1. Endometriosis and Cancer…Is there a Causal Link? Paula Payton Masters Project 2/22/06 Advisor: Prof Eileen VanDyke

2. Background Endometriosis is a chronic, progressive disease that affects women of child bearing age. Endometriosis is a chronic, progressive disease that affects women of child bearing age. It affects approximately 10% of women and is linked to female infertility. It affects approximately 10% of women and is linked to female infertility. Endometriosis is the third leading cause of gynecological hospitalizations and hysterectomies. Endometriosis is the third leading cause of gynecological hospitalizations and hysterectomies.

3. Background Women with endometriosis begin growing endometrial tissues on the outside of the uterus. Women with endometriosis begin growing endometrial tissues on the outside of the uterus. Instead of leaving the body as it should with the normal menstrual flow, the tissue begins to insert itself in different places within the body. Instead of leaving the body as it should with the normal menstrual flow, the tissue begins to insert itself in different places within the body.

4. Background Most common S/Sx Most common S/Sx –Infertility –Abdominal pain –Pain during intercourse –Pain during menstruation –No S/Sx

5. Risk Factors Risk factors Risk factors –First degree relative w/ endometriosis –Delayed childbirth –Shorter menstrual cycles –Heavier menstrual blood flow

6. The Purpose The purpose of this project was to review and analyze the information available regarding the following questions: The purpose of this project was to review and analyze the information available regarding the following questions: –Does endometriosis put women at an increased risk for cancer? –If these women are at increased risks for cancer, what kind of cancers do they need to be concerned about?

7. The Massachusetts Institute for Technology Center for Cancer Research Study performed on mice Study performed on mice The researchers found that due to a mutation in the Kras oncogene or the Pten tumor suppressor gene in the mouse ovary, the mice developed ovarian endometriosis-like lesions. The researchers found that due to a mutation in the Kras oncogene or the Pten tumor suppressor gene in the mouse ovary, the mice developed ovarian endometriosis-like lesions. MIT CCR was able to link the mutation to ovarian cancer. MIT CCR was able to link the mutation to ovarian cancer.

8. MIT CCR (cont.) Kras oncogene and Pten tumor suppressor genes are often mutated in human ovarian cancer. Kras oncogene and Pten tumor suppressor genes are often mutated in human ovarian cancer. Research conclusion: Research conclusion: –Patients with endometriosis could be at increased risk for ovarian cancer

9. Ness et al. Research Conducted 4 studies in an effort to link endometriosis and ovarian cancer Conducted 4 studies in an effort to link endometriosis and ovarian cancer Studies involved a combined total of 2098 subjects who had ovarian cancer and 2953 subjects who served as a control group Studies involved a combined total of 2098 subjects who had ovarian cancer and 2953 subjects who served as a control group 177 (8.5%) of the ovarian cancer patients and 184 (6.3%) of the control patients reported being diagnosed with endometriosis 177 (8.5%) of the ovarian cancer patients and 184 (6.3%) of the control patients reported being diagnosed with endometriosis Information about sexual history, fertility, breastfeeding, oral contraceptive use, and gynecological procedures were obtained from all of the subjects. Information about sexual history, fertility, breastfeeding, oral contraceptive use, and gynecological procedures were obtained from all of the subjects.

10. Ness et al. Research (cont.) Multivariable unconditional logical regression methods were then used to see if women with endometriosis were at an increased risk for ovarian cancer over those women without endometriosis Multivariable unconditional logical regression methods were then used to see if women with endometriosis were at an increased risk for ovarian cancer over those women without endometriosis Research conclusion : Research conclusion : –Women with endometriosis had a 30% increased chance of developing ovarian cancer

11. Swedish National Board of Health and Welfare Research Researchers obtained 20,686 subjects from the Swedish Inpatient Register from the period of 1969-1983 who had been hospitalized for endometriosis. Researchers obtained 20,686 subjects from the Swedish Inpatient Register from the period of 1969-1983 who had been hospitalized for endometriosis. These records were then linked up to the National Swedish Cancer Registry through 1989. These records were then linked up to the National Swedish Cancer Registry through 1989. Research Conclusion: Research Conclusion: –Patients with endometriosis were more than 20% more likely to develop ovarian cancer over the general population.

12. Endometriosis and its link to other forms of cancers? The Swedish study revealed that patients were at an increased risk for both breast cancer and Non-Hodgkin’s Lymphoma. The Swedish study revealed that patients were at an increased risk for both breast cancer and Non-Hodgkin’s Lymphoma. An increase in breast cancer may be due to the shared hormonal factors between the two disease states- disturbances of ovulation and excessive estradiol levels. An increase in breast cancer may be due to the shared hormonal factors between the two disease states- disturbances of ovulation and excessive estradiol levels. The finding of an increased incidence of Non- Hodgkin’s Lymphoma suggests that there may be a causal link associated with the advancement of treatment in more recent years- high potency progesterons and danazol The finding of an increased incidence of Non- Hodgkin’s Lymphoma suggests that there may be a causal link associated with the advancement of treatment in more recent years- high potency progesterons and danazol

13. Proposed cause and effect relationship One purposed hypothesis for the relationship between endometriosis and cancer looks at survivin, an inhibitor of apoptosis, as the link between the two disease states. One purposed hypothesis for the relationship between endometriosis and cancer looks at survivin, an inhibitor of apoptosis, as the link between the two disease states. Its presence is relatively undetected in normal tissue. Its presence is relatively undetected in normal tissue.

14. Proposed cause and effect relationship (cont.) The study took samples of endometrioic tissue from 35 women w/ endometriosis and 12 women w/o endometriosis. The study took samples of endometrioic tissue from 35 women w/ endometriosis and 12 women w/o endometriosis. Survivin was significantly elevated in those women with endometriosis and undetected in those women without the disease. Survivin was significantly elevated in those women with endometriosis and undetected in those women without the disease.

15. Proposed cause and effect relationship (cont.) Research conclusions Research conclusions –Survivin is found in endometrioic tissue of women with endometriosis. –Survivin inhibits apoptosis and is associated with several metastatic cancers- oral, esophageal, and ovarian cancer. –The presence of survivin could be the link between endometriosis and ovarian cancer.

16. Conclusion There is a limited amount of research available that looks at the link between endometriosis and cancer. There is a limited amount of research available that looks at the link between endometriosis and cancer. However, all of the currently available studies DO link endometriosis and cancer. However, all of the currently available studies DO link endometriosis and cancer. This research provides a framework for which future research can be based. This research provides a framework for which future research can be based.

17. References American Cancer Society. What Are the Key Statistics About Ovarian Cancer? November 9, 2005. Aphrodite Women’s Health. Endometriosis linked to cancer risk.January 1, 2004. Birnbaum, Michael. Endometriosis and Cancer. 2003. Available via World Wide Web: http://www.infertilityphysician.com/endometriosis/cancer.html Brinton, L., et al.. Cancer risk after a hospital discharge diagnosis of endometriosis. American Journal of Obstetrics and Gynecology March 1997; 176(3): 572- 579. Frackiewicz, E.. Endometriosis: An overview of the disease and its treatment. Journal of the American Pharmaceutical Association 2000; 40(5):645-657

18. References (cont.) Gebel, H., et al. Spontaneous apoptosis of endometrial tissue is impaired in women with endometriosis. Fertility and Sterility 1998; 69(6): 1042-1047. Modugno, F., et al.. Oral contraceptive use, reproductive History, and risk of epithelial ovarian cancer in women With and without endometriosis. American Journal of Obstetrics and Gynecology 2004; 191(3): 733-740. Ueda, M., et al. Survivin gene expression in endometriosis. The Journal of Clinical Endocrinology & metabolism 2002; 87(7): 3452-3459. Yoon, C.. Endometriosis and ovarian cancer modeled in mouse. Center for Cancer Research. January 7,2005. www.endofacts.com