Ovarian cancer screening in women with a family history of breast or ovarian cancer

OBJECTIVE: To evaluate positive predictive values of CA 125 or transvaginal ultrasonography screening for ovarian cancer according to family history of breast or ovarian cancer. METHODS: In the screening arm of a randomized controlled trial of screening compared with usual care, 28,460 women with family history data received baseline and annual CA 125 and transvaginal ultrasonography examinations. We analyzed CA 125 and transvaginal ultrasonography results from the first four rounds of screening. We classified women as average (n=22,687), moderate (n=2,572), or high (n=2,163) risk based on family history, or high risk due to a personal history of breast cancer (n=1,038). Cancers were identified by active follow-up of women with abnormal screening results and annual questionnaires. We calculated positive predictive values for screening combinations. RESULTS: Similar proportions (4.8-5.0%) of women in each group had abnormal screening results. Higher-risk women were more likely than lower-risk women to undergo biopsy after a positive screen. Screening identified 43 invasive ovarian cancers. The positive predictive values for abnormal screening results were 0.7% in average-risk, 1.3% in moderate-risk, and 1.6% in high-risk groups; one ovarian cancer occurred among the breast cancer survivors. The positive predictive values for postbaseline abnormal screening results were also higher in the higher-risk groups. The positive predictive values did not significantly differ across risk groups. CONCLUSION: Probabilities of abnormal annual CA 125 and transvaginal ultrasonography screens were similar across groups based on family history of breast or ovarian cancer. However, ovarian cancer was more likely to be diagnosed after an abnormal screening result among women at higher family history-based risk than among women at lower risk. LEVEL OF EVIDENCE: I.     

The multidisciplinary management of a family with epithelial ovarian cancer.

OBJECTIVE: To describe the management of a family with an inherited predisposition to ovarian and breast cancer. Particular attention is paid to the problems of contraception, screening, prophylactic surgery and hormone replacement therapy. SETTING: The multidisciplinary Grampian Familial Epithelial Ovarian Cancer Study Group. SUBJECTS: 162 members of a family extending over five generations. In the third generation, five of the 10 women died with epithelial ovarian cancer. Three women in generation IV have developed pre-menopausal breast cancer. There are now 78 family members in the fifth generation aged between 2 and 22 years. INTERVENTIONS: Counselling of female family members is started at the age of 18 years. The combined oral contraceptive pill is advocated to suppress ovulation. Gynaecological follow-up after the age of 28 includes yearly pelvic examination, transvaginal ultrasonography and serum CA125 estimation. Laparoscopy with peritoneal cytology is indicated if any part of this yearly assessment is abnormal. Prophylactic oophorectomy is advised between the ages of 35 and 40 years after the family is complete. In generation IV, 20 of the 29 women have undergone prophylactic oophorectomy. Oestrogen hormone replacement therapy with a cyclical progestogen is recommended after prophylactic oophorectomy. Breast cancer screening starts at the age of 25 and involves annual clinical breast examination augmented by mammography and breast ultrasound. CONCLUSIONS: Only by the careful questioning and recording of family history, including at least third degree relatives (cousins), will similar groups with familial ovarian/breast cancer be identified. When predisposing genes are characterized it will be possible to identify carriers within the family and concentrate clinical effort on them while offering appropriate reassurance to those with decreased risk.     

Epidemiologic differences between women with borderline ovarian tumors and women with epithelial ovarian cancer.

OBJECTIVE: The aim of this study was to study the relationship between borderline ovarian tumors (BLOT) and epithelial ovarian cancer (EOC) by comparing the epidemiologic features of women with BLOT with those of women with EOC of similar histology. MATERIAL AND METHODS: The epidemiologic features of 32 women with serous and mucinous BLOT were compared with those of 273 women with primary serous or mucinous EOC. We included all women with the documented respective histologic diagnoses admitted to Roswell Park Cancer Institute between 1982 and 1996 who returned a self-administered epidemiologic questionnaire which contained 44 items pertaining to reproductive, contraceptive, medical, social, dietary, occupational, and family histories of cancer. Individual variables between both groups were compared using the Student t test, chi2 analysis, the Mantel-Haenszel test, and the Wilcoxon nonparametric test. Two-tailed P < 0.05 was considered significant. RESULTS: The response rate to the questionnaire was 63% in the BLOT group and 60% in the EOC group. There was no significant difference between the two groups in geographic location, race, education, income, smoking, marital status, age at first pregnancy, age at first birth, history of hysterectomy, history of infertility, history of tubal surgery, use of hormone replacement therapy, or history of diaphragm or intrauterine contraceptive device use. There were no significant differences in family history of malignancy between women with BLOT and those with EOC. Women with BLOT were significantly younger than those with EOC (mean age 47 +/- 14.0 versus 56 +/- 13.7, P < 0.01). There was an apparent difference in oral contraceptive pill use between both groups. However, when we adjusted for age by stratification this difference was not significant (P = 0.089). CONCLUSIONS: The epidemiologic features of women with BLOT are similar to those of women with EOC with the exception of an earlier age of onset. These findings might be consistent with one etiology for both conditions.     

Fruit and vegetable consumption associated with reduced risk of epithelial ovarian cancer in southern Chinese women

Objective

To investigate the association between fruit and vegetable consumption and the risk of epithelial ovarian cancer in southern Chinese women.

Methods

A case–control study was undertaken in Guangzhou, Guangdong Province, between 2006 and 2008. Participants were 500 incident ovarian cancer patients and 500 hospital-based controls. Information on habitual fruit and vegetable consumption was obtained by face-to-face interview using a validated and reliable food frequency questionnaire. Unconditional logistic regression analyses were performed to assess the association between fruit and vegetable intakes and the ovarian cancer risk.

Results

The mean fruit and vegetable daily intakes of ovarian cancer patients (324.2 g (SD 161.9) and 582.7 g (SD 250.2)) were significantly lower (p < 0.001) than those of controls (477.3 g (SD 362.1) and 983.3 g (SD 739.9)). The adjusted odds ratios were 0.30 (95% confidence interval (CI) 0.21 to 0.44) and 0.07 (95% CI 0.04 to 0.12) for more than 490 g of fruits and 970 g of vegetables per day, relative to at most 320 g and 690 g per day, respectively. With the exception of lycopene, substantial risk reductions were evident for a variety of nutrients derived from fruits and vegetables.

Conclusion

Consumption of fruits and vegetables was inversely associated with the incidence of epithelial ovarian cancer in southern Chinese women.     

p53, c-erbB, and Ki-67 expression in ovaries removed prophylactically from women with a family history of ovarian cancer.

Prophylactically removed ovaries from 64 women were compared with those from 30 women with no known family history of ovarian cancer for expression of the p53 tumor suppressor protein, the c-erbB-2 oncoprotein, and for the proliferation antigen Ki-67. All analyses were performed without knowledge of the family history. Ki-67 was expressed in rare nuclei in both the surface and cyst epithelial cells, whereas p53 was expressed in rare nuclei only in cyst epithelial cells. Neither the proportion of positive cases nor the intensity of staining differed between groups. c-erbB2 was not expressed in surface or cyst epithelium in any case from either group. Nuclei of granulosa and granulosa lutein cells expressed both Ki-67 and p53. In conclusion, increased expression of p53, c-erbB2, and Ki-67 was not found in the epithelium of prophylactically removed ovaries, suggesting that increased expression occurs later in the development of carcinoma or invasive tumor evolves too quickly to identify expression of these proteins in preinvasive epithelium.     

Prevalence of a positive family history of type 2 diabetes in women with polycystic ovarian disease.

The known association between insulin resistance and polycystic ovarian disease (PCOD) has been studied by determination of the prevalence of a positive family history of diabetes in a consecutive series of oligomenorrheic women with polycystic ovaries and eumenorrheic women with normal ovaries who served as controls. A significantly greater proportion of the families of the patients with PCOD had at least one member affected by type 2 diabetes (39.1% of the PCOD group and 7.6% of the controls; p < 0.001). Both obese (54.8%) and non-obese women (24.2%) with PCOD had an increased prevalence of type 2 diabetes within their families. Paternal and maternal family members affected were in similar proportions, there being no evidence of preferential transmission through the female line in this study. The increased prevalence of type 2 diabetes in the families of women with polycystic ovaries is further evidence for the association between PCOD and insulin resistance, and provides a possible explanation for the familial nature of the ovarian disorder.     

Survival among U.S. women with invasive epithelial ovarian cancer

OBJECTIVE: Invasive epithelial ovarian cancer is a highly fatal disease, diagnosed at advanced stages when survival is poor. Relatively little is known about the variation in survival across U.S. women of different race/ethnicities. To investigate this issue, we evaluated pathological characteristics and death rates due to invasive epithelial ovarian cancer in a population-based sample of patients from six racial/ethnic groups. METHODS: The analysis included 38,012 women diagnosed with primary invasive epithelial ovarian cancer between 1973 and 1997 in the Surveillance, Epidemiology and End Results Program of the National Cancer Institute. RESULTS: Filipina patients were younger at diagnosis, more likely to have localized disease, and had more mucinous cancers than whites. African-Americans were more likely than whites to be diagnosed at older ages, with distant disease and with undifferentiated/unclassified cancers. After adjusting for age at diagnosis, stage of disease at diagnosis, and cancer histology, we found that, compared to whites, death rates were significantly elevated among African-Americans and significantly reduced among Hispanics and Filipina. We also found that death rates declined significantly with time since diagnosis among women with advanced disease. CONCLUSION: The declining death rates in women with advanced disease suggest the presence of considerable prognostic heterogeneity among these women, which could reflect differences in quality of care. This issue, as well as the survival disadvantage for African-American women and survival advantages for Hispanic and Filipina women, needs investigation.     

Oral contraceptive use in women with a family history of breast cancer

To evaluate the effect of oral contraceptive use on the risk of breast cancer from 20-54 years of age in women with a family history of the disease, we analyzed data from the Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. For 2 years, beginning December 1980, the study enrolled from eight geographical areas in the United States 4730 women with breast cancer and 4646 controls who were breast cancer-free. For women with a first-degree family history of breast cancer, 554 cases and 280 controls, there was no evidence that use of oral contraceptives, even long-term, contributed to their risk of the disease. Neither total duration of use nor duration of use before first term pregnancy bore any relationship with breast cancer risk. Analyses designed to reveal a potential latent effect also showed no evidence of an adverse effect. For women with a second-degree family history of breast cancer, 777 cases and 595 controls, some isolated elevations in risk were observed for selected subgroups of oral contraceptive users. Detailed analyses of oral contraceptive formulation, the characteristics of the women involved, and the patterns of risk observed by latent period and duration of use suggest that these results, most within the limits of chance variation, are not likely to be a consequence of oral contraception.     

In vitro model of normal, immortalized ovarian surface epithelial and ovarian cancer cells for chemoprevention of ovarian cancer

BACKGROUND: Epithelial ovarian cancer has the highest mortality rate among the gynecologic cancers. The synthetic retinoid, N-(4-hydroxyphenyl) retinamide (4-HPR), has been used in the chemoprevention of ovarian cancer. However, the effectiveness of its application for different populations has been questioned because of the genetic differences among normal, high risk, and women with cancer. OBJECTIVE: To explore the similarities and the differences in 4-HPR effects on different ovarian epithelial cells which mimic different populations of women, normal ovarian surface epithelium to represent the normal population of women, immortalized ovarian surface epithelium to represent premalignant changes, and cells derived from ovarian cancer cells to represent malignant changes were used as in vitro models. METHODS: Normal ovarian surface epithelial cells, immortalized ovarian surface epithelial cells, and ovarian cancer cells were incubated for different intervals with increasing concentrations of 4-HPR. Growth inhibition, the fraction of apoptotic cells, the expression of apoptosis-related genes, including p53, p16, p21, and caspase-3, and mitochondrial permeability transition were measured before and after 4-HPR treatment. RESULTS: Treatment with 4-HPR produced growth inhibition and apoptosis in a dose-dependent manner for all 3 cell types. 4-HPR produced the strongest activation of the p53 pathway in normal ovarian epithelial (NOE) cells, while it caused the largest increase in MPT in the cancer cells, suggesting a different mechanism for growth inhibition and/or apoptosis in these cell lines. 4-HPR, at a concentration of 10 muM, had a maximal effect on caspase-3 activity at 72 h in normal cells and at 48 h in immortalized and cancer cells, although the effects were modest. CONCLUSIONS: Normal ovarian surface epithelial cells, immortalized ovarian surface epithelial cells, and ovarian cancer cells showed a differential response to 4-HPR. Although the same endpoints of growth inhibition and apoptosis induction were present in response to 4-HPR, these endpoints may be regulated through different pathways. IMPLICATIONS: Clinical trials with higher concentrations of 4-HPR should prove beneficial.     

Oral contraceptive use, reproductive history, and risk of epithelial ovarian cancer in women with and without endometriosis

OBJECTIVE: Women with endometriosis may be at an increased risk of ovarian cancer. It is not known whether reproductive factors that reduce the risk of ovarian cancer in general also reduce risk in women with endometriosis. We investigated whether the odds ratios for ovarian cancer that were associated with oral contraceptive use, childbearing, hysterectomy, and tubal ligation differ among women with and without endometriosis. STUDY DESIGN: We pooled information on the self-reported history of endometriosis from 4 population-based case-controlled studies of incident epithelial ovarian cancer, comprising 2098 cases and 2953 control subjects. We obtained data on oral contraceptive use, childbearing, breastfeeding, gynecologic surgical procedures, and other reproductive factors on each woman. Multivariable unconditional logistic regression was used to calculate odds ratios and 95% CI for ovarian cancer among women with endometriosis compared with women without endometriosis. Similar methods were used to assess the frequencies of risk factors among women with and without endometriosis. Adjustments were made for age, parity, oral contraceptive use, tubal ligation, family history of ovarian cancer, and study site. RESULTS: Women with endometriosis were at an increased risk of ovarian cancer (odds ratio, 1.32; 95% CI, 1.06-1.65). Using oral contraceptives, bearing children, and having a tubal ligation or hysterectomy were associated with a similar reduction in the odds ratios for ovarian cancer among women with and without endometriosis. In particular, the use of oral contraceptives for >10 years was associated with a substantial reduction in risk among women with endometriosis (odds ratio, 0.21; 95% CI, 0.08-0.58). CONCLUSION: Women with endometriosis are at an increased risk of epithelial ovarian cancer. Long-term oral contraceptive use may provide substantial protection against the disease in this high-risk population.     

Prevalence of a positive family history of type 2 diabetes in women with polycystic ovarian disease

The known association between insulin resistance and polycystic ovarian disease (PCOD) has been studied by determination of the prevalence of a positive family history of diabetes in a consecutive series of oligomenorrheic women with polycystic ovaries and eumenorrheic women with normal ovaries who served as controls.

A significantly greater proportion of the families of the patients with PCOD had at least one member affected by type 2 diabetes (39.1% of the PCOD group and 7.6% of the controls; p < 0.001). Both obese (54.8%) and non-obese women (24.2%) with PCOD had an increased prevalence of type 2 diabetes within their families. Paternal and maternal family members affected were in similar proportions, there being no evidence of preferential transmission through the female line in this study.

The increased prevalence of type 2 diabetes in the families of women with polycystic ovaries is further evidence for the association between PCOD and insulin resistance, and provides a possible explanation for the familial nature of the ovarian disorder.     

BRCA1 and p53 protein expression in cultured ovarian surface epithelial cells derived from women with and without a BRCA1 germline mutation

Aim Mutations in the BRCA1 and TP53 genes are early genetic events leading to (hereditary) ovarian carcinoma. The human ovarian surface epithelium (OSE) is considered the tissue of origin of at least a subset of these tumours. Therefore, OSE cell cultures derived from women harbouring BRCA1 germline mutations can be a potential model to study hereditary ovarian carcinogenesis. In fact, previous in vitro studies indicate phenotypical differences between OSE from women with and without such germline mutations. Therefore, we have assessed whether differences in the expression of BRCA1 and p53 proteins in cultured OSE cells could contribute to these observations.Study design Thirty-two OSE cultures derived from women harbouring a BRCA1 mutation (Predisposed OSE [POSE]) and ten cultures from women without a cancer predisposition (Non predisposed OSE [NPOSE]) were grown under standard conditions. Immunocytochemistry was performed to assess the expression of the BRCA1- and p53 proteins. Ki67 immunocytochemical expression was assessed to determine possible differences in cell cycle status between the two groups. In addition, to study whether wild type p53 was expressed, induction of p53 by cis-platinum was assessed by Western blot.Results On the basis of Ki67 expression, three different groups were analyzed. In the group with all cultures that expressed Ki67 no significant difference was observed in BRCA1 (P = 0.19) and p53 expression (P = 0.09). In the group with moderate to high Ki67 expression no difference in BRCA1 expression (P = 0.50) was observed. However, p53 expression was significantly lower in the case group (P = 0.01). The same observation for p53 was made in the group with only high Ki67 expression (P = 0.02). Furthermore, the expression of both BRCA1 and p53 positively correlates with Ki67 expression. In POSE and NPOSE, p53 was induced by cis-platinum to a similar extent.Conclusion Our study indicates differences in the expression of p53, but not in the expression of BRCA1 between POSE and NPOSE. In addition, our findings do suggest the absence of losses of the wild type BRCA1 and p53 genes in the studied OSE cultures. This indicates that losses in these genes cannot account for observed differences in phenotypical traits between POSE and NPOSE, but that differences in levels of p53 might contribute.     

Fertility-sparing surgery and outcome in fertile women with ovarian borderline tumors and epithelial invasive ovarian cancer

OBJECTIVE: The aim was to evaluate the outcome of fertility-sparing treatment in ovarian borderline tumors and early invasive ovarian cancer. MATERIALS AND METHODS: All women diagnosed with an ovarian borderline tumor or early invasive ovarian cancer who were treated with fertility-sparing surgery at the University Hospital in Lund between 1988 and 2002 were identified and included in the study (n=23). RESULTS: During the follow-up period of a median 92 months, range 11-185 months, no relapse was found in the patients with Stage 1a tumors, including both borderline tumors (n=12) and invasive well-differentiated (n=9) and moderately differentiated (n=1) ovarian cancers. One patient with poorly differentiated ovarian cancer Stage 1c was 13 weeks' pregnant at the time of the primary operation. Although, unilateral oophorectomy was performed she insisted on continuing the pregnancy. At 37 weeks she had a cesarean section and the ovarian cancer was disseminated. Chemotherapy was given but she died less than a year later. None of the other patients received chemotherapy. In total, 30 children were born to 15 patients. Prophylactic removal of the remaining ovary+/-hysterectomy was accepted in only in six of the women after fulfilling their desire to have more children. CONCLUSIONS: Young women with Stage 1a epithelial ovarian cancer and borderline tumors do not have to give up their fertility in order to receive successful and safe treatment of their disease. However, several of these patients do not accept the recommendation of prophylactic oophorectomy of the contralateral ovary and hysterectomy after completion of childbearing.     

Symptoms and referral of women with epithelial ovarian tumors.

OBJECTIVE: To study referral to hospital units and the clinical characteristics of women with epithelial ovarian tumors in a prospective, population-based study. METHODS: Clinical information on all women diagnosed with epithelial invasive (n=486) and borderline ovarian tumors (n=137) in Norway during 2002 was derived from notifications to the Cancer Registry of Norway and medical, surgical and histopathological records. RESULTS: Sixty-one percent of women with invasive ovarian tumors were initially referred to gynecology units. The 38% of women referred to surgical and medical units were more likely to have symptoms as 'bowel irregularity', 'pain outside the abdominal cavity', 'persisting fatigue' and 'respiratory difficulties'. These women were older, had lower performance status and had a delay in treatment of 20 and 24 days respectively compared to 11 at gynecology units. CONCLUSION: Greater awareness of the symptoms of ovarian cancer might lead to earlier diagnosis and treatment and thus possibly improve survival.