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Abstract

Endometrial cancer is the most common gynecologic cancer in the USA and the second most common worldwide after cervical cancer. While common symptomatology of endometrial cancer leads to early diagnosis and favorable 5-year survival in most cases, there is a subset of cancers that have a poorer prognosis. The clinical and pathologic prognostic factors for endometrial cancer are well known and instrumental in determining the need for adjuvant therapy. Recently, research has been focused on the identification of molecular changes leading to different histologic subtypes to improve classification of endometrial cancer. The identification of novel mutations and molecular profiles should enhance our ability to personalize adjuvant treatment with genome-guided targeted therapy.

Keywords

biologic markers endometrial cancer prognosis targeted therapy

Background

Approximately four decades ago endometrial cancer became the leading gynecologic cancer in the USA [ 1 ]. While the incidence of endometrial cancer in the US reached a plateau for a few decades, it has been steadily increasing over the last 5 years from 39,080 estimated new cases in 2007 to 49,560 in 2013 [ 2 , 3 ]. In addition, the incidence of endometrial cancer worldwide has increased since 2000 and it is now the second most common gynecologic malignancy [ 4 , 5 ]. There has also been a concomitant increase in mortality from endometrial cancer. The incidence is comparable in developing and developed countries; however, the mortality rate is higher in developing countries [ 5 ] with a 5-year survival rate of 75% [ 6 ] compared with the US rate of 82% for all stages [ 3 ]. Clearly the burden of endometrial cancer is increasing in the US and worldwide, hence increasing the need to investigate its causes and improve prevention, early diagnosis and treatment.

The escalation in the number of women entering menopause in addition to risk factors, such as obesity and diabetes, may explain a fraction of the increased incidence of endometrial cancer [ 7 – 9 ]. The median age at diagnosis is 61 years with approximately 85% of the cases being diagnosed after 50 years of age [ 10 ]. Consequently, this is generally a disease of postmenopausal women and most cases are diagnosed in early stages owing to the clinical symptoms of postmenopausal bleeding and abnormal discharge. The 5-year survival for early-stage disease is as high as 95% but it rapidly declines to 67% for stage III and 16% for stage IV disease ( Figure 1 ) [ 3 ]. According to the Surveillance, Epidemiology and End Results (SEER) data collected from 2003–2009, 68% of endometrial cancer cases were diagnosed at an early stage, but a considerable number (28%) were diagnosed after regional or distant spread [ 11 ]. While some of the advanced cases may be attributable to delay in diagnosis, a subset of is comprised of a different histologic subtype that is more aggressive with a higher propensity of metastasis. The two histologic subtypes of type I and II are morphologically distinct and their heterogeneity in clinical outcomes and molecular markers is described in further detail throughout this review. Although type II histology represents a small proportion of endometrial cancers, it accounts for a relatively high recurrence and cancer-related death rate [ 12 ]. In order to improve overall survival and decrease recurrence, we need to identify the tumors with poor prognostic behaviors and treat them appropriately with adjuvant and targeted therapy ( Box 1 ).

Figure 1.

Five-year survival by race for each stage at diagnosis.

Box 1.

Prognostic factors for endometrial cancer.

Clinical

Age

Race

Pathologic

Histologic subtype

FIGO stage

Histologic grade

Lymphovascular space invasion

Molecular markers; mechanism

Hormone receptor; cellular expression

PTEN; loss-of-function mutation

P13K/AKT/mTOR; pathway aberrations

TP53; loss-of-function mutation

HER2/neu; activating mutation

MSI; MMR gene defects

Angiogenesis markers; mediates VEGF

MEK/ERK; activating mutation

K/Ras; activating mutation

Other

DNA ploidy

Metformin use

FIGO: International Federation of Gynecology and Obstetrics

MSI: Microsatellite instability.

Clinical prognostic factors

Age

Overall, older women have a worse prognosis and a lower 5-year survival than younger women. It is important to evaluate whether this difference is purely based on age or other poor prognostic features associated with age. In a study involving data from 15,471 endometrial cancer patients in the SEER database, Lee et al. showed that women older than 40 years were less likely to have stage I disease and grade I tumors but more likely to have uterine papillary serous histology than women aged 40 years and younger [ 13 ]. Furthermore, women older than 40 years had a survival disadvantage and significantly lower 5-year survival when stratifying by age and adjusting for histology and adjuvant therapy. Keys et al. identified increasing age as a factor associated with increased risk of recurrence in early stage patients [ 14 ]. The authors categorized age into the three groups <50, 50–70 and >70 years in defining a group of endometrial cancer patients with high intermediate risk of recurrence.

Using data from a GOG study of clinical stage I and II endometrial adenocarcinoma patients with type I or type II histology, Zaino et al. reported 5-year survival rates of 96.3% for patients 50 years or younger, 87.3% for patients aged 51–60 years, 78% for patients aged 61–70 years, 70.7% for patients aged 71–80 years, and 53.6% for patients older than 80 years [ 15 ]. After multivariate analysis of a subset of patients that were confirmed to have stage I or II disease by surgical staging, the significance of age at diagnosis in survival outcome was greater. In a proportional hazards model, with 45 years of age as the reference point, the relative risks for death from disease were 2.3 at 55 years, 4.6 at 65 years, and 7.6 at 75 years of age.

Both these studies show that age at diagnosis is an independent prognostic factor for survival. In addition to a lower 5-year disease-specific survival rate of 68% in patients aged over 75 years compared with 86% in patients aged 50–75 years (p < 0.0001), Lurain et al. found that increasing age was an independent risk factor for recurrence [ 16 ]. The odds ratio for age was 1.07, implying that for every 1-year increase in age the estimated rate of recurrence increased by 7%. None of the patients less than 50 years of age developed recurrence despite three patients being upstaged to stage IIIC after surgery.

Race

Compared to the US white population, the lifetime risk of being diagnosed with endometrial cancer is lower for African–Americans, Hispanics, Asian Pacific Islanders and Native Americans/Alaska Natives in decreasing order [ 11 ]. The risk of dying from cancer is lowest amongst American Indian/Alaska natives at 0.32 and comparable between white patients, Hispanics and Pacific Islanders at 0.52, 0.50 and 0.45, respectively. The topic of interest and further research in ethnic and racial disparities has been the almost twofold higher likelihood of death in African–American women when compared with white women.

African–American women have a 6% lower incidence rate of all cancers when compared with white women; however, the death rate is 16% higher [ 3 ]. This disparity is more evident in endometrial cancer with a 12% decrease in incidence rate and an 86% increase in death rate of African–Americans when compared with white women [ 11 ]. Several population-based and large institutional studies have shown that African–American women are more likely to present with advanced stage, unfavorable histologic subtypes (serous, clear cell, sarcoma and carcinosarcomas) and higher-grade tumors [ 17 – 19 ]. The 5-year survival of African–American women is lower than white women for every stage of diagnosis ( Figure 1 ); however, this is probably because they have higher grades and more aggressive tumors even when comparing patients with the same stage at diagnosis [ 20 ]. Two studies show conflicting data about the presence of survival differences between the two races when adjusting for histologic type and grade [ 18 , 19 ]. Smotkin et al. showed that race did not impact survival in a Cox proportional hazard model when adjusting for type I and II histology; however, he did not adjust for stage and grade, which are known to be disproportionate in the two races [ 18 ]. Using data from the SEER database, Sherman et al. concluded that survival was significantly lower for African–American women compared with white women in endometrioid cancer and every other histologic category when stratified by age, stage and grade of tumor [ 19 ].

Given the significant racial disparity with regards to histologic subtype, molecular and mutation analysis of endometrial cancer specimens from African–Americans and white patients has been performed in an attempt to identify potential genetic differences that can explain the magnitude of this disparity. As expected, in a study of advanced endometrial cancers, white women were more likely to have PTEN mutations that are associated with type I histology and a better prognosis [ 21 ], and in a study of stage I endometrial cancers African–American women were more likely to have p53 mutations that are associated with type II histology and poorer prognosis [ 22 ]. Her2/neu oncogene has been associated with poor treatment response and poor survival in endometrial cancers [ 17 ]. In a study specific to uterine papillary serous cancer, African–Americans were more likely to have cancers with Her2/neu receptor expression than white women [ 23 ]. Conversely, two studies looking at microarray-based expression profiles of endometrial cancers from African–American and Caucasian women found no evident gene-expression differences between the two races [ 24 , 25 ].

Differences in biologic features and the disproportionate distribution of poor histology between the two races are the principal factors leading to the disparity in endometrial cancer survival. To account for the rest, review articles make a strong argument that socioeconomic status plays an important role in explaining survival differences across races since African–Americans are more likely to live below the poverty level and in underserved areas [ 17 , 26 ]. Rationally, a low socioeconomic status would seem to affect access to appointments, time to diagnosis and access to treatment and follow-up; however, studies presented in the review articles mentioned above are still conflicting on whether it is an independent prognostic factor in endometrial cancer.

Pathologic prognostic factors

Histologic type

Bokhman first described the concept of two pathogenetic types of endometrial cancer arising in two clinically diverse subsets of patients in 1983 [ 27 ]. He prospectively observed 366 patients with endometrial cancer and compared prognostic factors between the two proposed histologic subtypes. He noticed that the subtype currently designated as type II histology was found in 35% of endometrial cancers and was associated with high nuclear grade, poor tumor differentiation, deep myometrial invasion, high frequency of lymph node metastasis, decreased sensitivity to progestins and poor 5-year survival rate (58.8%). This type is found in women who tend to be thin and lack the endocrine and metabolic disturbances leading to obesity, hyperlipidemia and a hyperestrogenic state. Type I histology was more common (65%), arose in obese women with endocrine and metabolic disturbances, were highly sensitive to progestins, and had favorable surgical–pathologic prognostic factors and 5-year survival rate (85.6%). In subsequent studies, type I histology is also referred to as endometrioid and type II referred to as nonendometrioid, papillary serous or serous, clear-cell and undifferentiated carcinomas ( Table 1 ). Currently, the term papillary is no longer being used to describe serous carcinomas.

Table 1.

Clinical-pathologic characteristics of type I and type II endometrial cancer.

Clinical-pathologic characteristics	Type I	Type II
Histology	Endometrioid	Nonendometrioid (serous, clear cell, undifferentiated)
Grade	1, 2	2, 3
Stage	I, II	III, IV
Hormone receptor	ER+/PR+	ER-/PR-
Mutations	PTEN	p53
Etiology	Unopposed estrogen	Sporadic
Survival	Favorable	Poor

Previously mentioned studies of clinical stage I endometrial cancer found that the 5-year survival for serous and clear cell histology was significantly lower than endometrioid with and without squamous differentiation [ 15 , 16 ]. A retrospective review shows that a majority of tumors with this histology have a higher extent of extrauterine disease and a higher frequency of recurrence despite adjuvant radiation treatment [ 28 ]. Even in surgical stage IA cancers with papillary serous and clear cell histology, the 5–year survival was 57% compared with >90% for endometrioid counterparts [ 29 ]. Adjusting for stage of disease, this continues to be the trend ( Table 2 ). Interestingly though, if poor histology is isolated to endometrial curettings without any evidence in hysterectomy specimen, this may not affect prognosis [ 30 ].

Table 2.

Five-year survival based on histology for each stage.

Histology	Stage I (%)	Stage II (%)	Stage III (%)	Stage IV (%)
Endometrioid	90.1	79.5	67.7	25.8
Serous	79.7	40.7	37.7	–
Clear cell	85.1	63.4	48.5	–

Data taken from [ 31 ].

Recent reviews state that since uterine papillary serous carcinoma is morphologically, genetically and clinically different than endometrioid carcinoma, there may be more heterogeneity between the two than originally thought [ 32 , 33 ]. Recent research on the genomics of endometrial cancer provides evidence that the differences between type I and type II histologic subtypes may be reflected in their genetic and molecular profiles [ 34 ]. Identifying the distinct genetic mutations that affect cell signaling pathways is the next step to make advancements in targeted therapies.

Tumor stage

The purpose of staging in malignancies is to classify tumors based on size and spread of disease in order to accurately assess prognosis. Prior to 1988, endometrial cancer was staged based on size of the uterus and clinical extent of disease. Since reports in the 1970s showed that survival of clinical early-stage endometrial cancer was not as high as expected, multiple studies were performed looking at pathologic prognostic factors for recurrence and survival. These studies noted a substantial discrepancy between clinical stage prediction and the actual extent of disease based on pathologic review of specimens from surgical staging [ 15 , 16 , 35 – 37 ]. In 1988, International Federation of Gynecology and Obstetrics (FIGO) classification changed from clinical to surgical staging for endometrial cancer. The staging classification was revised by FIGO in 2009 by combining stage IA and IB, removing stage IIA, and incorporating important prognostic variables regarding paramentrial involvement and lymph node status into stage III.

Surgical stage is the most significant prognostic variable for endometrial cancer. Data from GOG 33 looked at surgical and pathologic factors that were associated with extrauterine disease, lymph node involvement and recurrence in clinical early-stage disease. In a multivariate analysis, depth of myometrial invasion and extrauterine disease was associated with lymph node metastasis [ 36 ]. Degree of myometrial invasion was one of the most important prognostic factors related to recurrence in patients with early-stage endometrial cancer [ 15 , 16 , 38 , 39 ]. Recurrence was also highly dependent on pelvic and para-aortic lymph node status, which in turn was associated with extrauterine metastasis to the cervix, adnexa and peritoneum. Implications from these findings were important in confirming the importance of surgical staging and classifying patients in prognostic groups in order to provide adequate adjuvant treatment.

Histologic grade

Data from the GOG 33 protocol showed that poor tumor differentiation was associated with a higher depth of invasion [ 36 ]. In a multivariate analysis, grade of tumor was independently and significantly related to lymph node metastasis. Long-term data from the same patients showed that for patients with surgically confirmed stage I disease, the greatest determinant of recurrence was grade 3 histology with the relative risk of grade 3 being three-times greater than grade 1 [ 39 ].

The FIGO annual report of patients treated from 1999–2001 showed that the 5-year survival decreases with increasing grade for every stage of disease ( Table 3 ) [ 31 ]. Grade of tumor differentiation is a marker of prognosis and is associated with other prognostic factors such as myometrial invasion, extrauterine disease and lymph node status. It is included while reporting the FIGO stage assignment of endometrial cancer.

Table 3.

Five-year survival based on histologic grade for each stage.

Grade	Stage I (%)	Stage II (%)	Stage III (%)	Stage IV (%)
1	92.9	86.0	78.6	49.2
2	89.9	80.0	67.3	26.5
3	78.9	66.0	46.4	13.4

Data taken from [ 31 ].

Lymphovascular space invasion

Similar to histologic grade, the presence of malignant cells in the capillary-like space increases the risk of pelvic and para-aortic lymph node involvement by four- and six-times, respectively [ 36 ]. The relative risk of recurrence for patients with lymphovascular space invasion (LVSI) compared to without was 2.4 [ 39 ]. A retrospective review of 757 endometrioid endometrial cancers shows that the presence of LVSI is highly associated with lymph node metastasis in a univariate analysis (odds ratio: 11, p < 0.0001) and a significantly reduced progression-free survival and overall survival in a multivariate analysis [ 40 ].

In further support of this data, a more recent retrospective study looking at early stage endometrioid tumors from a single institution showed that LVSI was the only consistent prognostic factor affecting recurrence and survival [ 41 ]. In the multivariate analysis, after adjusting for other important prognostic factors such as age, myometrial invasion, grade and adjuvant therapy, LVSI was an independent risk factor with a 2.6 higher odds of recurrence. The hazard ratio for overall survival and disease-specific survival was 2.8 and 7.0, respectively. This pathologic factor is specifically important in early stage patients where the benefit of adjuvant therapy is debatable.

Molecular markers associated with prognosis & targeted therapies

As discussed previously, the majority of patients with endometrial cancer present with stage I disease, which is potentially curable by surgery with or without adjuvant radiotherapy [ 31 ]. Nonetheless the reported 5-year survival for surgical stage I disease treated between 1999–2001 ranged from 79–93% when taking into account grade and histologic subtype [ 31 ]. The decreased prognosis due to high grade and type II histology should be the main focus in current research to improve the overall survival of patients diagnosed with early-stage disease. As a result, molecular markers are being evaluated in an attempt to identify the patients with early stage but high risk of recurrence, since they would benefit from adjuvant and targeted therapies.

Mortality rates increase with advancing stage of disease despite advances in radiotherapy, surgery and chemotherapeutic efforts. The median overall survival in these patients is less than 1 year [ 42 , 43 ]. By improving our understanding of the disease at a molecular level and identifying the genetic changes that give rise to the heterogeneity in this spectrum of malignancies, we will enhance our ability to develop targeted therapies to supplement our current treatment strategies.

Hormone receptors

Reports on the prognostic value of hormone receptor status on endometrial cancer have been published since the 1980s. Estrogen and progesterone receptor positivity are independent prognostic factors with a significantly improved disease-free survival [ 44 , 45 ]. Hormone therapy including progestins, aromatase inhibitors and selective estrogen receptor modulators are attractive first-line therapies for young patients wanting fertility-sparing options and supplemental therapies for patients with advanced disease since they lack adverse toxicities. A few published cases report successful response in treating young patients with early-stage type I disease; however, the median progression-free survival in patients with recurrent or advanced disease are minimal at 1–3.7 months [ 46 – 48 ]. Hormone receptor status is still an important molecular prognostic factor and hormonal therapy should always be considered as supplemental and palliative targeted therapy.

PTEN

PTEN is a tumor suppressor gene encoding a phosphatase enzyme that regulates cell cycle arrest in the G1 phase and enables apoptosis through signaling pathways [ 49 ]. PTEN mutations leading to inactivation of the protein are the most common genetic defects in type I endometrial carcinomas and have been reported in 57–83% of cases [ 50 , 51 ]. By examining coexisting normal endometrium and precancerous tissue in hysterectomy specimens, Mutter et al. verified the presence of PTEN mutations in 55% of precancerous lesions and none of the normal endometrium. His results suggested that PTEN inactivation is one of the earliest changes in endometrial carcinogenesis and therefore its presence is especially important in detecting precursor lesions at high risk of progressing to cancer. While the prognostic value of PTEN mutation alone has not been evaluated, type I endometrial cancer has a sevenfold higher mutation rate than type II cancers [ 51 ] and therefore it is associated with a favorable histology and better outcome.

P13K/AKT/mTOR pathway

PTEN negatively regulates the downstream pathway of AKT-mediated signals that are important for cellular growth, proliferation and survival [ 49 , 52 ]. The PI3K/AKT/mTOR pathway is the most commonly deregulated signaling pathway and is affected in more than 80% of type I endometrial cancers [ 53 ].

In addition to the previously mentioned loss of PTEN function, activating mutations in PIK3CA (the gene encoding the catalytic subunit of PI3K) causes an upregulation of the PI3K/AKT/mTOR pathway. PIK3CA mutations occur in up to 36% of endometrial carcinomas, more frequently in tumors that also have PTEN mutations. [ 54 ]. The cooperative effect of heterozygous mutations is responsible for promoting neoplastic alterations in the endometrium. In an attempt to evaluate the status of PIK3CA in precursor hyperplastic lesions, Hayes et al. examined 29 cases of complex atypical hyperplasia and 44 cases of endometrial cancer [ 50 ]. Rates of PIK3CA mutations in complex atypical hyperplasia and cancer cases were 7 and 39%, respectively (p = 0.003), and rate of PTEN mutations were similar in both groups at 48 and 57%, respectively. The distribution of PIK3CA mutations was not correlated with grade or stage of disease, however the number of cases was small. Even though PTEN and PIK3CA mutations affect the same pathway, PIK3CA may serve as a marker of invasion given that mutations are significantly more common in invasive disease. Further studies are needed to determine whether this finding has significant clinical use in predicting prognosis.

Detecting mutations in this pathway has clinical significance as new treatment strategies targeting this pathway are being developed. The antitumor drugs have been classified as PI3K inhibitors, mTOR inhibitors, dual PI3K/mTOR inhibitors and AKT inhibitors [ 55 , 56 ]. Different mTOR inhibitors have proven benefit in other malignancies including renal cell carcinoma and sarcomas [ 57 , 58 ]. A Phase II trial conducted by the National Cancer Institute of Canada clinical trials group conveyed favorable results with the use of temsirolimus in chemotherapy naive patients and reported a 14% partial response rate and 69% stable disease rate in this subset of patients [ 59 ]. Phase II trials in recurrent endometrial cancer patients have shown disease stabilization with everolimus and significantly improved progression-free survival with ridaforolimus [ 60 ].

p53

The tumor suppressor gene p53 is activated in response to various stress signals in the cell and it provokes several pathways leading to inhibition of growth, cell cycle arrest and apoptosis [ 61 , 62 ]. In type II endometrial cancers, the most common mutation identified has been in p53 with mutations in up to 54% of nonendometrioid cancers and over 90% of serous carcinomas compared with only 20% of type I cancers [ 60 ]. Some studies suggest that loss-of-function mutations in p53 may be an early event in serous carcinogenesis since it is found in approximately 75% of precursor lesions [ 63 , 64 ].

In addition to the association with type II histology, p53 mutations are also associated with poor clinical outcome. In a retrospective review of 131 surgically staged endometrial cancer patients, p53 mutations were seen in 30% of cases and were associated with type II histology, high-grade tumor, absence of progesterone receptor and lower disease-free and disease-specific survival rates [ 65 ]. In a multivariate analysis adjusting for histology, grade, FIGO stage and lymph nodes metastasis, there was an 11-fold increased risk of death in patients with p53 mutations compared to those without.

Saffari et al. showed similar results of a significantly lower overall survival in women with alterations in the p53 gene compared with women with wild-type p53 [ 66 ]. The study also performed an analysis after stratifying patients based on p53 mutation and adjuvant radiation therapy. As expected, among the patients not receiving adjuvant therapy the presence of p53 alteration was associated with significantly lower survival rates. However, more importantly, within the group of women with p53 alterations the patients that received radiation therapy had an improved overall survival in comparison to the women who did not receive adjuvant therapy (log-rank p = 0.035). There was no survival difference with adjuvant radiation in the subgroup of patients without p53 alteration. Identifying patients with p53 mutations is critical as postsurgical adjuvant therapy can significantly improve the overall survival of these women.

HER2/neu & EGFR

The HER2 protein is a transmembrane glycoprotein from the human EGFR tyrosine kinase family. HER2 amplifications cause an overexpression of HER2 at the mRNA and protein levels and ultimately increase cell proliferation, differentiation, migration and survival [ 67 – 69 ]. HER2 gene amplification and receptor overexpression has been demonstrated in endometrial cancer with highest rates of overexpression occurring in serous histology carcinomas [ 69 ]. The same study showed that HER2 gene amplification is an independent prognostic factor related to poor overall survival.

While HER2 overexpression is associated with poor surgical–pathologic prognostic factors and poor survival, it also serves as an important target for the treatment of uterine serous carcinomas. Trastuzumab and pertuzumab are two US FDA-approved humanized monoclonal antibodies targeting the extracellular domain of the HER2 receptor and are currently being evaluated in clinical trials for the treatment of endometrial cancer [ 70 ]. While single agent trastuzumab did not have a significant response in advanced stage and recurrent disease, combination treatment with standard chemotherapy is still being evaluated in a multi-institutional Phase II trial [ 70 , 71 ].

In addition to verifying that high HER2 expression is an independent prognostic factor influencing progression-free and overall survival in endometrioidtype cancers, results from Mori et al. also suggest that there is a clinical linkage between HER2 expression and the P13K/AKT pathway [ 72 ]. Evidence of this interaction is seen in preclinical trials of the treatment of uterine serous carcinoma cell lines with two novel drugs; AZD8055 (a dual mTORC 1/2 inhibitor) and GDC-0980 (dual class I PI3K and mTOR kinase 1/2 inhibitor). There is significantly higher sensitivity to these drugs in uterine serous tumors with high HER2 expression when compared with tumors with low HER2 expression. Therefore, high HER2 expression and HER2 gene amplification should become an important biomarker in identifying uterine serous carcinoma patients that would benefit from treatment with these targeted therapies [ 73 , 74 ].

EGFR overexpression has also been reported in 40–46% of type I and 34% of type II endometrial carcinomas [ 72 , 75 ]. In a study of uterine serous carcinoma, no EGFR mutations were identified; however, immunohistochemistry analysis showed moderate to strong EGFR membrane staining in 56% of tumors [ 76 ]. Although EGFR overexpression is common in endometrial cancers, EGFR inhibitors have not proven to be clinically significant in treatment of advanced disease. Phase II trials of erlotinib and gefitinib in the treatment of recurrent endometrial cancer showed that treatment regimens were tolerable, however they lacked clinical efficacy in prolonging progression-free or overall survival [ 77 , 78 ]. Treatment with erlotinib had a 12.5% partial response rate, whereas only one of 26 patients treated with gefitinib had an objective tumor response. Both studies did not show any associations between response and tumor biomarkers or gene amplification.

Microsatellite instability

Microsatellite instability (MSI) is the tendency to develop alterations in the number of short segments of repetitive DNA owing to DNA repair errors during cell replication. MSI occurs owing to inactivation of DNA mismatch repair genes (MLH1, MSH2 and MSH6) , which is pathognomonic for Lynch syndrome, a clinical condition associated with an increased propensity of multiple malignancies. MSI can also occur owing to methylation of the MLH1 gene promoter leading to loss-of-function of the mismatch repair protein.

Studies from single institutions present conflicting data on the association of MSI with known prognostic factors, molecular markers and survival. In a prospective study of 229 endometrial cancers, white race was more common in MSI-positive tumors but advanced staged and type II histology was less frequent in MSI-positive tumors compared with microsatellite stable tumors [ 79 ]. Despite the significant association of MSI-positive tumors with favorable race and lower stage disease, there was no significant difference in recurrence or overall survival between the two groups. The ATR gene, which plays an important role in DNA repair and cellular responses to DNA damage, is a mutational target in endometrial cancers with MSI [ 80 ]. The ATR mutation rate in 141 MSI-positive and 107 MSI-negative endometrioid tumors was significantly different at 8.5 and 0% (p = 0.02), respectively [ 81 ]. ATR mutation was also associated with a significantly shorter overall survival (hazard ratio: 3.88, p = 0.002). Conversely, in a study of 131 endometrial cancers, MSI was associated with a lower incidence of p53 mutations, a higher incidence of PTEN mutations and an improved 5-year survival rate of 77% compared with 48% in the cases without MSI [ 82 ].

Microvascular proliferation

The importance of angiogenesis in the growth and metastasis of solid tumors was described over four decades ago [ 83 , 84 ]. Haldorsen et al. aimed to study the angiogenic profile of endometrial carcinomas by calculating microvessel density, microvascular proliferation and vascular proliferation index based on the histomorphological markers of KI67 and factor VIII [ 85 ]. Results from their study verified that high microvascular proliferation was correlated with high tumor volume and a reduced progression-free survival and prognosis.

VEGF ligands and its receptors are the main mediators of angiogenesis, and inhibitors of these targets have shown therapeutic benefit in multiple malignancies [ 86 ]. VEGF is also the main mediator for endothelial cell proliferation in endometrial carcinoma [ 87 ]. A Phase II trial of single-agent bevacizumab, a US FDA-approved recombinant human monoclonal IgG antibody binding to VEGF, showed encouraging results in the treatment of recurrent or persistent endometrial cancer [ 88 ].

While there was a modest response rate of 13.5%, median progression-free survival and overall survival were 4.2 and 10.5 months, respectively, and 40.4% of patients were progression free at 6 months. The combination of bevacizumab and temsirolimus showed a slightly improved response rate of 24.5%, median progression-free survival and overall survival was 5.6 and 16.9 months, respectively, and 46.9% of patients were progression free at 6 months [ 89 ]. However, the combination treatment was associated with significant toxicity. Bevacizumab is now under further investigation in combination with chemotherapy [ 90 ].

Metformin

Metformin is an oral antidiabetic medication recommended by the American Diabetes Association as first-line therapy for Type 2 diabetes [ 91 ]. It may not seem to be a targeted therapy at first, but several studies show that metformin use is associated with a reduced risk and greater overall survival for several malignancies including breast, ovarian and pancreatic cancer [ 92 – 94 ]. Metformin targets cancer stem cells and provides a synergistic effect with chemotherapy in obstructing tumor growth [ 95 ]. A review of laboratory research shows that metformin affects multiple targets and molecular pathways leading to antitumor activity [ 96 ].

In endometrial cancer, metformin use is associated with improved clinical outcomes including recurrence-free and overall survival [ 97 ]. A retrospective cohort study of nonendometrioid endometrial cancer patients showed that overall survival was significantly improved in diabetic patients on metformin when compared with diabetic patients not using metformin and non-diabetic patients [ 96 ]. Research is ongoing to determine whether genetic polymorphisms can predict a response to metformin [ 98 ].

Conclusion

The clinical, surgical and pathologic prognostic factors for endometrial cancer have been well studied over the last three decades. Current efforts are directed towards elucidating mutation profiles and molecular markers that will lead to better histologic classification of endometrial cancer and an improved ability to identify cancers with poor prognostic behaviors. In 2012, McConechy et al. classified a large series of endometrial cancers based on mutation profiles and showed a significant difference in mutation frequency of six genes between low-grade endometrioid, high-grade endometrioid, serous and carcinosarcoma histologic subtypes [ 99 ]. A multivariable logistic regression model differentiated low-grade endometrial cancers from high-grade cancers and serous cancers. The Cancer Genome Atlas (TCGA) research network performed a large-scale genomic and proteomic characterization of 373 endometrial cancers and identified four distinct categories: POLE ultramutated, MSI hypermutated, copy-number low and copy-number high [ 100 ]. The novel POLE ultramutated subtype consisted of 7% of tumors and was characterized by mutations in POLE, a catalytic subunit important in DNA replication and repair, and an improved progression-free survival. The molecular characterization by TCGA also reclassified 25% of high-grade endometroid tumors into uterine serous cancers owing to p53 mutations and extensive somatic copy-number alterations. Accurately identifying tumor histology is important in determining the prognosis and benefit from current adjuvant and targeted therapies.

Future perspective

The discovery of genetic and molecular changes that give rise to the heterogeneity in endometrial cancers has allowed us to reclassify these cancers. Genomic and proteomic characterization of endometrial cancer will become commonplace in the near future and will allow for accurate diagnosis, especially in cases where histologic diagnosis by pathologists is difficult or discordant. In addition to current standard adjuvant chemotherapy and radiotherapy regimens, upcoming endometrial cancer treatment regimens will be focused on novel drug therapies targeting genomic mutations and aberrant molecular pathways identified in individual tumors. The ultimate goal is to offer personalized cancer care in order to achieve improved clinical outcomes.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Executive summary

Background

The incidence of endometrial cancer in the USA and worldwide is increasing.

An understanding of prognostic factors affecting endometrial cancer is essential to determine the risk of recurrence and benefit of adjuvant therapy.

Clinical & pathologic prognostic factors

Clinical prognostic factors include age and race.

Surgical-pathologic factors include histologic subtype, stage, histologic grade and lymphovascular space invasion.

Molecular prognostic markers & targeted therapies

The identification of biologic markers and cellular pathways involved in the pathogenesis and heterogeneity of endometrial cancer is a focus of current laboratory and clinical research.

Biologic markers affecting prognosis of endometrial cancer include hormone receptors, PTEN, p53, P13K/AKT/mTOR pathway, HER2/neu, angiogenesis markers and microsatellite instability.

Novel drug therapies target mutations in molecular markers and aberrations in cellular pathways.

Combination therapy with current treatment strategies and recently discovered targeted therapies should lead us to the ultimate goal of individualized cancer care and improved clinical outcomes.

Conclusion & future perspective

Genomic and proteomic characterization of endometrial tumors have been performed to classify different subtypes.

Genetic profiling will become routine in characterizing endometrial tumors and predicting prognosis and benefit from targeted therapies.

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Update on Prognostic Markers for Endometrial Cancer

Abstract

Keywords

Background

Clinical prognostic factors

Age

Race

Pathologic prognostic factors

Histologic type

Tumor stage

Histologic grade

Lymphovascular space invasion

Molecular markers associated with prognosis & targeted therapies

Hormone receptors

PTEN

P13K/AKT/mTOR pathway

p53

HER2/neu & EGFR

Microsatellite instability

Microvascular proliferation

Metformin

Conclusion

Future perspective

Financial & competing interests disclosure

References