The penetrance of ductal carcinoma in situ among BRCA1 and BRCA2 mutation carriers

Abstract

Ductal carcinoma in situ (DCIS) is a precancerous lesion of the female breast and is strongly suspected to be a precursor of invasive breast cancer (IBC). Our goal is the estimation of the age-specific and lifetime penetrances of DCIS among carriers of either a BRCA1 or BRCA2 deleterious mutation. We jointly re-analyze the SEER9 database and a previous study by Claus et al. (JAMA 293:964-969, 2005). Estimation is performed via Bayes theorem after the evaluation of the ratio of age-specific DCIS incidences, and extrapolation to the general population of the study-specific penetrance obtained from Claus et al. From the SEER9 database, we estimate the lifetime risk of DCIS to be 0.98 %, in contrast to value of 12.5 % usually reported for IBC. By extending the result in Claus et al. to the general population, we obtain a lifetime risk for carriers of a deleterious mutation of either BRCA1 or BRCA2 of 6.21 % (95 % CI 6.09-6.33 %). The increase in lifetime risk of DCIS for a BRCA mutation carrier compared to a non-carrier is therefore about six-fold. Our quantification is directly relevant to the identification and genetic counseling of BRCA mutation carriers, and emphasizes the potential importance of including information on diagnoses of DCIS in counseling of individuals who are at familial risk for breast cancer. All these factors can contribute to a more specific and targeted prevention, potentially reducing the impact of IBC among BRCA mutation carriers.

Fig. 1

The curves Q_SEER(a) and P_SEER(a) after rescaling to achieve a lifetime probability of invasive breast cancer equal to the well known value of 0.125 [14]. Consistently, by maintaining fixed the empirical ratio between age-specific risks for IBC and DCIS from the original curves, we are able to obtain the lifetime risk of DCIS in the general population

Fig. 2

The curves P_Claus(a|B), r(a) and P_SEER(a|B) and the data used to estimate them. P_Claus(a|B) is the age-specific penetrance of DCIS for mutation carriers estimated from the data in Claus study [8]. The points in the same color are positioned at the ages for the cases, and their height corresponds to the frequencies obtained estimating the parameters of a gamma distribution via maximum-likelihood method; the interpolating curve is the complete estimated density. The curve P_SEER(a|B) is the estimated age-specific penetrance for DCIS in the carrier population. The areas under the solid lines are equal to 0.0079 and 0.0621. They represent, respectively, the estimates of the lifetime risk of being diagnosed with DCIS for a woman participating in study [8] and the lifetime risk for the carrier population overall. The gray-shaded area is the 95 % bootstrap confidence interval for the age-specific penetrance for the carrier population. Also graphed are curve r(a) and the SEER-based empirical ratios used to estimate it

Fig. 3

The curves P_SEER(a), or the age specific risk for DCIS in the general population, and P_SEER(a|B) or the age-specific risk for carriers of a BRCA mutation in the general population. The gray-shaded area is the 95 % bootstrap confidence interval for the age-specific penetrance for the carrier population