Estimate of the penetrance of BRCA mutation and the COS software for the assessment of BRCA mutation probability.

We have designed the user-friendly COS software with the intent to improve estimation of the probability of a family carrying a deleterious BRCA gene mutation. The COS software is similar to the widely-used Bayesian-based BRCAPRO software, but it incorporates improved assumptions on cancer incidence in women with and without a deleterious mutation, takes into account relatives up to the fourth degree and allows researchers to consider an hypothetical third gene or a polygenic model of inheritance. Since breast cancer incidence and penetrance increase over generations, we estimated birth-cohort-specific incidence and penetrance curves. We estimated breast and ovarian cancer penetrance in 384 BRCA1 and 229 BRCA2 mutated families. We tested the COS performance in 436 Italian breast/ovarian cancer families including 79 with BRCA1 and 27 with BRCA2 mutations. The area under receiver operator curve (AUROC) was 84.4 %. The best probability threshold for offering the test was 22.9 %, with sensitivity 80.2 % and specificity 80.3 %. Notwithstanding very different assumptions, COS results were similar to BRCAPRO v6.0.

Serum levels of IGF-I and BRCA penetrance: a case control study in breast cancer families.

High serum levels of insulin-like growth factor I (IGF-I) are associated with an increased risk of sporadic breast cancer (BC). The aim of the present work is to evaluate the association between IGF-I and hereditary BC risk, using a case-control approach. The work represents an "ad interim" cross-sectional analysis of an ongoing study with a prospective design whose aim is to recruit a cohort of women belonging to high genetic risk families to test potential modulators of penetrance and prognosis. The odd of exposure to high serum IGF-I levels among women with a previous diagnosis of BC ("cases") was compared with the odd among unaffected "controls". The odds ratio (OR) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression, controlling for confounders. We analysed 308 women (209 cases and 99 controls) at high genetic risk of BC. The adjusted OR of BC for the upper tertile of serum IGF-I versus the lowest one was 3.5 (95%CI 1.4-8.8). Excluding from the analysis 64 women under current Tamoxifen or GnRH analogues treatment, the adjusted OR of BC became 3.7 (95%CI 1.4-9.9). The association became stronger restricting the analysis to the 161 women (97 cases and 64 controls) with a proven BRCA mutation. If confirmed by a prospective approach, the association between IGF-I and familial BC will open further options for reducing BC risk in susceptible women.

Oral contraceptive use and BRCA penetrance: a case-only study.

BACKGROUND: Women with deleterious mutations in BRCA genes are at increased risk of breast cancer. However, the penetrance of the genetic trait may be regulated through environmental factors. This multinational case-only study tested the interaction between oral contraceptive use and genetic susceptibility in the occurrence of breast cancer. METHODS: We recruited 3,123 patients diagnosed with breast cancer before the age of 45 years. Participants were classified according to their probability of carrying a BRCA mutation on the basis of their family history of breast and ovarian cancer. According to a case-only approach, the frequency of relevant exposures among breast cancer cases with high probability of BRCA mutation ("genetic cases") was compared with the frequency of the same exposures among breast cancer cases with a low probability of BRCA mutation ("sporadic cases"). The interaction odds ratios (OR) and 95% confidence intervals (CI) for oral contraceptive use were estimated by unconditional logistic regression, after controlling for potentially confounding variables. RESULTS: The analysis was carried out comparing 382 "genetic" and 1,333 "sporadic" cases. We found a borderline significant interaction between genetic breast cancer and oral contraceptive use for ever users compared with never users (OR, 1.3; 95% CI, 1.0-1.7). The greatest interaction OR was found for women who started using pill at 18 to 20 years (OR, 1.6; 95% CI, 1.1-2.3). CONCLUSION: These results suggest that BRCA mutation carriers, as well as women with a significant family history of breast and ovarian cancer are more vulnerable to exogenous hormones in oral contraceptives.