Natalia Teixeira

Proven non-carriers in BRCA families have an earlier age of onset of breast cancer

BACKGROUND Risk estimates for proven non-carriers in BRCA mutation families are inconsistent for breast cancer and lacking for ovarian cancer. We aimed to assess the age-related risks for breast and ovarian cancer for proven non-carriers in these families. METHODS A consecutive cohort study ascertained 464 proven non-carriers who had a first-degree relative with a pathogenic BRCA mutation. Kaplan-Meier analyses were used to estimate the age-related cancer risks, and we calculated standardised incidence ratios. RESULTS In the 464 non-carriers, 17 breast cancers and two ovarian cancers were detected at a mean age of 47 years (95% confidence interval (CI) 32-61) and 49 years (95% CI 32-67), respectively. Overall, by the age of 50, the breast and ovarian cancer risks among non-carriers were 6.4% (95% CI 2.9-9.8%) and 0.4% (95% CI 0-1.3%), of which the breast cancer risk was statistically significantly higher than the risk in the general population. In particular, the number of breast cancers among non-carriers in BRCA1 families was higher than expected for the general population (standardised incidence ratio (SIR) 2.0, 95% CI 1.1-3.3). In the BRCA1 cohort, the mean number of breast cancer cases was higher in families in which non-carriers were diagnosed before the age of 50 (p=0.04). CONCLUSION The age at diagnosis of breast cancer in non-carriers in BRCA mutation families is younger than expected, yielding an increased risk in the fifth decade. This effect is most evident in BRCA1 families. If our results are confirmed by others, this could affect the advice given on breast cancer screening to proven non-carriers between the age of 40 and 50 in such families.

Variation in Mutation Spectrum Partly Explains Regional Differences in the Breast Cancer Risk of Female BRCA Mutation Carriers in the Netherlands

Background: We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) older than 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk. Methods: This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with HRs and ORs. HRs were adjusted for birth year and mutation spectrum. Results: All BRCA1 carriers and BRCA2 carriers younger than 60 had a significantly lower breast cancer risk in the Northern Netherlands; HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands [HR, 3.99; 95% confidence interval (CI), 1.11–14.35]. Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60, and BRCA2 ≥60 years by −3%, +32%, and +11% to 0.75, 0.50, and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR, 1.03; 95% CI, 0.97–1.09). Conclusions: Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers. Impact: The increased risk in BRCA2 carriers older than 60 may warrant extension of intensive breast screening beyond age 60. Cancer Epidemiol Biomarkers Prev; 23(11); 2482–91. ©2014 AACR.

Association of family risk and lifestyle/comorbidities in ovarian cancer patients

OBJECTIVES to analyze factors that might indicate familial predisposition for ovarian cancer in patients diagnosed with this disease. METHODS in a prospective single center cohort study at the Institute of Cancer of the State of São Paulo (ICESP), 51 women diagnosed with ovarian cancer were included. Familial predisposition for ovarian cancer was defined as having a higher than 10% chance of having a BRCA1/2 mutation according to the Manchester scoring system, a validated method to assess the likelihood of mutation detection. Each patient was interviewed with a standardized questionnaire on established risk factors for ovarian cancer and other factors that might influence the risk to develop ovarian cancer. Logistic regression analyses were performed to estimate the impact of the evaluated factors on the likelihood of mutation detection, by calculating odds ratios and 95% confidence intervals. RESULTS seventeen out of 51 patients had a family history of breast and/or ovarian cancer, four patients had a history of breast or endometrial cancer, 11 were diagnosed before the age of 50, and 12 presented a risk of familial predisposition to ovarian cancer higher than 10%. Patients with comorbidities, such as hypertension, diabetes, hormonal disorders, dyslipidemia and psychiatric conditions, presented a lower chance of having a familial predisposition for ovarian cancer (OR: 0.22; 95% CI: 0.06-0.88; p=0.03). CONCLUSION in this study, having comorbidities was associated with a lower risk of having a familial predisposition for ovarian cancer. Other factors associated with the risk of ovarian cancer did not have an impact on this predisposition.

Predictability of BRCA1/2 mutation status in patients with ovarian cancer: How to select women for genetic testing in middle-income countries

OBJECTIVES To evaluate the accuracy of algorithms for predicting BRCA1/2 germ-line mutation carrier probability, and to identify factors that could improve their performance among Brazilian women with ovarian cancer (OC). STUDY DESIGN In this cross-sectional study, we enrolled patients (unselected for family history of cancer) undergoing treatment or follow-up for OC in a single centre in Brazil. Clinical and demographic data, including family history of cancer, were obtained. Blood samples were collected for genetic testing. MAIN OUTCOME MEASURES The entire coding sequence of BRCA1 and BRCA2 was evaluated for mutations. Mutation carrier probability was calculated using BOADICEA, BRCAPRO, Myriad and the Manchester score. Sensitivity, specificity, positive and negative predictive values, and area under the receiver operating characteristic curves (AUC) were calculated for each algorithm. Logistic regression was used to detect additional factors associated with BRCA1/2 status, and these were added to the algorithms before recalculating the AUCs. RESULTS BRCA1/2 mutations were identified in 19 of the 100 included patients. BOADICEA outperformed other algorithms (sensitivity, 73.7%; specificity, 87.7%; AUC, 0.87, with a threshold of a 10% risk of mutation). Later menarche was associated with the presence of a BRCA1/2 mutation. Although adding age at menarche resulted in a larger AUC for all models, this increase was significant only for the Myriad algorithm. CONCLUSION A BOADICEA risk evaluation of 10% or more most accurately predicted BRCA1/2 status, and the inclusion of age at menarche tended to improve the performance of all algorithms. Using these tools could reduce the number of tests, but at the expense of missing a significant proportion of mutation carriers.

Bone mineral density and fractures after surgical menopause: systematic review and meta‐analysis

Oophorectomy is recommended for women at increased risk for ovarian cancer. When performed at premenopausal age oophorectomy induces acute surgical menopause, with unwanted consequences.

Inverse birth cohort effects in ovarian cancer: Increasing risk in BRCA1/2 mutation carriers and decreasing risk in the general population

OBJECTIVE BRCA1/2 carriers are at increased risk of ovarian cancer, and some reports suggest an increasing risk in more recent birth cohorts. In contrast, decreasing incidences have been observed in the general population. The aim was to assess the birth cohort effect on ovarian cancer risk in BRCA1/2 carriers relative to their background general population. METHODS Data on ovarian cancer incidence was collected for a cohort of 1050 BRCA1/2 mutation carriers ascertained by our regional clinic and retrieved from the general Dutch population cancer registry. Birth cohorts were categorized as pre-1935, 1935-1953, post-1953. Birth cohort effects on the ovarian cancer risk were estimated using hazard ratios (HRs) in BRCA1/2 carriers and Poisson rate ratios in the general population. Standardized incidence ratios (SIRs) were calculated to compare populations. HRs were adjusted for mutation position and family history. RESULTS Compared to the pre-1935 cohort, BRCA1 carriers in the 1935-1953 and post-1953 cohorts had an increased ovarian cancer risk of HRadjusted 1.54 (95% CI 1.11-2.14) and 2.40 (95% CI 1.56-3.69), respectively. BRCA2 carriers in the 1935-1953 cohort had an HRadjusted of 3.01 (95% CI 1.47-6.13). The SIRs for the 1935-1953 and post-1953 cohorts were 1.7 and 2.7, respectively, for the BRCA1 carriers and 1.6 times and 2.4 times, respectively, for BRCA2 carriers. CONCLUSIONS Mutation carriers, particularly BRCA1 carriers, born in the most recent cohorts, have the highest additional ovarian cancer risk as compared to the general population.

Ovarian cancer in BRCA1/2 mutation carriers: The impact of mutation position and family history on the cancer risk

OBJECTIVES Assessing the combined impact of mutation position, regarding the ovarian cancer cluster region (OCCR), and type of cancer family history (FH) on age-related penetrance of ovarian cancer (OC) in women from BRCA1/2 families from the northern Netherlands. STUDY DESIGN A consecutive series of 1763 mutation carriers and their first-degree relatives from 355 proven BRCA1/2 families with a history of breast and/or ovarian cancer with in total 248 OC cases was included. Mutations were stratified for gene (BRCA1 or BRCA2) and location (within or outside the OCCR). FH was stratified for type of cancer occurring in first and second-degree relatives (OC only, breast cancer (BC) only or both OC and BC). MAIN OUTCOME MEASURES Cox-proportional hazard models were applied to estimate the OCCR effect, including and excluding a FH of cancer. RESULTS Among BRCA1 families, OC risks were higher in women with OCCR mutations versus those with non-OCCR mutations (HR=1.59, 95%CI=1.19-2.12). This effect remained significant after adjustment for the type of FH (HR=1.50, 95%CI=1.11-2.01). In BRCA2 families, mutation position did not significantly affect the OC risk (HR=1.50, 95%CI=0.74-3.04). However, in the BRCA2 group, a FH including only OC presented by itself a strong impact on OC risk (HR=4.63, 95%CI=2.38-9.02), which remained stable after adjustment for mutation position (HR=4.48, 95%CI=2.28-8.81). CONCLUSION OCCR mutations significantly increased the OC risk in BRCA1 families regardless of the type of FH, but in BRCA2 families, type of FH seems to have a higher impact than mutation position on OC risk.

How Should Genetic Counseling for Ovarian Cancer Be Implemented in a Middle-Income Country? An Insight Based on the Brazilian Scenario

Our aim is to focus attention on epithelial ovarian cancer (EOC), a serious health problem and a burden for women in Brazil. Ovarian cancer is the seventh most common cancer among Brazilian women and one of the deadliest, with 3,320 deaths in 2014 and estimates of 6,150 new cases in 2016.1 Unfortunately, in most parts of the world, 5-year survival for patients with ovarian cancer is dismal, in the range of 30% to 40%,2 mainly because the disease has already reached an advanced stage at first diagnosis.

The association between cancer family history and ovarian cancer risk in BRCA1/2 mutation carriers: can it be explained by the mutation position?

This observational study aimed to investigate whether the reported association between family history (FH) of breast cancer (BC) or ovarian cancer (OC) and OC risks in BRCA1/2 mutation carriers can be explained by mutation position on the gene. In total, 3310 female BRCA1/2 mutation carriers participating in a nationwide prospective cohort (Hereditary Breast and Ovarian Cancer in the Netherlands) were included. FH was classified according to cancer occurrence in first-degree relatives (BC only, OC only, both, neither) and mutations were classified according to their position on the gene (OC cluster region (OCCR), BC cluster region, neither). The main outcome was OC occurrence. Cox proportional-hazard models were applied to investigate the association between FH and OC risks before and after adjusting for mutation position. Of all women included, 202 were diagnosed with OC. A BC-only FH tended to be associated with lower OC risks when compared with a FH without BC/OC (HR: 0.79, 95% CI: 0.52–1.17; HR: 0.59, 95% CI: 0.33–1.07 for BRCA1 and BRCA2, respectively) while an OC-only FH tended to be associated with higher risks (HR: 1.58, 95% CI: 0.90–2.77; HR: 1.75, 95% CI: 0.70–4.37 for BRCA1 and BRCA2, respectively). After adjusting for mutation position, association between FH and OC risks was slightly smaller in magnitude (HR: 0.85, 95% CI: 0.55–1.30; HR: 0.64, 95% CI: 0.34–1.21 for BC-only FH in BRCA1 and BRCA2, respectively; HR: 1.46, 95% CI: 0.80–2.68; HR: 1.49, 95% CI: 0.44–4.02 for OC-only FH in BRCA1 and BRCA2, respectively), indicating that mutation position explains only part of the association. Considering the magnitude of the observed trend, we do not believe FH should be used to change counseling regarding OC prevention.