The woman at risk for developing ovarian cancer

Defining the woman at risk for developing ovarian cancer can identify factors that cause the disease and lead to earlier diagnosis and improved survival. Our 3-year case-control study of 197 women with histologic proven primary ovarian cancer of the epithelial type reveals the typical patient to have a family history of gynecologic cancer, be exposed to rubella in the peripubertal period, be nulliparous or of low parity, experience difficulty in conceiving, have certain exacerbated premenstrual symptoms, and to rarely undergo surgically induced menopause. In women with carcinomas of low malignant potential a later onset of menarche as well as menstrual disorders occur.     

Worry about ovarian cancer risk and use of ovarian cancer screening by women at risk for ovarian cancer

OBJECTIVE: This study examined reports of perceived risk of ovarian cancer, worry, and screening use in a large sample of women. While screening for asymptomatic women is not generally recommended, in 1994 a consensus conference concluded that women with multiple affected relatives are at high risk for ovarian cancer and should be encouraged to participate in screening. The consensus report also suggested that women with a single affected first-degree relative are at elevated risk and while these women were not encouraged to get screening it was suggested that they may choose to pursue screening outside of a randomized trial [NIH Consensus Conference. JAMA 1995;273(6) 491-7]. METHODS: A total of 3257 women participated in this research by completing a mailed survey on ovarian cancer risk, worry, and use of screening. One hundred forty-two of these women were at high risk for this disease due to a strong family history. An additional 144 women were at elevated risk due to a single first-degree affected relative with ovarian cancer. RESULTS: Family history did predict perceived risk, difficulties due to worry, and use of ovarian cancer screening. However, the group of women most likely to report high levels of perceived risk and to have received screening for ovarian cancer were women with a single affected relative rather than those at high risk, for whom screening is recommended. CONCLUSIONS: These results suggest that many women need additional education about ovarian cancer risk. Most women overestimated their risk for this disease. Some average-risk women get screening although it is not recommended outside of randomized trials, and a significant percentage of women at high risk fail to get recommended screening.     

Should women with familial ovarian cancer undergo prophylactic oophorectomy?

OBJECTIVES: To estimate the lifetime probabilities of ovarian cancer in women from families with hereditary ovarian cancer syndromes and those with a family history of ovarian cancer, and to assess the needs for prevention and surveillance in such women. DATA SOURCES: We searched for studies of familial ovarian cancer published since 1966 and used ovarian cancer incidence data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute. METHODS: Pooled estimates of relative risk of ovarian cancer among women with a family history of ovarian cancer were derived using statistical methods based on fixed effects. Modified life-table methods were used to estimate the lifetime probability of ovarian cancer. DATA SYNTHESIS: The lifetime probability of ovarian cancer increases from about 1.6% in a 35-year-old woman without a family history of ovarian cancer to about 5% if she has one relative and 7% if she has two relatives with ovarian cancer. The lifetime probability may decrease to about 3-4% if she takes oral contraceptives for 5-9 years. Women from families with hereditary ovarian cancer syndromes may have as high as a 50% lifetime risk of ovarian cancer. CONCLUSIONS: The risk of ovarian cancer in women from families with hereditary ovarian cancer syndromes is sufficiently high to warrant prophylactic oophorectomy. Among women with one relative with ovarian cancer, the lifetime probability of ovarian cancer is not high enough to recommend oophorectomy. However, some women may choose oophorectomy depending on their attitudes concerning risk-taking, surgery, and hormone replacement. Oral contraceptives should be considered as preventive therapy to decrease the risk of ovarian cancer in women with a family history of ovarian cancer.     

A systematic review and meta-analysis of family history and risk of ovarian cancer

Objective To estimate the relative risk and lifetime risk of ovarian cancer in women with various categories of family history.
Design A meta-analysis of all published caseecontrol and cohort studies.
Methods Pooled relative risk estimates were calculated for the caseecontrol studies, using the Mantel-Haenzel method. These estimates were combined with the relative risks from the cohort studies. The pooled estimates of relative risk were used to estimate lifetime risks of ovarian cancer from age 15 Up to age 75, for various categories of family history.
Main outcome measures Relative risks and lifetime risks of developing ovarian cancer were calculated for the categories of women with 1. an affected first degree relative; 2. an affected mother; 3. an affected sister; and 4. women with more than one affected relative.
Results The relative risk to first degree relatives is 3.1 (95% CI 2.6–3.7). There is some evidence that this relative risk declines with age. The relative risk to mothers of cases 1.1 (95% CI 0.8–1.6) was lower than the relative risks to sisters: 3.8 (95% CI 2.9–5.1), and daughters: 6.0 (95% CI 3.0–11.9); the explanation of this difference is unclear.
Conclusions Women with a family history of ovarian cancer have a substantially higher risk of developing ovarian cancer compared with women without such a history. However the risk is small for most categories of family history, except for the small number of individuals who have more than one affected relative.     

Ovarian conservation at the time of hysterectomy for benign disease

OBJECTIVE: Prophylactic oophorectomy is often recommended concurrent with hysterectomy for benign disease. The optimal age for this recommendation in women at average risk for ovarian cancer has not been determined. METHODS: Using published age-specific data for absolute and relative risk, both with and without oophorectomy, for ovarian cancer, coronary heart disease, hip fracture, breast cancer, and stroke, a Markov decision analysis model was used to estimate the optimal strategy for maximizing survival for women at average risk of ovarian cancer. For each 5-year age group from 40 to 80 years, 4 strategies were compared: ovarian conservation or oophorectomy, and use of estrogen therapy or nonuse. Outcomes, as proportion of women alive at age 80 years, were measured. Sensitivity analyses were performed, varying both relative and absolute risk estimates across the range of reported values. RESULTS: Ovarian conservation until age 65 benefits long-term survival for women undergoing hysterectomy for benign disease. Women with oophorectomy before age 55 have 8.58% excess mortality by age 80, and those with oophorectomy before age 59 have 3.92% excess mortality. There is sustained, but decreasing, benefit until the age of 75, when excess mortality for oophorectomy is less than 1%. These results were unchanged following multiple sensitivity analyses and were most sensitive to the risk of coronary heart disease. CONCLUSION: Ovarian conservation until at least age 65 benefits long-term survival for women at average risk of ovarian cancer when undergoing hysterectomy for benign disease.     

Advances in the understanding of risk factors for ovarian cancer

The identification of risk factors for ovarian cancer is central to the goal of preventing deaths from this disease. Reproductive and hormonal history clearly modulate the risk of ovarian cancer. Continuous ovulation associated with nulliparity increases the likelihood of ovarian malignancy. Protective factors include conditions that suspend ovulation, such as pregnancy, lactation and oral contraceptive use. Hereditary syndromes account for 10% of ovarian cancer cases. The breast ovarian cancer syndrome is caused by mutations in the BRCA1 and BRCA2 genes and is associated with an 11-40% risk of developing ovarian cancer. The hereditary nonpolyposis colorectal cancer syndrome (HNPCC, or Lynch II) is caused by mutations in DNA mismatch repair genes and carries a 12% risk of ovarian cancer. Due to a lack of adequate screening techniques, women with BRCA1, BRCA2 or HNPCC mutations should consider prophylactic removal of the ovaries and fallopian tubes when childbearing is complete. Genetic polymorphisms are hereditary genetic variations that may act in concert with other genetic, hormonal or environmental factors to potentiate the risk of ovarian cancer. Finally, ovarian cancer risk is altered by environmental and behavioral factors. Further study of the risk factors for ovarian cancer is needed to develop effective preventive strategies.     

Family history of cancer, oral contraceptive use, and ovarian cancer risk.

OBJECTIVE: The purpose of this study was to determine whether women with a family history of ovarian cancer are at reduced risk of ovarian cancer from the use of oral contraceptives and to compare their risk with that of women with no family history of ovarian cancer. STUDY DESIGN: A population-based case-controlled study was conducted from May 1994 through July 1998 in which 767 women aged 20 to 69 years with a diagnosis of epithelial ovarian cancer were ascertained from 39 hospitals in 3 northeastern states. Personal interviews with the women and 1367 control subjects provided data that allowed us to estimate the relative risk of ovarian cancer in relation to a family history of cancer and total duration of oral contraception. RESULTS: Among the 33 case patients and 24 control subjects with a first-degree family history of ovarian cancer, risk of ovarian cancer declined with increasing duration of oral contraception (P =.01). Risk reduction from short-term use of oral contraceptives (< or = 48 months) did not differ significantly by family history (combined estimate of odds ratio, 0.72; 90% CI, 0.59%-0.87%). Risk reduction from long-term use of oral contraceptives (>48 months) was greater in women with a positive family history of ovarian cancer (odds ratio, 0.12) than in women with a negative family history of ovarian cancer (odds ratio, 0.51; test of interaction, P =.04; 692 case patients, 1279 control subjects). CONCLUSION: Four to 8 years of oral contraception may substantially reduce the risk of ovarian cancer by age 70 years in women with a family history of the disease, from approximately 4 women per 100 women who did not use oral contraceptives to only 2 women per 100 women who did use oral contraceptives.     

Advances in the management of epithelial ovarian cancer

More than 23,400 new cases of ovarian cancer and 13,900 deaths are expected in the United States this year. Epithelial ovarian cancer is the most common histologic type of ovarian malignancy. Although there have been advances in the chemotherapeutic treatment of ovarian cancer, the five year survival of women with advanced-stage disease is 25-30%. Because the disease is typically asymptomatic until the disease has metastasized and because effective screening strategies are not unavailable, 70-75% of women present with advanced-stage disease. Of ovarian cancer cases, 90-95% are sporadic and 5-10% associated with germ-line mutations, including BRCA1 and BRCA2. Known risk factors for ovarian cancer include nulliparity and a strong family history of ovarian cancer. The use of oral contraceptives is known to decrease the risk of ovarian cancer: five years of use will decrease the risk by 50%. The staging of ovarian cancer (according to the International Federation of Obstetrics and Gynecology) requires surgical exploration. Determining the extent of disease is essential to appropriate management. Survival in patients with metastatic disease is improved in those who undergo optimal primary cytoreductive surgery. Adjuvant chemotherapy is recommended in patients with high-risk, early-stage disease and all patients with advanced-stage disease. Standard chemotherapy is a combination of paclitaxel and carboplatin. Selected patients with recurrent disease can undergo secondary cytoreductive surgery. Second-line chemotherapy for patients who initially respond to paclitaxel and carboplatin and who have a prolonged disease progression-free intervals (longer than 12 months) can be re-treated with either drug or both. Those whose responses to initial therapy were less successful can be treated with other chemotherapeutic agents--e.g., liposomal doxorubicin, topotecan, etoposide, gemcitabine or taxotere.     

Occult fallopian tube cancer in a patient with BRCA1 breast cancer

Primary fallopian tube cancer is very rare form of ovarian cancer. However, despite the infrequent incidence, emerging evidence suggests that patients who have a deleterious mutation of BRCA1 or -2 mutation may be more vulnerable to developing this disease. A patient with breast carcinoma was initially treated for her disease in 1994. She had a new primary lesion on the contralateral side in 2001 and was eventually identified with a positive BRCA1 germline mutation in 2007. The patient subsequently underwent a laparoscopic-assisted vaginal hysterectomy and bilateral salpingo-oophorectomy surgery performed by her gynecologist. Final pathology revealed occult stage IIC fallopian tube cancer with bilateral ovarian serosal involvement. Consequently, the patient was referred to gynecologic oncology and underwent a pelvic and paraaortic lymphadenectomy and laparoscopic omentectomy, followed by chemotherapy. Although fallopian tube cancer is rare, women who are positive for the BRCA mutation are at greater risk for developing this disease. Therefore, physicians should consider the associated risk factors and perform comprehensive risk-reducing surgery and staging when treating these patients.     

The Role of Prophylactic Oophorectomy in Cancer Prevention

Prophylactic oophorectomy is presently the only effective method of ovarian cancer prevention. This study reviews current data on how prophylactic oophorectomy (PO) should be used in different risk groups. It is estimated that 7% of ovarian cancer patients have positive family history, of which 3-9% may end up having hereditary cancer syndromes. Women in direct genetic lineage of family cancer syndromes may have up to 50% lifetime risk of ovarian cancer. Because of such a high risk, PO is indicated for women with familial cancer syndromes after childbearing or the age of 35-40 at the latest. Most women with positive family history of ovarian cancer do not have one of the recognized hereditary cancer syndromes. However, women with one or two affected relatives do have an increased lifetime risk of ovarian cancer from a baseline of 1.6 to 5-7%. This risk is not high enough to warrant PO recommendation for a large number of women. After being properly informed and the patient still desires surgical prevention (i.e., cancer phobia), PO then becomes an indicated procedure. In women without family history of ovarian cancer, the role of PO remains controversial. The decision of PO as a concurrent procedure to other indicated gynecologic surgeries should depend on the individual patient and her ability to comply with lifelong estrogen replacement therapy.     

Ovarian conservation at the time of hysterectomy for benign disease

Approximately 78% of women between the ages of 45 and 64 years have prophylactic oophorectomy when hysterectomy is performed for benign disease to prevent the development of ovarian cancer. However, after menopause, the ovary continues to produce androstenedione and testosterone in significant amounts and these androgens are converted in fat, muscle, and skin into estrone. Evidence suggests that oophorectomy increases the subsequent risk of coronary heart disease (CHD) and osteoporosis and whereas 14,000 women die of ovarian cancer every year nearly 490,000 women die of heart disease and 48,000 women die within 1 year after hip fracture. PubMed and the Cochrane database were used to identify studies that examined the incidence of disease and mortality from 5 conditions that seem to be related to ovarian hormones: CHD, ovarian cancer, breast cancer, stroke and hip fracture, and also data for death from all other causes. The data were applied to a Markov decision analytic computer model to calculate risk estimates for mortality from these conditions until the age of 80. The model shows for a hypothetical cohort of 10,000 women undergoing hysterectomy and who chose oophorectomy (vs. ovarian conservation) between the ages of 50 and 54 [without estrogen therapy(ET)], that by the time they reach age 80, 47 fewer women will have died from ovarian cancer, but 838 more women will have died from CHD and 158 more will have died from hip fracture. Therefore, the decision to perform prophylactic oophorectomy should be approached with great caution for the majority of women who are at low risk of developing ovarian cancer.     

Pathology of the ovary

Recent medical articles on pathology of the ovary have contributed to a better understanding of ovarian cancer. Postmenopausal women with ovarian neoplasms, especially bilateral ones, are at great risk that they are malignant. Methods for histologic and frozen-section sampling of ovarian neoplasms may vary from one pathology laboratory to another. Primary peritoneal cancer is a distinct clinical entity and all physicians operating on women with pelvic cancers should be alert for its presence. Serum CA 125 analysis may be of value in determining whether to carry out a second-look operation in women with epithelial ovarian cancer. The influence of rupture of the capsule of epithelial ovarian tumors, hydronephrosis, and disease limited to the ovaries and survival are discussed.     

Ovarian cancer associated with testosterone supplementation in a female-to-male transsexual patient

Ovarian cancer is the most fatal gynecologic malignancy. Women often present late and though median survival has improved, a majority of women will succumb to their disease. The incidence of ovarian cancer among female-to-male transsexuals is not known. We report only the second case of ovarian cancer in a female-to-male transsexual while on androgen supplementation therapy. Staining of his tumor for androgen receptors showed abundant expression. Androgen supplementation in this population may be associated with an increased risk of both ovarian cancer and of endometrial cancer. Consideration for bilateral salpingo-oophorectomy as part of gender reassignment surgery should be given, especially in this poorly studied group of patients whose overall risk of ovarian cancer remains unknown.     

Ovarian cancer and genetic susceptibility in relation to the BRCA1 and BRCA2 genes. Occurrence, clinical importance and intervention

The Nordic countries have the highest incidences of ovarian cancer in the world (around 15 cases per 100,000 women). We have conducted a review of the recent literature with focus on the Nordic countries, on genetic susceptibility to ovarian cancer, and the clinical implications in relation to the BRCAI and BRCA2 genes. One of the strongest risk factors for ovarian cancer is a family history of ovarian and/or early-onset breast cancer. It is thought that germline mutations in BRCA1/2 might be responsible for as much as 10% of all ovarian cancer cases and all families containing either multiple case, site-specific ovarian cancer cases or breast and ovarian cancers together. Data from several international studies suggest that the lifetime risk of ovarian cancer in a BRCA 1 mutation carrier can vary from 18 to 56% and from 14 to 27% in a BRCA2 carrier, depending on the presence/absence of a family history of the disease. Genetic evaluation and testing is used in many countries to identify families with BRCA1/2 mutations. Once a mutation has been identified, genetic counseling and testing can be offered to unaffected family members. Prophylactic oophorectomy in unaffected mutation carriers will eliminate the risk of ovarian cancer, although there is a slight residual risk of peritoneal cancer. During oophorectomy, the Fallopian tube should also be removed. If a woman does not want prophylactic oophorectomy, then tubal ligation or oral contraceptive use can be considered as these have been shown to reduce ovarian cancer risk also in mutation carriers.     

Outcomes of women with metachronous breast and ovarian carcinomas

INTRODUCTION: Women with a history of breast cancer have a significantly increased risk of developing a second primary ovarian cancer and vice versa. We proposed to determine the characteristics and outcomes of women diagnosed with metachronous breast and ovarian cancer. METHODS: Patients were identified from the Surveillance, Epidemiology, and End Results program database between 1988 and 2001. Kaplan-Meier and Cox proportional hazards regression tests were used to determine survival outcomes. RESULTS: Of 704 women, 526 developed breast cancer then ovarian cancer (B-O) and 178 developed ovarian cancer then breast cancer (O-B). The mean age at diagnosis of the first cancer in the B-O versus O-B group was 60.3 versus 58.9 years, respectively (P = 0.23). Twenty-five percent of women in the B-O group had stage I-II ovarian cancer versus 63% in the O-B group (P < 0.001). The percentage of those with stage I-II breast cancer was 94% and 91% in the B-O versus O-B group, respectively (P = 0.13). Women in the B-O group had more high grade of ovarian cancer compared to those in the O-B group (P < 0.001). The mean time interval between diagnoses of breast then ovarian versus ovarian then breast cancer was 58 versus 56 months, respectively (P = 0.42). CONCLUSIONS: In the largest series to date, we found that women diagnosed with ovarian cancer first had significantly more early stage and lower grade ovarian cancers with better survival compared to those with breast cancer followed by ovarian cancer. Since half of the women had their second cancer beyond 5 years, continued surveillance of these high risk patients is recommended.     

Intraperitoneal chemotherapy for epithelial ovarian cancer

A large, recent study has shown significantly improved survival in women with epithelial ovarian cancer treated with intraperitoneal chemotherapy. This review is intended for all clinicians caring for women with ovarian cancer, including family physicians, general gynecologists, and oncologists. The subset of patients most likely to derive a survival benefit from intraperitoneal chemotherapy should be distinguished. Because effective surgical debulking is critical to long-term survival for ovarian cancer, it is important that women known or suspected to have ovarian cancer should be referred to centers with the surgical expertise and resources necessary for aggressive tumor debulking and safe delivery of intraperitoneal chemotherapy. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to state that there is a subset of women with widespread intraabdominal ovarian cancer who will have improved survival after a debulking procedure and intraperitoneal (IP) chemotherapy and explain that there needs to be the expertise and resources necessary to follow these patients.     

Long-term follow-up of the Stockholm screening study on ovarian cancer

OBJECTIVES: Seventy percent of ovarian cancer is diagnosed at advanced stages. Having a method for early diagnosis is a very attractive concept. Several attempts have been made, using monoclonal antibody-based immunoassays, ultrasound, or combinations of both, to identify methods that might prove to be sufficiently sensitive and specific as a screening test. Despite promising results, a mortality study of a large population has yet to be completed due in part to the high cost involved. METHODS: One of the first studies aimed at devising a screening strategy for ovarian cancer used the CA 125 immunoassay followed by ultrasound. The study was performed in Stockholm from 1986 through 1988. Ten years now having passed, an analysis has been performed to further evaluate the results of that study. RESULTS: Screening led to the diagnosis of ovarian cancer in six patients, five of whom have since died of the disease. By searching the Cancer Registry, we were able to identify 20 ovarian cancer patients who developed the disease after the screening period. Of these, 12 died of the disease, 2 are alive with disease, and 6 have no evidence of disease following treatment. The median survival for patients diagnosed by screening was 100 months. Median survival for ovarian cancer patients identified subsequent to screening was 20 months. Although there was no difference in survival between these two groups, median survival was better for women diagnosed by screening (borderline significance, P = 0.059). CONCLUSION: These results indicate that a study of a large number of women with a sufficiently long observation time will be required to establish whether or not screening can reduce ovarian cancer mortality. Such a study may also provide insight into the natural history of ovarian cancer.     

FAMILIAL BREAST AND OVARIAN CANCER: THE ROLE OF THE BRCA GENES

Sporadic breast cancer and ovarian cancer constitute two of the top four cancers occurring in women in the 1990s. Familial forms of these diseases also have been recognized; breast cancer is heritable in 5–10% of cases and ovarian cancer in 3–13% of cases. Screening for early disease has been useful for breast cancers but not for ovarian cancers. Genetic testing allows for predicting who will be at risk for developing either disease. The Breast Cancer (BRCA) genes are thought to be involved in 99% of all combined familial breast and ovarian cancers; the best defined gene is BRCA1. The presence of a mutated BRCA1 allele confers a lifetime risk of breast cancer of 70–80% and a risk of ovarian cancer of 40–50%. Individuals with this mutation also have an increased risk of developing colon, prostate, and pancreatic cancer. Genetic analysis for these genes is complex, and management of the information gained from testing needs to be handled with care. Nonetheless, the discovery of the BRCA genes and the determination of their role in familial breast and ovarian cancers represent major steps in cancer prevention.     

Estrogen replacement therapy and ovarian cancer

Estrogen replacement therapy (ERT) has been shown to be of benefit for menopausal women, especially in prevention of coronary heart disease and osteoporotic fractures. Cancer fear is an important obstacle to use of ERT. From our literature review, there is a weak or no association between ERT and ovarian cancer risk. Individual risk of cancer should be considered before ERT use. The second issue in this review is ERT in patients with ovarian cancer. The majority of patients with ovarian cancer are postmenopausal or become menopausal after surgery. ERT is considered by many physicians to be contraindicated in patients with cancer. However, there is evidence that ERT in selected cancer patients may be of benefit for survival and quality of life. After weighing the evidence from studies on ERT in patients with ovarian, breast or endometrial cancer, we propose the use of ERT in selected ovarian cancer patients who are suffering from or are at a high risk of debilitating menopausal symptoms, osteoporosis, and coronary heart disease. The benefit of ERT to selected patient's health and quality of life appears to outweigh the risk of cancer recurrence.