The Overview: Recent Studies on Endometrial Cancer

S. Dhanalakshmi¹*, N. Harikrishnan², N. Janani³, P. Shakthi priya⁴,

M. Srinivasan⁵, A. Karthikeyan⁶, A. Anishkumar⁷, R. Harinathan⁸, N. Srinivasan⁹

¹Department of Pharmacognosy, Faculty of Pharmacy, Dr. M.G.R Educational and Research Institute

(Deemed to be Univ), Velappanchavadi, Chennai – 600077.

²Department of Pharmaceutical Chemistry and Analysis, Faculty of Pharmacy,

Dr. M.G.R Educational and Research Institute (Deemed to be Univ), Velappanchavadi, Chennai – 600077.

^3-8Pharma Buddy, Faculty of Pharmacy, Dr. M.G.R Educational and Research Institute

(Deemed to be Univ), Velappanchavadi, Chennai – 600 077.

⁹Department of Pharmacy, Faculty of Engineering and Technology, Annamalai University,

Annamalai Nagar, Chidambaram.

*Corresponding Author E-mail: dhanadinesh2011@gmail.com

ABSTRACT:

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States. Prognosis depends on patient age, histological grade, depth of myometrial invasion and/or cervical invasion, and the presence of lymph node metastases. Although EC is staged surgically according to the International Federation of Gynecology and Obstetrics (FIGO) system, preoperative imaging can assist in optimal treatment planning. Several imaging techniques such as transvaginal ultrasonography (TVUS), computed tomography (CT), and magnetic resonance imaging (MRI) have been used as diagnostic tools for preoperative staging of EC. Recently, positron emission tomography (PET), PET/CT, and PET/MRI have also been used in staging these patients. In this article, we review stageing, risk factors, value of imaging in diagnosis, recent research on treatment planning, and detection of recurrent disease in patients with EC.

KEYWORDS: Endometrial cancer, prognosis, diagnosis, treatment (chemotherapy).

1. INTRODUCTION:

Endometrial cancer is one of the most common gynecological malignancy worldwide, which is manifestated with severe vaginal bleeding after menopause, between the periods and pelvic pain. It is estimated 63,230 new cases and 11,350 endometrial cancer deaths in 2018 is recorded in worldwide. The average age of female, diagnosed with endometrial cancer is 60-65 years¹.

1.1 TYPES OF ENDOMETRIAL CANCER²

Endometrial cancer is traditionally classified to estrogen-dependent endome-trioid adenocarcinoma (Type I) and non-estrogen-dependent cancer (Type II).

Type I tumors comprise as much as 75% of endometrial cancer and are associated with good prognosis.

Type II tumor are highly aggressive variant of endometrial cancer and account for most recurrences and cancer death from endometrial cancer.

1.2 Prognosis:

Prognosis depends on patient age histological grade, depth of myometrial invasion and/or cervical invasion, and the presence of lymph node metastases been used in staging these patients. Recent studies suggest mutations maybe present in individual genes such as p53, HER2/neu, and phosphates and tensin homolog (PTEN) in patients with high grade endometrial tumors. Mutant tumor suppressor p53 overexpression has been associated with poor histological grade, non endometrioid grade, advanced stage, and poor survival rates. Positive biomarker, p21, and micro satellite instability have a better prognosis [8] and PTEN mutations are typically associated with more favorable prognosis.

1.3 Diagnosis and Treatment:

Although EC is staged surgically according to the International Federation of Gynecology and Obstetrics (FIGO) system, preoperative imaging can assist in optimal treatment planning. Several imaging techniques such as transvaginal ultrasonography (TVUS), computed tomography (CT), and magnetic resonance imaging (MRI) have been used as diagnostic tools for preoperative staging of EC. Recently, positron emission tomography (PET), PET/CT, and PET/MRI have also used. The current treatment recommended by the European guidelines is an pelvic lymph node dissection (PLND) and infrarenal paraaortic lymph node dissection (IRPALND) in high-risk endometrial cancer (HREC). The overall information about endometrial cancer and its recent researches were is discussed as follows.

1.4 Stages of Endometrial Cancer:

Table No. 1: Stages of Endometrial Cancer:³

Stage 1 Tumor confined to the corpus uteri.	Definition The tumor is found in the uterus but has not spread outside the uterus. Stage I is divided into stages IA and IB according to the thickness of the tumor in the uterus.
Stage 1A No or less than half myometrial invasion.	The tumor is either limited to the endometrial or has invaded less than 50% of the thickness of the muscle of the uterus
Stage 1B Invasion equal to or more than half of the myometrial	The tumor has invaded more than 50% of the thickness of the muscle of the uterus
Stage II	The tumor is found in the uterus and has spread to the cervix Since 2009, stage II endometrial cancer is not divided into stage IIA and IIB anymore.
Stage III Stage III is divided into stages IIIA, IIIB, IIIC1 and IIIC2 based on the organs to which the tumor has spread.	The tumor has spread beyond the uterus and cervix to other part(s) of the female genital organ (vagina, ovary, fallopian tube or tissues* around the uterus) or to lymph nodes* in this area.
Stage IIIA	The tumor has invaded the outer membrane of the uterus (called the serosa) or the fallopian tubes or the ovaries
Stage IIIB	The tumor has invaded the vagina or the parametrium, the tissue surrounding the cervix
Stage IIIC1	Tumor cells are found in pelvic, lymph nodes.
Stage IIIC2	Tumor cells are found in para-aortic lymph nodes.
Stage IV	The tumor has spread to the bladder or the bowel or to other organs in the body (metastasis*). Stage IV is divided into stages IVA and IVB.
Stage IVA	The tumor has invaded the bladder or the bowel mucosa.
Stage IVB	Tumor cells are found in lymph nodes* in the groin or in the abdomen or in distant organs such as the liver or the lungs

Figure 1: Staging of uterine cervix carcinoma according to figo⁽³⁾

2. Risk Factors³

The Actual influencing factor of endometrium is exactly unknown exactly but we do know certain risk factors, particularly hormone imbalance. We know that most endometrial cancer cells contain estrogen and/or progesterone receptors on their surfaces. Somehow, interaction of these receptors with their hormones leads to increased growth of the endometrium. This can mark the beginning of cancer. The increased growth can become more and more abnormal until it develops into a cancer.

2.1 Unopposed Estrogen Exposure:

Prolonged unopposed estrogen exposure is associated with most type I endometrial cancers. Estrogen replacement therapy prescribed to control menopausal symptoms increases the risk of developing endometrial cancer by 2- to 20-fold, with an increasing risk correlating with the duration of use. Concomitant administration of progestins continuously or intermittently (10 to 15days/month) significantly reduces this increased risk of cancer.⁴

2.2 Tamoxifen⁵

Tamoxifen, a selective estrogen receptor modulator, acts as an estrogen antagonist in breast tissues and an agonist in bone and endometrial tissues. Tamoxifen use is associated with a 6- to 8-fold increase in the incidence of endometrial cancer.

2.3 Obesity Induced Diabetics:

The obesity epidemic in the Romania may have a profound impact on the incidence of endometrial cancer seen this country. The profound increased incidence of endometrial cancer associated with obesity may be explained by higher endogenous estrogen production via aromatization in adipose tissues.

2.4 Hypertension:

Hypertension has been epidemiologically associated with an increased risk of endometrial cancer, but whether hypertension represents an independent risk factor or the association is confounded by the presence of medical co morbidities, such as diabetes and obesity, is unclear.

2.5 Age Factor⁶:

Age also represents an important risk factor for developing endometrial cancer. Most women are diagnosed after menopause, with only 15% diagnosed before the age of 50 years and only 5% before 40 years of age.

2.6 Use of Combination Oral Contraceptive Pills.

Importantly, the use of combination oral contraceptive pills, depot medroxyprogesterone acetate, and progesterone secreting intra-uterine devices reduces the risk of developing endometrial cancer.

2.7 Lynch Syndrome⁷

Genetic disorders can also cause endometrial cancer. Overall, hereditary causes contribute to 2–10% of endometrial cancer cases. Lynch syndrome, an autosomal dominant genetic disorder that mainly causes colorectal cancer, also causes endometrial cancer, especially before menopause. Women with Lynch syndrome have a 40–60% risk of developing endometrial cancer, higher than their risk of developing colorectal (bowel) or ovarian cancer. With MLH1 mutations, the risk is 54%; with MSH2, 21%; and with MSH6, 16%. BRCA1 and BRCA2, do not cause endometrial cancer (Mutter GL. et al., 2014). There is an apparent link with these genes but it is attributable to the use of tamoxifen, a drug that itself can cause endometrial cancer, in breast and ovarian cancers.

2.8 Cowden Syndrome⁸

The inherited genetic condition Cowden syndrome can also cause endometrial cancer. Women with this disorder have a 5–10% lifetime risk of developing endometrial cancer, compared to the 2–3% risk for unaffected women.

3. CLINICAL FEATURES:

3.1 Diagnosing Techniques⁹

The Pap smear is not a reliable screening procedure for the detection of endometrial cancer, even though a retrospective study found a strong correlation between positive cervical cytology and high-risk endometrial disease (i.e., high-grade tumor and deep myometrial invasion. A prospective study found a statistically significant association between malignant cytology and increased risk of nodal disease. And the following procedure may employed for the detection of cancer cells inside the uterus.

Endometrial biopsy:

The removal of tissue from the endometrium (inner lining of the uterus) by inserting a thin, flexible tube through the cervix and into the uterus. The tube is used to gently scrape a small amount of tissue from the endometrium and then remove the tissue samples and examined.¹⁰

Other tests and procedures used to diagnose endometrial cancer include the following¹¹:

An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken

Transvaginal Ultrasound¹²:

A procedure used to examine the vagina, uterus, fallopian tubes, and bladder. An ultrasound transducer (probe) is inserted into the vagina and used to bounce high-energy sound waves (ultrasound) off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. The doctor can identify tumors by looking at the sonogram.

Recent Researches on the Therapy of Endometrium Cancer¹³

Novel Surgical Treatment:

Surgery includes hysterectomy with possible removal of fallopian tubes and ovaries bilaterally and consideration of lymph node assessment. The requirement for surgical staging reflects the increasing data on the prognostic significance of lymph node status and the implications for treatment in node-positive cancers;.

Molecular targeting¹⁴

Our understanding of endometrial cancer has shifted dramatically. Historically, endometrial cancer has been designated as type 1 and type 2, each type being associated with its own genetic aberrations. Further targets novel therapies, and genome-guided clinical trials may arise as we gain a deeper understanding of the molecular pathways and genetic aberrations in endometrial cancer¹⁵.

Anti-Angiogenic Agent:

Once a tumor reaches a critical point of hypoxemia, malignancies require proliferation of new blood vessels, or angiogenesis, in order to grow, progress, and metastasize¹⁶. Vascular endothelial growth factor (VEGF) induces new blood vessel formation and has been associated with a poor prognosis.¹⁷

Table No.2: Vascular Endothelial Growth Factor Vs Endometrial Cancer Treatment:

Treatment	Molecular target	Mechanism of action	Population	Result
Bevacizumab	VEGF-A	Recombinant humanized monoclonal antibody against VEGF-A	Recurrent and pesistance endometrium cancer	RR: 7/52 (13.5%) CR: 1/52 (2%) PR: 6/52 (11.5%)
Thalidomide	VEGF-A	Anti-angiogenic agent (unknown mechanism)	Phase II stage of advanced endomerium cancer	RR: 3/24 (12.5%) CR: 0/24 (0%) PR: 3/24 (12.5%) SD: 2/24 (8%)
Aflibercept	VEGF-A and VEGF-A isoforms	Immunoglobulin G that acts as a decoy receptor to bind VEGF-A and neutralize VEGF-A isoforms.	Phase II stage of recurrent or persistent endometrium cancer	RR: 3/42 (7%) CR: 0/42 (0%) PR: 3/42 (7%)
Sorafenib	TKI, VEGF receptors	A multiple-targeted kinase inhibitor that also inhibits VEGF receptors	Advance uterine carcinoma or carcinosarcoma	RR: 2/40 (5%) CR: 0/40 (0%) PR: 2/40 (5%)
Dovitinib, nintedanib, brivanib, sunitinib.	TKI, VEGF receptors	Multiple small molecule tyrosine kinase inhibitors (TKIs) that have inhibitory activity at the VEGF receptor involving anti-angiogenic agents in other tumor s	Progressive or advanced endometrial cancer	R: 6/53 (11%) CR: 0/53 (0%) PR: 6/53 (11%) RR: 3/32 (9%) CR: 0/32 (0%) PR: 3/32 (9% RR: 8/43 (19%) CR: 1/43 (2%) PR: 7/43 (17%) RR: 6/33 18%) CR: 0/33 (0%) PR: 6/33 (18%) SD: 10/33 (30%)

Table No.3: EGF Vs Endometrial Cancer Treatment:

Treatment	Molecular target	Mechanism of action	Population	Result
Gefitinib	EGF receptors	Correlated with tumor grade, deep myometrial invasion, and poor prognosis.	Endometrial cancer owing to low response	RR: 1/26 (4%) CR: 1/26 (4%) PR: 0/26 (0%) SD: 7/26 (27%)
Erlotinib	EGF receptors	Correlated with tumor grade, deep myometrial invasion, and poor prognosis	Despite the success of EGFR inhibitors in other malignancies, discouraging results have been observed in endometrial cancer owing to low response	RR: 4/32 (12.5%) CR: 0/32 (0%) PR: 4/32 (12.5%)

Table No.4: HER2 / neu inhibitors Vs Endometrial Cancer Treatment:

Treatment	Molecular Target	Mechanism of Action	Population	Result
Trastuzumab	HER2/neu	A monoclonal antibody that interferes with HER2, showed limited activity in one phase II trial; the trial was ultimately closed because of poor accrual.	Advanced Endometrium Cancer	RR: 0/33 (0%) CR: 0/33 (0%) PR: 0/33 (0%) SD: 12/33 (36%)

Table No.5: PI3K-PTEN-AKT-mTOR pathway inhibitors Vs Endometrial Cancer Treatment:

Treatment	Molecular target	Mechanism of action	Population	Result
Ridaforolimus	mTOR	Aside from pure mTOR inhibition, other drugs attempt to inhibit key components to the PI3K-PTEN-AKT-mTOR pathway.	Advanced Endometrium Cancer	RR: 0/64 (0%) CR: 0/64 (0%) PR: 0/64 (0%)  SD: 22/64 (35%)
Everolimus	mTOR	Aside from pure mTOR inhibition, other drugs attempt to inhibit key components to the PI3K-PTEN-AKT-mTOR pathway.	Phase II Stage of Endometrium Cancer	RR: 0/28 (0%) CR: 0/28 (0%) PR: 0/28 (0%) SD: 12/28 (43%)
Temsirolimus	mTOR	Aside from pure mTOR inhibition, other drugs attempt to inhibit key components to the PI3K-PTEN-AKT-mTOR pathway.	Phase II Stage of Endometrium Cancer	RR: 9/54 (17%) CR: 0/54 (0%) PR: 9/54 (17%) SD: 32/54 (59%)

EGFR inhibitors¹⁸

EGFR overexpression is common in endometrial cancer and has been correlated with tumor grade, deep myometrial invasion, and poor prognosis. The EGFR family consists of four distinct tyrosine kinase cell-surface receptors: ErbB-1 (EGFR), ErbB-2 (HER2/neu), ErbB-3, and ErbB-4.

HER2/neu inhibitors¹⁹

The HER2/neu protein consists of a cysteine-rich extracellular ligand-binding domain, a hydrophobic membrane-spanning domain, and an intracellular tyrosine kinase domain. The overexpression of HER2/neu results in modulation of cell proliferation, differentiation, migration, and survival and upregulation of the PI3K/AKT/mTOR and Ras/Raf/MAPK pathways. Furthermore, HER-2/neu overexpression has been demonstrated in advanced endometrial cancers – specifically, type 2 cancers – and is associated with a poor prognosis.

PI3K-PTEN-AKT-mTOR pathway inhibitors²⁰

Endometrial cancer demonstrates the highest rate of PI3K pathway alterations of all solid tumors, and 40–80% of women with type 1 endometrial cancers harbor PTEN mutations. PTEN acts similarly as a tumor suppressor; it inhibits cell adhesion and migration and antagonizes the PI3K/AKT/mTOR pathway.

Metformin, an oral biguanide known for its role in the management of diabetes, has been investigated for its role in endometrial cancer

4. CONCULSION:

This endometrial cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of endometrial cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions. Several trials suggested that it supports combination chemotherapy for stage III, stage IV, and recurrent carcinosarcoma patients.

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Received on 28.03.2020           Modified on 20.05.2020

Accepted on 15.06.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(7):3998-4002.

DOI: 10.52711/0974-360X.2021.00693