic index of 3 or lower). Psammoma bodies, hyaline bodies, and targetoid bodies are associated with some cases without the solid pattern of the tumor Image 2B, Image 2C, and Image 2D.12,17,22
Carcinosarcoma
Carcinosarcoma (CS) accounts for 2% to 5% of all malignancies of the uterine corpus and almost half of all uterine sarcomas and usually presents in postmenopausal women.23 Uterine CS shares risk factors with EC. Both tumors may occur after long-term tamoxifen treatment for breast cancer and may be associated with obesity, nulliparity, and the use of exogenous estrogen.12,13 Recent immunohistochemical and molecular genetic studies support the clonal origin of both tumor components (epithelial and mesenchymal-like elements) and are now thought to be “undifferentiated” or “metaplastic” carcinomas rather than uterine sarcomas.24,25 Carcinosarcomas have distinctive clinical and pathologic features that warrant their distinction from ECs.23
The minimum criteria for diagnosis specify a tumor composed of malignant epithelial and mesenchymal components Image 2E. The carcinomatous component is serous in 66% or endometrioid in 33% of cases. The sarcomatous component may be homologous or heterologous. The homologous sarcoma-like component often contains hypercellular sheets of small, hyperchromatic, round to spindle-shaped cells with a high mitotic rate and lacks apparent differentiation. It may also resemble fibrosarcoma, high-grade endometrial stromal sarcoma, leiomyosarcoma, undifferentiated sarcoma, or a combination of these tumor types. The heterologous tumor component contains malignant skeletal muscle or cartilage, resembling pleomorphic rhabdomyosarcoma or embryonal rhabdomyosarcoma Image 2F.12,17,23,25
Survival of CS tends to be worse for patients with a nonendometrioid epithelial component in comparison to those with an endometrioid epithelial component (5-year survival: 26% and 55%, respectively). Survival is worse for patients with uterine CS in comparison to high-risk grade 3 EEC and NEEC. The 5-year survival rates are 42%, 77%, and 57%, respectively. The epithelial component determines the prognosis, and this component is present in most metastases, including foci of vascular invasion.24
Molecular Features of Endometrial Carcinoma
Molecular Heterogeneity
The dualistic model of endometrial adenocarcinoma is supported by molecular studies. Types I and II ECs are characterized by distinctive types of genetic instability and molecular alterations. Four major genetic changes are responsible for the tumorigenesis in endometrioid (type I) carcinoma: the silencing of the PTEN tumor suppressor gene, the presence of microsatellite instability, a mutation of the K-ras proto-oncogene, and alteration of the β-catenin gene. On the other hand, a p53 mutation, a p16 mutation, loss of E-cadherin, and overexpression of the Her2/neu oncogene are major genetic alterations in serous and clear cell (type II) carcinomas.26‐30
Identity Overlap of Grade 3 Endometrioid Carcinoma
Overlapping molecular alterations are found in grade 3 endometrioid adenocarcinoma between type I and type II EC. Alvarez et al18 showed that grade 3 endometrioid adenocarcinoma shares the overexpression but not amplification of cyclin D1 with low-grade endometrioid adenocarcinoma and a low frequency of Her-2 overexpression and amplification. In contrast, grade 3 EEC shares p53 and p16 overexpression and a low frequency of the loss of mismatch repair genes with SC but rarely overexpresses Her-2, cyclin D1, or WT-1. In addition, there are clinical correlations between molecular alterations and the stage of EEC. Patients with tumors showing loss of mismatch repair genes (MLH1/MSH2) or cyclin D1 overexpression have low-stage tumors, whereas patients with p-53, p16, or Her-2 overexpression have high-stage tumors. Pathologists often encounter endometrioid and serous carcinomas showing mixed, combined, or hybrid morphologic and molecular characteristics. Serous and clear cell carcinomas have been classified within the same category of NEEC, based on their common characteristic of high nuclear grade and aggressive behavior. Recent studies have demonstrated that these carcinomas are distinct tumor types that exhibit different immunohistochemical and molecular characteristics. Molecular analyses have suggested that in the EEC-NEEC mixed carcinomas, the NEEC component develops as a result of tumor progression from preexisting EEC and that these tumors retain the molecular structure of the typical EEC.27
Molecular Features of Clear Cell Carcinoma
Clear cell carcinomas (CCC) are type II carcinomas that follow a pathway that shows some overlap with serous and endometrioid carcinomas. P53 mutations are present in only 30% to 40% of CCCs in comparison to 90% of serous carcinomas. The frequency of microsatellite instability (MSI) and PTEN alterations in CCC is higher than those in serous carcinoma (15% vs <5% for MSI and 30% vs 10% for PTEN) but lower in comparison to endometrioid carcinoma (20%-40% and 35%-50%, respectively).27 Most pure CCCs show no mutations in either PTEN or p53. These findings suggest that CCC may arise through a distinct pathologic pathway.16
Molecular Features of CS
CS develops along distinctive molecular genetic pathways and exhibits biological features that are distinct from EC. A review by Okuda et al31 states that p53 alterations occur early in the progression of CS, just prior to clonal expansion and acquisition of genetic diversity. They also mention that changes in the AKT/β-catenin pathway may be essential for the establishment and maintenance of the phenotypic characteristics of CS, playing key roles in the regulation of E-cadherin through transactivation of the Slug E-cadherin repressor gene.
A study from the Netherlands reported the following in the epithelial component of CS. As determined by immunostaining results: estrogen receptors α (8%) and β (32%), progesterone receptors A (0%) and B (23%), β-catenin (4%), and cyclin D1 (7%). PTEN, MLH1, MSH2, and MSH6 mutations occurred in 39%, 33%, 22%, and 21%, respectively. Overexpression of p53 was observed in 38% of tumors. The expression patterns of p53, MSH2, and MSH6 were mirrored in the epithelial and mesenchymal tumor components. The epithelial component caused the majority of metastases (72%) and vascular invasion (70%). These findings support the monoclonal origin of uterine carcinosarcomas.24
Chromosomal dysregulation is also observed in CS. Gains or amplifications of 8q are the most common genetic aberration in CS. One of the genes located within 8q is C-MYC (8q24).32 CS displays unique patterns of miRNA dysregulation in comparison to EEC and SC, with an overlap of only 5% among the three tumor types. Nearly one-third (28%) of the miRNAs dysregulated in CS tissues are located in a single small (250-kb) imprinted region of chromosome 14q32, in comparison to benign endometrium. These disruptions contribute to the unique histology and poor outcome of this type of cancer.33
Treatment Modalities of Endometrial Carcinoma
The initial treatment for endometrial adenocarcinoma is surgery and may include a total hysterectomy with bilateral salpingo-oophorectomy and selective pelvic and para-aortic lymphadenectomy. The treatment choice and outcome depend on lymph node involvement and depth of myometrial invasion (MI). The protocol was established by the GOG study34 and is supported by others.35‐37 Further treatment in the postoperative period is based on risk stratification. Surgical staging in conjunction with certain prognostic factors determines the need for additional treatment for endometrial cancer. Clinicians will place the patient in a risk category (low, low intermediate, high intermediate, or high risk) according to the histologic features of the tumor and the patient age. Patients at low risk for lymphatic dissemination have been traditionally defined as those with grade 1 ECC and/or superficial MI (inner third).34 In contrast, the GOG defined intermediate high–risk patients as those associated with (1) a moderate to poorly differentiated tumor and lymphovascular invasion, outer third MI; (2) age 50 years or older with any two risk factors listed above; or (3) age at least 70 years with any risk factor listed above.38 Women without these risk factors are considered to have intermediate low–risk disease. A subsequent study demonstrated that myometrial invasion, tumor diameter, FIGO grade, cervical stromal invasion, and lymphovascular space invasion were significantly associated with high-risk morbidity using a univariate analysis.37 Other factors may affect risk but may not be independent risk factors: low uterine segment involvement, positive pelvic wash cytology, and the pattern of MI, such as a microcystic, elongated, and fragmented pattern of MI.
Postoperative treatment for high-risk patients can include chemotherapy and radiation therapy or a combination dictated by the presence of risk factors. Radiation therapy (vaginal brachytherapy and/or pelvic irradiation) remains the mainstay of postoperative treatment. It is associated with a decrease in local recurrence. A large prospective clinical trial (GOG study 33) demonstrated that radiation therapy has no impact on the survival rate.38 Chemotherapy is the treatment of choice for metastatic disease.39 The most effective regimen consists of anthracyclines, platinum compounds, and taxanes. GOG study 117 found that the response rate for therapy with doxorubicin, cisplatin, and paclitaxel is 57%; however, the regimen is accompanied by significant side effects.3,4,6,40 A trial initiated through the GOG to evaluate alternative treatment modalities for all stages of endometrial cancer (GOG study 258) is currently evaluating the impact of carboplatin and paclitaxel given with or without cisplatin-sensitizing radiation therapy. Hormone therapy is used in women with low-grade, hormone receptor–positive endometrioid adenocarcinomas.39 An alternative treatment with progestin-containing intrauterine devices (IUDs) has shown successful results for women of childbearing age who want to preserve their fertility.41,42 Brown et al43 reported on the effectiveness of a progestin IUD in an adolescent with grade 2 endometrial cancer.
Breast Cancer as a Model for Personalized Medicine
Breast cancer treatment provides an excellent example of individualized medicine. Estrogen receptor (ER) status is not only a powerful independent prognostic factor and indicator of favorable prognosis for women with breast cancer but also a treatment target, identifying women who will and will not benefit from endocrine therapy.44,45 Amplification of Her-2 is a predictive factor for clinical response to anthracycline-containing therapy and a therapeutic marker for trastuzumab.45‐48 The Oncotype DX test (Genomic Health, Redwood City, CA) is now used to predict tumor recurrence in node-negative ER-positive breast cancer.40 It is an RT-PCR assay that analyzes the expression of 21 genes and provides a distant disease recurrence score, which is significantly correlated with a relapse-free interval and overall survival.40,49 Similarly, it is feasible that a gene signature for recurrence prediction of EC may be developed and find acceptance in clinical practice. We now describe the current and emerging concepts related to biomarkers for EC and targeted therapies.
Promising Biomarkers
Some studies have yielded biomarkers with clinical and therapeutic application. Significant pathways can be therapeutically targeted. The ones that we have chosen to review are ER and PR, E-cadherin/β-catenin, PI3K/AKT/mammalian target of rapamycin (mTOR), the epidermal growth factor receptor (EGFR) family, and vascular endothelial growth factor (VEGF).50
Estrogen and Progesterone Receptors
Estrogen binds to at least three major classes of receptors, ER-α, ER-β, and GPR30.51 Endometrial carcinogenesis is regulated by estrogen and downregulated by the differentiating effects of progesterone. ER-α is the predominant type of receptor in the endometrium. Estrogen drives proliferation, while progesterone acts through PRs (PR-A, PR-B, and PR-C) to counteract these effects by inducing differentiation, promoting apoptosis, and inhibiting invasion. Progesterone is a powerful tumor suppressor in the endometrium, a function that has long been exploited therapeutically in progestin-based hormonal therapy for endometrial hyperplasia and carcinoma. PR expression decreases significantly with disease severity.52
Leslie et al53 have provided support for the use of ER-α as a cancer biomarker and predictor of outcome. ER-α receptors are induced by estrogen in the absence of progesterone in type I EC grades 1 to 2. A Canadian study analyzed the circulating levels of 18 steroids, including adrenal precursors, androgens, estrogens, and their glucuronide metabolites, and assessed the correlation between hormonal levels in healthy postmenopausal women and women with different types of EC. They found that circulating levels of all these endogenous steroids were associated with an increased risk of both type I and type II EC. Estrogens were predictive of low-grade, noninvasive, type I EC. Levels of estrone-sulfate in patients with recurrent EC were 2-fold higher than in those without recurrence and 4.5-fold higher than those in healthy women. The authors suggest that circulating estrogen may represent a biomarker predictive of increased risk of recurrent tumors.54
The loss of receptor positivity for ER-α, PR-A, and PR-B is associated with decreased survival in patients with EC, while ER-β has no correlation with survival. PR-B immunoreactivity in tumors is a significant independent prognostic factor for cause-specific survival and can be used as a marker to identify high-risk patients for more aggressive adjuvant therapy.55 Similarly, Jongen et al56 from the Netherlands reported that the expression of ER-α in EEC is associated with early stage, while the expression of ER-β, PR-A, and PR-B is associated with lower grade tumors. A ratio of ER-α/ER-β less than 1 has been reported to indicate a shorter disease-free survival, while a ratio of PR-A/PR-B greater than 1 has been reported to be associated with a shorter disease-free survival and a shorter overall survival. The absence of ER-α in early stage disease was independently associated with death due to the disease, while the absence of PR-A was an independent prognostic factor for disease relapse. Singh et al57Software acak nomor undian. report from GOG study 119 that the ER status of EC can predict response to hormonal therapy with tamoxifen and intermittent medroxyprogesterone acetate in advanced EC. This study showed that 40% of patients who express ER at a level above an H-score of 75 show median survival rates of 19 months, which is comparable to the survival time with some chemotherapy regimens. Hormonal therapy in a select patient pool can achieve the same response rate as chemotherapy but with fewer side effects. The authors recommend ER and PR testing for all cases of EC Image 3A and Image 3B by immunohistochemistry prior to hormonal therapy.
Prognostic biomarkers for endometrial carcinoma. A, Positive staining for estrogen receptor (ER) in endometrioid endometrial carcinoma (ER immunostain, ×200). B, Positive staining for progesterone receptor (PR) in endometrioid endometrial carcinoma (PR immunostain, ×200).
Prognostic biomarkers for endometrial carcinoma. A, Positive staining for estrogen receptor (ER) in endometrioid endometrial carcinoma (ER immunostain, ×200). B, Positive staining for progesterone receptor (PR) in endometrioid endometrial carcinoma (PR immunostain, ×200).
Intracellular 7-transmembrane G protein–coupled estrogen receptor (GPR30) has been implicated in mediating rapid response and transcriptional events associated with estrogen.58 It represents an estrogen-responsive receptor that is overexpressed in tumors with downregulation of estrogen and progesterone receptors and, in patients with high-risk endometrial cancer, with lower survival rates. High levels of GPR30 expression are reported in high-grade, advanced stage, and high-risk subtypes of endometrial cancer, including SC, CCC, and CS.59 He et al60 demonstrated that GPR30 is highly expressed in EC tissues and cancer cell lines and positively regulates cell proliferation and invasion.
E-Cadherin/β-Catenin Pathway
E-cadherin binds to β-catenin, which in turn binds to α-catenin to form a complex.61 Aberrant reactivation of the epithelial-mesenchymal transition (EMT) can promote cancer cell plasticity and promote tumor initiation and metastasis. The loss of E-cadherin expression is a crucial event in EMT.62
ZEB1 acts as a master repressor of E-cadherin and other epithelial markers. We have found high levels of Zeb1 expressed in the tumor-associated stroma of low-grade EECs. It is aberrantly expressed in the epithelial-derived tumor cells of highly aggressive endometrial cancers, such as FIGO grade 3 EEC, SC, and CS. Improper ZEB1 expression in epithelial-derived tumor cells represses E-cadherin expression in both human endometrial cancer specimens and cell lines. This inverse relationship is correlated with increased migratory and invasive potential.63
A negative E-cadherin expression is associated with histologic grade 3 ECs and NEECs. Furthermore, combined E-cadherin, α-catenin, and β catenin expression is a significant prognostic factor for survival.64
Singh et al,65 using tissues from the GOG study 119 demonstrated that patients with high E-cadherin expression had a reduced risk of disease progression and a reduced risk of death. In addition, high expression of p16 in the tumor epithelium was associated with a poor survival and an increased risk of death.
PI3K/PTEN/AKT/mTOR Cascade
PI3K pathway alterations occur in more than 80% of EECs.26,66,67 PIK3R1 is somatically mutated in 43% of EECs and 12% of NEECs. Most mutations (93%) are localized to the p85a-nSH2 and -iSH2 domains.68
The PI3K-mTOR pathway is the key mechanism for controlling cell survival, division, and metabolism. mTOR is a serine-threonine protein kinase that exists in two forms called mTOR complex 1 and 2 (mTORC1 and mTORC2). It is regulated through the PI3K/AKT pathway. The expression of mTORC1 is stimulated by growth factors, energy status, amino acid levels, and cellular stress. mTORC2 activity regulates cytoskeletal organization, cell survival, and lipid metabolism.69
The PI3K signal transduction pathway represents an important therapeutic target. Temsirolimus (CCI-779) is a cytostatic cell cycle inhibitor with antitumor properties. A phase II study using temsirolimus in a chemotherapy-naive group of patients with advanced endometrial cancer showed that 14% of patients had an independently confirmed partial response and 69% had stable disease. Only 18% of patients had progressive disease. In the chemotherapy-treated group, 4% of patients had an independently confirmed partial response, and 48% had stable disease. Immunohistochemistry and mutational analysis show that PTEN loss and molecular markers of the PI3K/Akt/mTOR pathway are not correlated with the clinical outcome.
A two-stage phase II GOG study assessing the activity of a combination of temsirolimus and bevacizumab (anti–VEGF-A) in patients with recurrent or persistent EC showed a response rate of 25%, and 55% of the patients showed stabilization of the disease. However, this regimen was associated with significant toxicity.70 An additional GOG study evaluated temsirolimus alone or in combination with megestrol acetate and tamoxifen in women who had undergone one or no prior chemotherapy regimens. The combination arm was closed early due to excess venous thrombosis.71
A phase II trial of everolimus (rapamycin inhibitor) in recurrent endometrioid endometrial cancer, with prior chemotherapy, demonstrated that 43% of patients had a clinical benefit response (CBR) of greater than 8 weeks, and 21% had a CBR at 20 weeks.11 These clinical trials have evaluated the activity of mTOR inhibitors in women with advanced or recurrent endometrial cancer, with mixed results.
EGFR Family
Cancer cells promote angiogenesis, proliferation, invasion, and metastasis via the four EGFR-specific cell surface receptors: EGFR, ErbB-2, ErbB-3, and ErbB-4.72 EGFR is commonly expressed in normal endometrium and is also overexpressed in endometrial cancer in association with advanced stage and poor prognosis. The GOG study 177 reported by Grushko et al73 found significantly increased frequency of overexpression of Her-2/neu in serous carcinoma and an association between grade and Her-2 amplification among nonserous carcinomas. Similar EGFR expression was significantly lower in type II EC in comparison to type I EC (34% vs 46%, P = .041). EGFR expression but not HER2 gene amplification is significantly associated with poor overall survival in patients with type II EC. EGFR expression maintains prognostic independence after adjusting for histology, stage, grade, and age. Konecny et al74 suggest that assessment of HER2 gene amplification and/or EGFR expression may help select patients with type II EC who could benefit from therapeutic strategies targeting both HER2 and EGFR.
Buza et al75 from Yale recommend the use of breast American Society of Clinical Pathology/College of American Pathologists scoring criteria for Her-2/neu to obtain concordance between immunohistochemistry and fluorescent in situ hybridization study results. They also recommended assessment of HER2 immunohistochemistry on multiple tumor sections or sections with large tumor areas due to significant tumor heterogeneity of HER2 protein expression. Although the HER2 overexpression observed in serous carcinoma of the uterus provides a strong molecular basis for the use of trastuzumab in the treatment of this malignancy, a phase II trial of advanced and recurrent endometrial cancer with overexpression or amplification of HER2 found that the use of trastuzumab was not associated with progression-free survival (PFS) or overall survival.76
Antagonists to EGFR include small-molecule tyrosine kinase inhibitors such as lapatinib, erlotinib, and gefitinib. The therapeutic impact of lapatinib, a HER2 and EGFR dual-kinase inhibitor, was studied in a preclinical trial using a panel of human endometrial cancer cell lines. The data demonstrate that increased expression of either HER2 or EGFR is significantly associated with in vitro sensitivity to lapatinib.77 This has been cited as a rationale for the use of lapatinib in endometrial cancer with HER2 overexpression. However, a GOG phase II trial found that lapatinib had insufficient clinical activity to warrant its use as a single agent in a cohort of unselected patients with advanced or recurrent endometrial cancer.78
The use of erlotinib (NCIC IND-148) in a chemotherapy-naive group of women with recurrent or metastatic endometrial cancer demonstrated a partial response in 13%, and 47% of the patients had stable disease without significant side effects. A corresponding analysis of EGFR mutation or gene amplification did not show any correlation with clinical response.79
Phase II GOG study 229-C, which evaluated the effectiveness of gefitinib in patients with persistent or recurrent endometrial cancer after prior chemotherapy treatment, did not show sufficient efficacy. Expression of EGFR in the tumors showed no correlation with the clinical response.51
VEGF
VEGF is tightly associated with EGFR in promoting tumor-associated neo-angiogenesis and metastasis.72 Overexpression of VEGF correlates with poor outcome in endometrial cancer. Antivascular therapy is efficacious in the treatment of endometrial cancer in orthotopic model female mice/xenografts.80,81 The concentration of VEGF in preoperative serum is correlated with the presence of metastases in EEC.82 Bevacizumab, a monoclonal antibody against VEGF-A, has been shown to be effective in a mouse xenograft model of endometrial cancer.83 A GOG phase II trial of bevacizumab in metastatic endometrial cancer showed clinical response in 14%, and 40% survived progression-free for 6 months.84 A phase II trial of a combination of bevacizumab and temsirolimus in metastatic endometrial cancer showed 25% had a clinical response and 47% survived progression free; however, this was associated with significant toxicity.70
The novel VEGF ligand-binding fusion protein aflibercept (VEGF trap) was evaluated in a phase II GOG study of recurrent or persistent endometrial cancer and demonstrated that 41% of the patients had PFS at 6 months. There was a high rate of treatment discontinuation and two treatment-related deaths.85 These studies have revealed that targeted therapy against VEGF, in isolation or in combination with other agents, currently has many challenges to be overcome.
Other Potential Pathways of Interest
Dellinger et al86 report that Wnt pathway inhibitors’ (DKK3, sFRP1, and sFRP4) expression is downregulated in EEC in comparison to normal Müllerian tissue. Another study29 showed a diminished survival rate for younger obese patients with low-grade EEC. This pathway is still under investigation, and its story in EC has yet to unfold.
Efficacy of Single-Agent vs Combination-Agent Therapy
Are there differences in the efficacy of single-agent vs combination-agent therapy? Brivanib, a tyrosine kinase inhibitor with activity against VEGF and fibroblast growth factor receptor (FGFR), was investigated in a phase II trial in recurrent or persistent endometrial cancer. The results showed that 19% of patients experienced clinical response, with a median response duration of 6.3 months, and 30% had PFS at 6 months.87
A phase II trial of nintedanib (BIBF-1120), a triple receptor tyrosine kinase inhibitor of PDGFR α and β, FGFR1/3, and VEGFR 1 to 3, was conducted in patients with advanced, recurrent, or metastatic endometrial cancer and demonstrated disappointing results along with serious toxicity.39 The same agent was evaluated in combination with paclitaxel to achieve lethality for endometrial cancers using mutant p53 cell lines. The results of this study were promising and showed this agent can be used to restore sensitivity to paclitaxel and induce mitotic cell death in cells. This agent may be a candidate for future clinical trials.88
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Miscellaneous Therapeutic Agents
Several other agents could be utilized in EC treatment but still require additional clinical trials. The use of metformin as a potential agent has been investigated, because there is a well-established association between obesity, diabetes, and EC. A high-concentration treatment regimen with metformin has been shown to inhibit the growth of cancer cells.89 There is an ongoing trial of metformin in nondiabetic patients with histologically confirmed EC.90 Reports from this trial are pending.
Insulin-like growth factor I receptor inhibitor (NVP-AEW541) was investigated in vitro utilizing type I and type II endometrial cancer cell lines. This demonstrated inhibition of proliferation and increased apoptosis.91
Prevention of Endometrial Carcinoma
The prevention and treatment of obesity has potential for EC prevention since it is a principle risk factor for type I EC. Reasons include estrogen and progesterone hormone imbalance with increased estrogen levels via different mechanisms, such as increased aromatase levels, decreased circulating progesterone, insulin resistance, insulin-like growth factor, and adipokines.92
Conclusions
Endometrial cancer is the most common gynecological cancer in the Western world and has shown increasing mortality over the past few decades. Advanced stage and recurrent EC is associated with unfavorable outcome, and there is an urgent need to identify novel targeted therapies. Various opportunities for intervention are provided by distinct underlying molecular mechanisms for the two types of EC. Many therapeutic agents have been evaluated in laboratory studies as well as via clinical trials, with some promising results. Others are still under investigation. As we have illustrated in this review, there is no one-size-fits-all cure for EC. Caution is necessary in choosing personalized treatment for patients, so as to balance benefit vs toxicity. The developments over the past 2 decades have opened the door to survival and cure for many, but not all, patients. The hope is that the future will be brighter for all patients with EC.