Epidemiology of uterine cancer
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Epidemiology of uterine cancer
- 1. EPIDEMIOLOGY AND MOLECULAR PATHOGENESIS OF ENDOMETRIAL CANCER DR. N. SRAVANTHI
- 2. Incidence Estimated new cases and deaths from endometrial (uterine corpus) cancer in the United States in 2015 New cases: 54,870. Deaths: 10,170. Most common gynecologic malignancy in the United States and accounts for 6% of all cancers in women. Cancer Facts and Figures 2015. Atlanta American Cancer Society, 2015.
- 3. Developed countries Most common malignancy of female genital tract Fourth most common cancer in women (Breast>Lung>Colorectal) Developing countries 4-5 times lower rates India & South-Asia with lowest rates
- 4. GLOBOCAN – 2012 Estimated age standardized incidence and mortality rates: women (WORLD)
- 6. GLOBOCAN – 2012 Estimated age standardized incidence and mortality rates: women (INDIA) Incidence Mortality 5-year prevalence
- 7. GLOBOCAN – 2012 Estimated age standardized incidence and mortality rates: women WORLD INDIA
- 8. SEER Stat Fact Sheets: Endometrial Cancer ● Constitutes 3.2% of all new cancer cases ● 1.5% of all cancer deaths ● 5-years survival rate of 81.5%
- 9. SEER 9 Incidence & U.S. Mortality 1975-2011, All Races, Females. Rates are Age-Adjusted
- 10. Lifetime Risk of Developing Cancer: Approximately 2.7 percent of women will be diagnosed with endometrial cancer at some point during their lifetime, based on 2009-2011 data. Prevalence of this cancer: In 2011, there were an estimated 610,804 women living with endometrial cancer in the United States. Surveillance, Epidemiology, and End Results Program
- 11. AGE Most frequently diagnosed among women aged 55-64. Median age at diagnosis is 62years.
- 13. SURVIVAL For endometrial cancer, 67.9% are diagnosed at the local stage. The 5-year survival for localized endometrial cancer is 95.1%. Overall 5-year survival rate is 81.5%. (Based on data from SEER 18 2004-2010)
- 14. SEER 18 2004-2010, All Races, Females by SEER Summary Stage 2000
- 15. 5-year relative survival rates in the US by FIGO stage Stage 5-year survival rate I-A 88% I-B 75% II 69% III-A 58% III-B 50% III-C 47% IV-A 17% IV-B 15% “Survival by stage of endometrial cancer”. American cancer society. March 2014
- 16. Mortality The percent of endometrial cancer deaths is highest among women aged 65-74. Median age at death is 71 years SEER 18 U.S. 2007-2011, All Races, Females
- 19. Risk factors CHARACTERISTICS RELATIVE RISK Nulliparity 2-3 Late Menopause (>52years) 2.4 Obesity (21-50 lb overweight ) 3 Obesity (>50 lb overweight) 10 Diabetes Mellitus 2.8 Unopposed Estrogen Therapy 4 - 8 Tamoxifene 2 .3 Atypical Endometrial Hyperplasia 8 - 29 Lynch II Syndrome 20
- 20. ROLE OF ESTROGEN Estrogen stimulation – growth & proliferation of endometrium Progesterone (Corpus luteum) – inhibits proliferation of the endometrium & stimulates secretions in the glands & predecidual changes Continuous estrogen stimulation of the endometrium bypasses the normal recycling of the endometrium. Transitions in women’s life – with absence of ovulation predisposes to unopposed estrogen stimulation e.g. menarche, menopause, PCOS & obesity.
- 21. ESTROGENS Mitogenic effect on endometrium Higher rate of proliferation Increased frequency of Spontaneous mutations Presence of estrogens may facilitate “Clonal expansion” of the genetic damage occurred PROGESTINS Down regulate estrogen receptor levels Decrease proliferation Increase Apoptosis
- 22. TAMOXIFENE selective estrogen receptor modulators or SERMs. acts like estrogen on some tissues in the body, such as the uterus, Blocks the effects of estrogen on other tissues, such as the breast. Used to prevent breast cancer in women who are at high risk for the disease. Relative risk of 2-3 for development of endometrial cancer while receiving Tamoxifene
- 23. Obesity Peripheral conversion of androgens secreted in adrenals & ovaries into estrone (by the enzyme aromatase). Amount of body fat – associated with decreased circulating levels of both progesterone & Sex- hormone binding globulin (SHBG). Lower SHBG – Higher endogenous production of non- protein bound estradiol.
- 24. PROTECTIVE FACTORS Combination oral contraceptives (0.5 relative risk when used at least for 12months) Addition of progestin appears to be protective
- 25. PROTECTIVE FACTORS Physical activity Pregnancy and breast-feeding Diet low in saturated fats and high in fruits and vegetables soy - based foods Smoking – Lowers estrogen & protects against endometrial cancer (But cannot be encouraged as a protective measure for obvious reasons)
- 26. Molecular Pathogenesis TYPE I (Endometrioid) TYPE II (Non - Endometrioid) 75% - 85% cases 15% Younger women Older women Perimenopausal Postmenopausal H/o Unopposed Estrogen Therapy Without Estrogenic stimulus Better differentiated Less differentiated More favorable prognosis Poorer prognosis Microsatellite instability & mutation in PTEN, PIK3CA, K - ras & β - catenins P-53 mutations & chromosome instability
- 27. TCGA – The Cancer Genome Atlas Project Four broad categories of endometrial cancers were identified 1. Microsatellite instability cancers : • Predominantly Endometrioid tumors. • Mutation rates 10 fold higher • Frequent K-ras mutation 2. Microsatellite stable cancers – Low CNV: • High frequency mutation in beta-catenins (CTNNB1- involved in cell-cell adhesions & WNT Signaling pathway
- 28. TCGA – The Cancer Genome Atlas Project 3. Microsatellite stable cancers – High CNV: • Frequent TP53 mutations • Serous & Grade 3 Endometrioid tumors • Share molecular features with High grade serous ovarian ca & basal like breast Ca 4. Ultrahigh mutation rate cancers (more than 100 fold) – • Mutation in POLE – a catalytic subunit of DNA polymerase epsilon • Also been associated in colorectal cancers.
- 30. LYNCH SYNDROME In the United States, about 140,000 new cases of colorectal cancer are diagnosed each year. Approximately 3 to 5 percent of these cancers are caused by Lynch syndrome. Characterized by an increased risk for colon cancer and cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and skin.
- 31. LYNCH SYNDROME Hereditary Non - Polyposis Colorectal cancer (HNPCC) Autosomal dominant pattern of inheritance caused by a germline mutation (i.e. pathogenic variant in the germline) in a mismatch repair genes (MSH2,MLH1 MSH6, MSH3, PMS1 & PMS 2) and associated with tumors exhibiting microsatellite instability (MSI). Most cases result from alterations in MSH2 and MLH 1
- 32. Loss of mismatch repair Mutator Phenotype Accumulation of genetic mutations through out the genome (in repetitive DNA sequences - MICROSATELLITES ) Accumulation of Mutations in Tumor- suppressor gene Accelerated malignant transformation
- 33. LYNCH SYNDROME – Genetic screening Analysis of cancers for microsatellite instability MSI (Microsatellite instability) seen in >90% of colonic cancers % in >75% of endometrial cancers Overall only 20%-25% of endometrial cancers exhibit MSI - Majority of cases – Silencing of MLH 1 gene because of a promoter methylation rather than germline mutation.
- 34. LYNCH SYNDROME Following life time risks for cancer are seen: o 52%-82% for colorectal cancer (mean age at diagnosis 44-61 years); o 25%-60% for endometrial cancer in women (mean age at diagnosis 48-62 years); o 6% to 13% for gastric cancer (mean age at diagnosis 56 years); and o 4%-12% for ovarian cancer (mean age at diagnosis 42.5 years; approximately 30% are diagnosed before age 40 years).
- 35. Mean age of onset of endometrial cancer – Before menopause(often before 40years) Clinical features are similar to the sporadic cases. Well differentiated & Endometrioid type & early stages. Survival is approximately 90%
- 36. SURVEILLANCE & PREVENTION IN HIGH RISK POPULATION Annual Pelvic examination Transvaginal Ultrasound Endometrial biopsy – Beginning from 30 -35years of Age. Guidelines for the clinical management of Lynch syndrome (HNPCC) J Med Genet 2007; 44:353 – 362 Role of hysterectomy!!
- 37. THANK YOU
Notes de l'éditeur
- Keeping track of the number of new cases, deaths, and survival over time (trends) can help scientists understand whether progress is being made and where additional research is needed to address challenges, such as improving screening or finding better treatments. Using statistical models for analysis, rates for new endometrial cancer cases have not changed significantly over the last 10 years. Death rates have been rising on average 1.0% each year over 2002-2011. 5-year survival trends are shown below the figure.
- Cancer stage at diagnosis, which refers to extent of a cancer in the body, determines treatment options and has a strong influence on the length of survival. In general, if the cancer is found only in the part of the body where it started it is localized (sometimes referred to as stage 1). If it has spread to a different part of the body, the stage is regional or distant. The earlier endometrial cancer is caught, the better chance a person has of surviving five years after being diagnosed. For endometrial cancer, 67.9% are diagnosed at the local stage. The 5-year survival for localized endometrial cancer is 95.1%.
- White American women are at higher risk for endometrial cancer than black American women, with a 2.88% and 1.69% lifetime risk respectively.[22] Japanese-American women and American Latina women have a lower rates and Native Hawaiian women have higher rates.[24]
- Tamoxifene a weak estrogen, The benefit suggests 121.3 fewer breast related events per 1000 treated with tamoxifene were seen compared with 6.3 endometrial cancers per 100 women. Therefore the benefit is apparent. An increase was not found in poor prognostic histologic findings , tumor differentiation, or stage compared with what would be expected in in a similar group of non- tamoxifene treated patients with uterine cancer.
- The following protective factors may decrease the risk of endometrial cancer
- Copy-number variations (CNVs)—a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal or, for certain genes, a normal variation in the number of copies of one or more sections of the DNA. CNVs correspond to relatively large regions of the genome that have been deleted (fewer than the normal number) or duplicated (more than the normal number) on certain chromosomes. For example, the chromosome that normally has sections in order as A-B-C-D might instead have sections A-B-C-C-D (a duplication of "C") or A-B-D (a deletion of "C").
- The National Institutes of Health has directed the TCGA project to perform an integrated genomic and proteomic analysis of more than 20 types of cancer . Ovarian and endometrial cancers were among the first cancer types evaluated. In the endometrial carcinoma project, tumor samples were collected from 373 patients, consisting primarily of endometrioid histology (82.3%) with fewer serous (14.2%) or mixed histology (3.5%) cases(93) The Wnt signaling pathways are a group of signal transduction pathways made of proteins that pass signals from outside of a cell through cell surface receptors to the inside of the cell.
- DNA polymerase epsilon involved in DNA replication & repair
- Copy-number variations (CNVs)—a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal or, for certain genes, a normal variation in the number of copies of one or more sections of the DNA. CNVs correspond to relatively large regions of the genome that have been deleted (fewer than the normal number) or duplicated (more than the normal number) on certain chromosomes. For example, the chromosome that normally has sections in order as A-B-C-D might instead have sections A-B-C-C-D (a duplication of "C") or A-B-D (a deletion of "C").
- The official name of EPCAM gene is “epithelial cell adhesion molecule.” PMS2 post-meiotic segregation increased 2 MSH 6 = mutS homolog 6 MSH 2 = mutS homolog 2 MLH 1 = mutL homolog 1 About 50 percent of all cases of Lynch syndrome with an identified gene mutation are associated with mutations in the MLH1 gene.
- Most endometrial carcinomas are sporadic but about 10% cases have hereditary basis. Two genetic models are described in development of familial endometrial cancer – 1. LYNCH II syndr.(Majority studies) 2. Predisposition for endometrial cancer. The MSH2 gene provides instructions for making a protein that plays an essential role in DNA repair. This protein helps fix mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH2 protein joins with one of two other proteins, MSH6 or MSH3 (each produced from a different gene), to form a protein complex. This complex identifies locations on the DNA where mistakes have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then repairs the errors. The MSH2 gene is a member of a set of genes known as the mismatch repair (MMR) genes.
- SThe MLH1 gene provides instructions for making a protein that plays an essential role in DNA repair. This protein helps fix mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MLH1 protein joins with another protein called PMS2 (produced from thePMS2 gene), to form a protein complex. This complex coordinates the activities of other proteins that repair mistakes made during DNA replication. The repairs are made by removing a section of DNA that contains mistakes and replacing the section with a corrected DNA sequence. The MLH1 gene is a member of a set of genes known as the mismatch repair (MMR) genes. ome microsatellites will be in the region of non-coding areas of genome, whereas others within genes.
- For unknown reasons, these EPCAM gene mutations cause the MSH2 gene to be turned off (inactivated) by a mechanism known as promoter hypermethylation. The promoter is a region of DNA near the beginning of the gene that controls gene activity (expression). Hypermethylation occurs when too many small molecules called methyl groups are attached to the promoter region. The extra methyl groups attached to the MSH2 promoter reduce the expression of the MSH2 gene, which means that less protein is produced in epithelial cells.The MSH2 protein plays an essential role in repairing mistakes in DNA; loss of this protein prevents proper DNA repair, and mistakes accumulate as the cells continue to divide. These mistakes can lead to uncontrolled cell growth and increase the risk of cancer
- The MSH6 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH6 protein joins with another protein called MSH2 (produced from the MSH2 gene) to form a protein complex. This complex identifies locations on the DNA where mistakes have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then repairs the errors. The MSH6 gene is a member of a set of genes known as the mismatch repair (MMR) genes.
- Screening in general population in asymptomatic women is not justified. TVS or Ebs may be appropriate for perimenopausal or post menopausal women at risk for endo ca, like obese, unopposed estrogen therapy, tamoxifene, or HNPCC families. IN 2006, A European workshop of 21 experts in the treatment of hereditary GI cancer from 9countries recommended the following surveillance strategy for patients with HNPCC or LYNCH II syndrome. BUT cost-effectiveness or impact on mortality from endometrial or ovarian is still not clear.