Ovarian Cancer
Samantha Massoth

BIO 342—Genetics
April 15, 2013

Abstract
Ovarian cancer is described as a malignant tumor located in the ovaries. Malignant tumors can invade only one or both ovaries. Malignant tumors can also shed cancerous cells from the original tumor and “seed” these shedding on the surface of tissues and organs near the ovaries. The final way for ovarian cancerous cells to move is through “spreading” (metastasis). This is done by the cancerous cells entering the lymphatic system and/or bloodstream to other organs in the body. Ovarian cancer has many risk factors such as non pregnancy, menopause, family history of cancer, personal history of cancer, and others. The studies in this paper were to discuss three major themes of ovarian cancer. The first theme is the screening process of people suspected to have ovarian cancer yet show no signs or symptoms of the disease. The capability of doctors to detect, diagnose, and treat ovarian cancer is researched in these studies. The second major theme is the general prevention of ovarian cancer mainly in women who are at high risk of the disease. The third major theme of ovarian cancer is the general treatment of ovarian cancer and the affects over the counter drugs have as treatment of the disease.

Introduction: Cancer is a disease that affects the basic building block of tissues, the human cell. Cells will grow and divide to provide the body with new cells when needed. However, this process is disrupted as the cells continue to grow when not needed or if the process of necrosis does not occur. As this process continues this excess of cells will create a mass called a tumor. There are two different types of tumors: benign and malignant. Benign tumors are noncancerous tumors that do not spread to other parts of the body and they are hardly life threatening(MedicineNet.com). Malignant tumors are cancerous and divide without control. These tumors can invade nearby tissues and organs such as the fallopian tubes. These cells can also spread to the body by “shedding” from the main ovarian tumor causing new tumors to form on other tissue and organs. Another method for cancer cells to spread throughout the body is through the lymphatic system to lymph nodes and the bloodstream (MedicineNet.com). A malignant tumor that originates in the ovaries is called ovarian cancer (MedicineNet.com). Ovarian cancer can develop based on family history of cancer, non-pregnancy, menopausal hormone therapy, personal history of cancer, and being over 55 years of age. Ovarian cancer is categorized depending on where it occurs in the ovary, also if it is likely to spread to other parts of the body. There are several types of ovarian cancer; the three most common types are ovarian epithelial cancer, ovarian germ cell cancer, and low malignant potential ovarian cancer. The symptoms of ovarian cancer include abdominal, pelvis, back or leg pain or pressure, nausea, indigestion, diarrhea, constipation, and feeling tired all the time. The least common symptoms are frequent urination, unusual vaginal bleeding, and feeling full very quickly. There are a few simple medical tests that can be used to detect and diagnose ovarian cancer. These include a physical examination (including a pelvic exam), ultrasound, X-rays, blood test, and biopsy (laparotomy) of the ovary. Before determining the type and level of treatment for the patient, the grade of the tumor and the extent (stage) of the disease must be determined(MedicineNet.com). “The stage is based on whether the tumor has invaded nearby tissues, whether the cancer has spread, and if so, to what parts of the body. Usually, surgery is needed before staging can be complete. The surgeon takes many samples of tissue from the pelvis and abdomen to look for cancer”(MedicineNet.com). Doctors may also sometimes order a series of tests to determine if the cancer has spread to other parts of the body. These tests may include a CT scan, chest x-ray, barium enema x-ray, or a colonoscopy. Ovarian cancer is commonly separated into four stages. Stage one of ovarian cancer refers to malignant cells that are located within one or both ovaries. Stage two refers to cancer cells that have spread from the ovaries to surrounding pelvic tissue. Stage three is when the cancer cells have spread to tissue outside of the pelvic region or to lymph nodes. Stage four, the most severe of the stages, is when cancer cells have spread to tissues outside the abdomen and pelvis which may include the lungs, liver, or other organs (MedicineNet.com). The common treatment for ovarian cancer is chemotherapy and surgery. Few women have radiation therapy as their initial method of treatment, but may have it done to relieve pain and other problems caused by the disease (MedicineNet.com). Local therapy, surgery and radiation therapy, are used when the cancer cells are localized in one location (the pelvis). If the cells have spread to other tissues in the body, localized therapy can be used in an attempt to maintain the disease in specific areas. Intra-peritoneal chemotherapy is treatment of administering drugs directly into the abdomen or pelvis through a thin tube. Another type of chemotherapy is known as systematic chemotherapy. This type of treatment is taking drugs through the mouth or injected intravenously directly into the bloodstream to kill or destroy cancer cells in the abdomen or pelvis (MedicineNet.com). Some patients who have a higher stage of cancer must resort to surgery as their treatment. A laparotomy is the most common surgical procedure doctors use on ovarian cancer patients. The procedure requires the surgeon to make a long incision in the wall of the abdomen. If the surgeon finds signs of ovarian cancer, there are many outlets the surgeon can take to removing the infected areas or areas. (MedicineNet.com) If the disease has infected both ovaries and fallopian tubes, the surgeon will perform a salpingo-oophorectomy. The surgeon may also remove the uterus through a hysterectomy if needed. Another area of possible for surgical removal is the omentum, nearby lymph nodes, and/or samples of tissue from the pelvis and abdomen. (MedicineNet.com). Regular checkups after treatment help maintain the health of cancer patients and monitors for reoccurring cancer in patients who have been declared cancer free. Cancer can reoccur due to malignant cells that may have been missed through out the body during treatment. Checkups can be composed of blood tests, physical exams, and other imaging exams. There are also some complementary medicines that are prescribed to cancer patients to help them feel better (MedicineNet.com). “An approach is called complementary medicine when it is used along with standard cancer treatment. Acupuncture, massage therapy, herbal products, vitamins or special diets, and meditation are examples of such approaches” (MedicineNet.com).

Review of Literature: Doctors all across the world are spending hours conducting clinical studies to find ways to better detect, diagnose, treat, and prevent ovarian cancer. These studies use volunteers who are willing to participate to find approaches that are safe and effective. One category of studies that is being performed is for patients who have a family history of ovarian cancer. Some researchers feel that removing the ovaries before cancer is detected through a surgery called prophylactic oophorectomy, could decrease the chance of development of the disease. “Women who are at high risk of ovarian cancer are taking part in trials to study the benefits and harms of this surgery” ( MedicineNet.com). Previous authors on this topic have reported primary peritoneal carcinoma, different from primary ovarian adenocarcinoma, developing in five women with a history of familial ovarian cancer who had participated in prophylactic oophorectomy. (Piver et al. 1993). In the study conducted by Piver (1993), the researchers reviewed records of patients from the Gilda Radner Familial Ovarian Cancer Registry for occurrences of primary peritoneal carcinoma after having prophylactic oophorectomy performed. “From 1981 through July 1992, the Gilda Radner Familial Ovarian Cancer Registry accessioned 931 families (a total of 2221 cases of familial ovarian cancer). Currently, 324 women in these families have undergone prophylactic oophorectomy as a preventive measure against the subsequent development of ovarian cancer. Primary peritoneal carcinoma indistinguishable histologically from primary ovarian adenocarcinoma has developed in six of these women 1-27 years after prophylactic oophorectomy” (Piver 1993). When compared with the general population, women who carry BRCA1 or BRCA2 mutations are at a high risk for breast and ovarian cancer. These women generally will undergo a bilateral prophylactic oophorectomy to reduce their risk of these disease (Reddeck 2002). Reddeck (2002) conducted a study to determine if women who carried the mutation of BRCA1 or BRCA2 mutations were at a lower risk for breast and ovarian cancer after having a prophylactic oophorectomy performed. His results matched the results in the study done by Piver (1993) in that both studies reduced the risk of both ovarian and breast cancer in women who had prophylactic oophorectomy conducted. Some doctors are conducting research to determine if over the counter drugs are capable of preventing ovarian cancer in high risk women. Cramer et al. (1998) performed a study to examine the evidence of over the counter drugs affect on ovarian cancer. “The odds ratio for risk of ovarian cancer for aspirin use was 0.75 (95% CI 0.52-1.10), that for ibuprofen was 1.03 (0.64-1.64), and that for paracetamol was 0.52 (0.31-0.86), after adjusting for age, study centre, education, religion, parity, oral contraceptive use, and menstrual, arthritic, or headache pain. Relative to no use, the lower risk of ovarian cancer associated with paracetamol was more apparent for use on a daily basis, 0.39 (0.21-0.74), for more than 10 years of use, 0.40 (0.19-0.88), or for more than 20 tablet years defined as (tablets per day x years of use), 0.45 (0.20-0.99)” (Cramer 1998). When interpreting the data, Cramer and his colleagues (1998) found that paracetamol use increased the risk of ovarian cancer. They also found a moderate yet non significant connection between aspirin use and an increase in the risk of ovarian cancer. There was no signs of ibuprofen use having any significant affect on ovarian cancer risk. Moysich et al. (2001) followed Cramer’s (1998) research to also test certain drugs’ association with ovarian cancer. “Logistic regression was used to compute crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Aspirin users were not at reduced risk of ovarian cancer compared with nonusers (adjusted OR, 1.00; CI, 0.73–1.39). There was also no evidence of a decrease in risk as a function of greater frequency of use or prolonged duration of use. Regular acetaminophen use was associated with a reduced risk (adjusted OR, 0.56; 95% CI, 0.34–0.86), and risk reductions were observed for women with the greatest frequency of use (adjusted OR, 0.32; 95% CI, 0.09–1.08) and longest duration of use (adjusted OR, 0.51; 95% CI, 0.27–0.97)” (Moysich et al. 2001). The data from this study proved that due to a regular use of acetaminophen, there was a lower risk of ovarian cancer. The data also suggested that aspirin had no affect on the risk of ovarian cancer (Moysich et al. 2001). Doctors have compiled studies to improve the ways of screening women for ovarian cancer who are showing no signs or symptoms for the disease. Epithelial ovarian cancer is not a single disease that contains only one tumor. It is a disease containing multiple different tumors that are categorized based on their molecular genetic and morphologic features. (Kurman et al. 2010). “ Recent studies have also provided cogent evidence that what have been traditionally thought to be primary ovarian tumors originate in other pelvic organs and involve the ovary secondarily. Thus, it has been proposed that serous tumors arise from the implantation of epithelium (benign or malignant) from the fallopian tube. Endometrioid and clear cell tumors have been associated with endometriosis, which is regarded as the precursor of these tumors. Since it is generally accepted that endometriosis develops from endometrial tissue by retrograde menstruation it is reasonable to assume that the endometrium is the source of these ovarian neoplasms. Finally, preliminary data suggest that mucinous and transitional (Brenner) tumors arise from transitional-type epithelial nests at the tubal-mesothelial junction by a process of metaplasia. Appreciation of these new concepts will allow for a more rationale approach to screening, treatment and prevention which potentially can have a significant affect reducing the mortality of this devastating disease” (Kurman et al. 2010). Gil Mor et al. (2005) conducted a study using proteins to try to determine the origin and pathogenesis of epithelial ovarian cancer. “These four proteins then were evaluated in a blind cross-validation study by using an additional 106 healthy females and 100 patients with EOC (24 stage I/II and 76 stage III/IV). Upon sample decoding, the results were analyzed by using three different classification algorithms and a binary code methodology. The four analyses test was further validated in a blind binary code study by using 40 additional serum samples from normal and EOC cancer patients. No single protein could completely distinguish the cancer group from the healthy controls. However, the combination of the four analyses exhibited the following: sensitivity 95%, positive predictive value (PPV) 95%, specificity 95%, and negative predictive value (NPV) 94%, a considerable improvement on current methodology” (Mor et al. 2005). Unfortunately, there is still little to know about the molecular development of this aggressive disease. MicroRNAs (miRNA) are a small discovery scientists have made in the molecular level of this disease. MiRNAs are noncoding RNAs triggering translation repression and/or RNA degradation by targeting mRNAs. (Iorio et al. 2007). In a recent report, Marilena V. Iorio et al. (2007) revealed that in human ovarian cancer, miRNAs are expressed as a deviation when compared to a normal human ovary. The researchers discovered the miRNA expression could distinguish and separate normal body tissue from cancerous tissue. “The most significantly over expressed miRNAs were miR-200a, miR-141, miR-200c, and miR-200b, whereas miR-199a, miR-140, miR-145, and miR-125b1 were among the most down-modulated miRNAs. Moreover, the levels of miR-21, miR-203, and miR-205, up-modulated in ovarian carcinomas compared with normal tissues, were significantly increased after 5-aza-2′-deoxycytidine demethylating treatment of OVCAR3 cells, suggesting that the DNA hypomethylation could be the mechanism responsible for their over expression” (Iorio et al. 2007) Iorio and his colleagues discovered that miRNAs could be used in the pathogenesis of epithelial ovarian cancer. (Iorio et al. 2007). There has also been other research on miRNA molecules and their affect on ovarian cancer including the study done by Hau Yang et al. (2008). These researchers showed “several miRNAs are altered in human ovarian cancer, with the most significantly deregulated miRNAs being miR-214, miR-199a*, miR-200a, miR-100, miR-125b, and let-7 cluster. Further, the researchers showed the frequent deregulation of miR-214, miR-199a*, miR-200a, and miR-100 in ovarian cancers. Significantly, miR-214 induces cell survival and cisplatin resistance through targeting the 3′-untranslated region (UTR) of the PTEN, which leads to down-regulation of PTEN protein and activation of Akt pathway. Inhibition of Akt using Akt inhibitor, API-2/triciribine, or introduction of PTEN cDNA lacking 3′-UTR largely abrogates miR-214–induced cell survival.” (Yang et al. 2008). Doctors have tested novel drugs by creating new combinations to determine if they affect ovarian cancer. Many are studying monoclonal antibodies aid in treatment for the disease. Monoclonal antibodies are antibodies that bind to cancer cells to prevent their cell growth and the cancer from spreading (MedicineNet.com). A study conducted by Epenetos et al. (1987) was used to test this theory of monoclonal antibodies in ovarian cancer. “The researchers concluded that the intraperitoneal administration of 140 mCi or more of 131I-labeled tumor-associated monoclonal antibodies represents a new and potentially effective form of therapy for patients with small-volume stage III ovarian cancer” (Epenetos et al. 1987). R.C Bast Jr.’s (1981) study discussed the discovery of a monoclonal antibody that reacts with each of the six epithelial ovarian cancer cell lines and with cryopreserved tumor tissue of ovarian cancer patients. He also discovered the antibody was not capable of binding to a variety of nonmalignant tissues. (Bast et al. 1981).

Discussion: Results in the Bast et al. (1981) and Epenetos’ et al. (1987) studies suggest the use of monoclonal antibodies as a treatment source for epithelial ovarian cancer. The findings in the study conducted by Yang et al. (2008) indicated miR-214 targets the PTEN/Akt pathway to influence cell survival and cisplatin resistance. In Iorio’s et al. (2007) study, the results indicated miRNAs capability to be used in the pathogenesis of epithelial ovarian cancer. The results of Mor’s et al. (2005) study indicated sensitivity 95%, positive predictive value (PPV) 95%, specificity 95%, and negative predictive value (NPV) 94%. The data from the Moysich et al. (2001) study proved that due to a regular use of acetaminophen, there was a lower risk of ovarian cancer. The data also suggested that aspirin had no affect on the risk of ovarian cancer. Cramer et al. (1998) found that paracetamol use increased the risk of ovarian cancer. They also found a moderate yet non significant connection between aspirin use and an increase in the risk of ovarian cancer. There was no signs of ibuprofen use having any significant affect on ovarian cancer risk. In both Piver et al. (1993) and Reddeck et al. (2002) studies, they discovered a reduction in the risk of both ovarian and breast cancer in women who had prophylactic oophorectomy conducted.

Conclusion: One of the major themes in ovarian cancer research is screening process of people suspected to have ovarian cancer. The capability of doctors to detect, diagnose, and treat ovarian cancer would be increased through further studies in the hidden signs and symptoms of ovarian cancer. Another theme was the general treatment of ovarian cancer and the affects over the counter drugs have on the treatment of ovarian cancer. There has been many clinical studies done to determine which drugs do and do not have an affect on ovarian cancer risk. To aid this theme, researchers need to continually conduct studies of newly developed drugs for possible beneficial affect. A final theme of ovarian cancer is research of the general prevention of ovarian cancer mainly in high risk women. Further research for this theme may included studies of pre-diagnoses drugs, tests to determine a patients possible symptoms, and more successful treatment methods.

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