Anne Dørum

Oral Contraceptives and the Risk of Hereditary Ovarian Cancer

Background Women with mutations in either the BRCA1 or the BRCA2 gene have a high lifetime risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they also protect against hereditary forms of ovarian cancer. Methods We enrolled 207 women with hereditary ovarian cancer and 161 of their sisters as controls in a case–control study. All the patients carried a pathogenic mutation in either BRCA1 (179 women) or BRCA2 (28 women). The control women were enrolled regardless of whether or not they had either mutation. Lifetime histories of oral-contraceptive use were obtained by interview or by written questionnaire and were compared between patients and control women, after adjustment for year of birth and parity. Results The adjusted odds ratio for ovarian cancer associated with any past use of oral contraceptives was 0.5 (95 percent confidence interval, 0.3 to 0.8). The risk decreased with increasing duration of use (P for trend, <0.001); use for six or...

Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers

Aim: To assess the effectiveness of annual ovarian cancer screening (transvaginal ultrasound and serum CA125 estimation) in reducing mortality from ovarian cancer in women at increased genetic risk. Patients and methods: A cohort of 3532 women at increased risk of ovarian cancer was screened at five European centres between January 1991 and March 2007. Survival from diagnosis of ovarian cancer was calculated using Kaplan–Meier analysis and compared for proven BRCA1/2 carriers with non-carriers and whether the cancer was detected at prevalence or post-prevalent scan. Screening was performed by annual transvaginal ultrasound and serum CA125 measurement. Results: 64 epithelial ovarian malignancies (59 invasive and 5 borderline), developed in the cohort. 26 tumours were detected at prevalent round; there were 27 incident detected cancers and 11 interval. 65% of cancers were stage 3 or 4, however, stage and survival were little different for prevalent versus post-prevalent cancers. Five year and 10 year survival in 49 BRCA1/2 mutation carriers was 58.6% (95% CI 50.9% to 66.3%) and 36% (95% CI 27% to 45%), which was significantly worse than for 15 non-BRCA carriers (91.8%, 95% CI 84% to 99.6%, both 5 and 10 year survival p = 0.015). However, when borderline tumours were excluded, the difference in survival between carriers and non-carriers was no longer significant. Conclusion: Annual surveillance, by transvaginal ultrasound scanning and serum CA125 measurement, in women at increased familial risk of ovarian cancer is ineffective in detecting tumours at a sufficiently early stage to influence substantially survival in BRCA1/2 carriers.

Evaluation of endometrial thickness measured by endovaginal ultrasound in women with postmenopausal bleeding

Endovaginal ultrasound scanning was used preoperatively in 100 women with postmenopausal vaginal bleeding referred for dilatation and curettage. The ultrasonographic appearance of the endometrium was related to the histologic diagnosis. Endometrial malignancy was found in 15 patients, in 2/45 (4.4%) of women aged less than 60 years and in 13/55 (23.6%) of women aged 60 years or more. Out of 54 patients with an endometrial thickness of less than 5 mm as measured by ultrasound, 3 had an endometrial malignancy, and 12 of 45 with an endometrial thickness of 5 mm or more, had an endometrial malignancy. The sensitivity of ultrasound to detect malignancy was 80%, the specificity was 60%, the positive and negative predictive values were 26% and 94.4%. The sensitivity and the negative predictive value was not high enough to replace histologic examination of the endometrium.

Bilateral oophorectomy before 50 years of age is significantly associated with the metabolic syndrome and Framingham risk score: A controlled, population-based study (HUNT-2)

OBJECTIVE Bilateral oophorectomy (BOE) is often recommended in order to prevent cancer at hysterectomy for non-malignant diseases and when familial risk of ovarian and breast cancer has been identified. Surgical menopause increases the risk of cardiovascular mortality, however, the intervening mechanisms are not clear. We compared the prevalence of the metabolic syndrome (MetS) and Framingham cardiovascular risk scores in women with BOE before 50 years of age to age-matched controls in a population-based study. METHODS 20,765 women aged 40-69 years were invited to a health study (HUNT-2 Norway 1995-97) and 17,650 (85%) attended. We compared 263 women with BOE before 50 years of age [63 with intact uterus (BO1 group), and 200 with hysterectomy also (BO2 group)] with 3 age-matched controls per case (n=789). Data on demographic, somatic, mental, and lifestyle variables, physical measurements and blood tests were obtained. RESULTS The BO1 and BO2 groups did not differ significantly regarding risk variables, and 4% had natural menopause. The combined BOE group had increased prevalence of MetS compared to controls according to the International Diabetes Federations definition (47% versus 36%; p=.001) and the revised NCEP ATP III definition (35% versus 25%; p=.002), which remained after adjustments (for reproductive, global health, and lifestyle variables). The prevalence of Framingham risk score > or =10% was higher in cases (22%) versus controls (15%) p=.005. CONCLUSION The higher prevalence of MetS and increased Framingham risk scores in women with bilateral oophorectomy before 50 years of age suggests that these women may be at higher risk of type 2 diabetes and cardiovascular disease compared to their counterparts in the general population.

Therapy effect of either paclitaxel or cyclophosphamide combination treatment in patients with epithelial ovarian cancer and relation to TP53 gene status

Cell death after treatment with chemotherapy is exerted by activation of apoptosis, and the p53 protein has been shown to actively participate in this process. This recent focus on TP53 status as a possible determinant of cancer therapy response has raised the question of whether or not mutations in the TP53 gene have an influence on paclitaxel therapy. The TP53 status has been analysed at the DNA level in tumours from 45 ovarian cancer patients randomized to treatment with paclitaxel and cisplatin or cyclophosphamide and cisplatin. Therapy response was obtained for 38 patients with clinically evaluable disease after initial surgery. The positive response rate to the paclitaxel/cisplatin therapy was 85% vs 61% for the patients who received the cyclophosphamide/cisplatin regimen. A significant difference in relapse-free survival in favour of paclitaxel/cisplatin chemotherapy was found (P = 0.001). A total of 33 tumour samples (73%) had detectable sequence alterations in the TP53 gene. When relapse-free survival was estimated for all patients with TP53 alterations in their tumours, a significant better outcome for the paclitaxel/cisplatin group was found compared with the patient group receiving cyclophosphamide and cisplatin therapy (P = 0.002). We did not observe an association between TP53 tumour status and prognosis for patients who received paclitaxel/cisplatin combination treatment, indicating that the effect of this therapy is not influenced by this parameter.

Early detection of familial ovarian cancer

When ovarian cancer is detected at an early stage, prognosis is good, which has led to discussion of a screening programme. The aim of this study was to identify and examine women at high risk of familial ovarian cancer, and to evaluate the inclusion criteria and the diagnostic methods for early detection of ovarian cancer. We report the first round screening findings in a prospective study of 180 women (mean age 43.4 years) considered to be at high risk of ovarian cancer based on family history. They were subjected to gynaecological examination with transvaginal ultrasound (TVU), CA125 and breast examination. Of these, 13 women with oestrogen receptor positive breast cancer had therapeutic oophorectomy and the ovaries were histologically examined. Among 180 women examined, nine ovarian cancers (among them two found at oophorectomy because of breast cancer) (mean age 49.0 years), seven benign tumours of the ovary (mean age 48.1 years), one cancer of the cervix, and four breast cancers were diagnosed. The prevalence of ovarian cancers (5%) was significantly more than in any previous series. TVU as a diagnostic method proved useful and detected 7/9 cancers, whereas CA125 was elevated in 4/9 cancers. To our knowledge, this is the first programme which has successfully delineated a high risk group and prospectively demonstrated their high prevalence of ovarian cancer. Possible biases are discussed.

Controlled Study of Fatigue, Quality of Life, and Somatic and Mental Morbidity in Epithelial Ovarian Cancer Survivors: How Lucky Are the Lucky Ones?

PURPOSE There are few studies of somatic and mental morbidity in epithelial ovarian cancer survivors (EOCSs). The aim of this controlled, cross-sectional study was to explore fatigue, quality of life (QOL), and somatic and mental morbidity in EOCSs. PATIENTS AND METHODS Among 287 EOCSs treated according to protocols at The Norwegian Radium Hospital between 1977 and 2003, 189 patients (66%) participated. Information was collected by a questionnaire containing demographic and morbidity items and self-rating scales. Internal comparisons of various subgroups of EOCSs were performed, and EOCSs were compared with age-adjusted controls from the general population. RESULTS Minimal differences were observed relating to somatic and mental morbidity, fatigue, and QOL between EOCSs with and without relapse, long or short follow-up time, and prognostic index status. Chronic fatigue was found in 22% (95% CI, 16% to 28%), and only body image was significantly associated with chronic fatigue in multivariable analyses. EOCSs showed significantly more somatic and mental morbidity, somatic complaints, use of medications, and use of health care services than controls. The levels of anxiety and fatigue were also significantly higher in EOCSs than in controls, whereas the levels of depression and of several QOL dimensions were lower. The prevalence of chronic fatigue was 12% among controls. CONCLUSION EOCSs had more somatic and mental morbidity, more fatigue, poorer QOL, and used more medication and health services than controls. Minimal differences were observed between various EOCS subgroups. Health care professionals should try to improve and be attentive to the health of EOCSs.

Prospectively detected cancer in familial breast/ovarian cancer screening

BACKGROUND Early diagnosis and treatment are shown to improve survival of breast and ovarian cancer. Identification and medical follow-up of high-risk groups may be important for early diagnosis. METHODS A prospective study of 845 women from breast/ovarian- and ovarian cancer kindreds who were classified according to pre-set inclusion criteria (Table I), were offered genetic counseling and annual medical examinations of breasts and ovaries. The material consisted of three series: 1) 754 unaffected women, 2) 49 women with breast cancer, and 3) 42 women with ovarian cancer. RESULTS In series 1) nine ovarian cancers and 20 breast cancers, in series 2) seven ovarian cancers, and in series 3) three breast cancers were found. All but one of the ovarian cancers were 40 years or older, and 4/16 (25%) were Borderline cancer. All breast cancers were 30 years or older, and 89% were detected before spread. CONCLUSIONS This is to our knowledge the first prospective report of the combined breast/ovarian cancer findings in breast/ovarian cancer kindreds. A woman with both breast and ovarian cancer is the hallmark of inherited breast/ovarian cancer, and 50% of the ovarian cancers were detected in these families. Borderline ovarian cancer may represent a manifestation of this syndrome. If prophylactic oophorectomy prevents ovarian cancer, oophorectomy at age 45 would have prevented 75% of such cancers. Based on these results we revised our protocol for annual follow-up in these kindreds: 1) clinical breast examination and mammography (ultrasound/cytology if indicated) from 30 years of age, 2) gynecologic examination (including vaginal ultrasound, serum-CA125) from 35 years of age, and 3) discuss oophorectomy at 45 years of age.

BRCA1 mutations in ovarian cancer and borderline tumours in Norway: a nested case–control study

The aims of the present study were to find the frequency of the most common BRCA1 mutations in women with ovarian tumours identified from a population-based cancer registry and in the general population, to estimate the relative risk of ovarian tumours among the mutation carriers, and to explore the value of using CA125 as a prediagnostic test. The study was designed as a nested case–control study within a cohort mainly consisting of participants in population-based health examinations. The data files of The Cancer Registry of Norway and the Janus serum bank were linked to identify cases with ovarian cancer and borderline tumours. Hereditary BRCA1 mutations were determined using archived serum samples and capillary electrophoresis. Altogether 478 ovarian cancer patients and 190 patients with borderline tumours were identified, and 1421 and 568 matching controls were selected. Odds ratios (OR) of developing ovarian cancer and borderline tumours in the presence of BRCA1 mutations and CA125 level were derived from conditional logistic regression models. Among the 478 ovarian cancer patients, 19 BRCA1 mutations were identified (1675delA, 1135insA, 816delGT and 3347delAG), none among the patients with borderline tumours. Only two of the 1989 controls were BRCA1 mutation carriers (0.10%). The risk of ovarian cancer among the mutation carriers was strongly elevated (OR=29, 95% CI=6.6–120). CA125 was a marker for ovarian cancer, but the sensitivity was low. This study showed that BRCA1 mutation carriers have a very high risk of ovarian cancer. However, since the prevalence of BRCA1 mutations in the Norwegian population was low, the proportion of ovarian cancers due to BRCA1 mutations seemed to be low, about 4%. The sensitivity of using CA125 only as a screening test for ovarian cancer was low.

Metabolic syndrome after risk-reducing salpingo-oophorectomy in women at high risk for hereditary breast ovarian cancer: A controlled observational study

Surgical menopause may increase the risk of cardiovascular diseases (CVDs). The aim of this study was to determine the risk of metabolic syndrome in women who had undergone risk-reducing salpingo-oophorectomy (RRSO) because of increased risk of hereditary breast ovarian cancer (HBOC). A sample of 326 (65% of invited) women at risk of HBOC who had undergone RRSO was compared to 679 women from the general population. Mean follow-up after surgery was 6.5 years (standard deviations [SD] 4.4). RRSO was significantly associated with metabolic syndrome according to the 2005 National Cholesterol Education Program Adult Treatment Panel III criteria (odds ratio [OR] 2.46 [95% confidence interval (CI) 1.63, 3.73]) and according to the International Diabetes Federation criteria (OR 2.49 [CI 1.60, 3.88]), as were increasing age and body mass index (BMI). RRSO in women at risk of HBOC is significantly associated with the metabolic syndrome, and the follow-up after RRSO should take these findings into consideration.