Do women remain at risk even if they do not inherit a familial BRCA1/2 mutation?

The primary purpose of testing for mutations in BRCA1 and BRCA2 has been to improve the management of patients who carry these mutations. A substantial body of work now supports the use of intensive surveillance or risk-reducing surgery to manage the increased risks of breast and ovarian cancer that are associated with mutations. Evolving research suggests that affected mutation carriers may also benefit from specific treatment approaches, such as treatment with poly(adenosine diphosphate–ribose) polymerase inhibitors. An equally important reason for BRCA mutation testing is to inform management recommendations for family members of the proband. The opportunity to help family members is often the primary motivation for women to consider testing. If a mutation is identified, family members can undergo presymptomatic testing to determine whether they share the predisposition. Individuals who do not carry the mutation have been advised that they are not at a heightened risk for breast and ovarian cancer and therefore do not need to undergo increased screening or consider preventive surgery. In the article that accompanies this editorial, Kurian et al address the appropriateness of this recommendation. Smith et al were the first to propose that breast cancer risk remained elevated among women who tested negative for a previously identified familial BRCA mutation (true negative). In their study of 277 families with mutations, the relative risk of breast cancer in women who tested negative was calculated to be 5.3 (95% CI, 3.5 to 7.7) compared with incidence rates from the regional cancer registry. There were concerns, however, that a cross-sectional analysis of a subset of women in a prevalent, clinic-based ascertainment could be susceptible to an ascertainment bias that would result in a substantial overestimate of risk with respect to women who tested mutation negative. In support of this possibility, Smith et al also described the prospective follow-up of a subset of 153 women in their study (818 person-years), in which the relative risk of women who were mutation negative compared with the general population was less elevated and not statistically significant (relative risk, 2.1; 95% CI, 0.4 to 6.2). Despite the concerns, this report generated considerable interest because the result, if confirmed, would undermine a major rationale for presymptomatic testing. The authors proposed that women who were true negative remained at risk because they had inherited alleles that were both modifiers of the risk associated with BRCA mutations and susceptibility alleles in their own right. The hypothesis is plausible, given that there is considerable evidence for genetic modification of BRCA1/2 penetrance, and genome-wide association studies have uncovered a number of modifying loci, including common variants that are associated with risk in the general population. The breast cancer risks associated with these common variants are insufficient, however, to account for the five-fold residual risk suggested by Smith et al. Before the findings of Smith et al could be used to guide routine clinical practice, it was important to address the concerns about methodology and, of course, to replicate the findings. A small, prospective study by Rowan et al described a nonsignificantly increased risk in women who were mutation negative (standardized incidence ratio [SIR], 2.9; 95% CI, 1.0 to 8.6). But larger prospective cohort studies did not confirm the increased risk. A combined analysis from Memorial Sloan-Kettering Cancer Center and the University of Pennsylvania reported an SIR of 0.52 (95% CI, 0.13 to 2.09) for invasive cancer in 375 women who were observed for 1,962 personyears. Korde et al calculated an SIR of 0.82 (95% CI, 0.59 to 1.51) in 395 women who were observed for 7,008 person-years. Taken together, these prospective studies indicate that a five-fold increase in breast cancer risk is unlikely in women who are true negative, but they do not exclude a more modest risk in the range of two-fold. In the article that accompanies this editorial, Kurian et al provide another analysis of the question of whether patients who are true negative remain at increased risk for breast cancer. A limitation of the prospective cohort studies previously described is that they are relatively small, with short follow-up and with subjects who were members of families referred to risk assessment clinics for genetic testing. Kurian et al take a different approach and use segregation analysis to calculate the relative risk of breast cancer in women without mutations. Apart from the methodology used to calculate risk in noncarriers, their study population differs in two important respects from those of the other studies. First, the mutation-carrying families were identified through population-based rather than clinic-based ascertainment. Second, the breast cancer risk in noncarriers of familial mutations was compared with that of women in BRCA mutation– negative families with multiple cases of breast cancer. Segregation analyses are complex modeling endeavors and require that a number of assumptions be made with respect to input parameters that cannot be measured directly. There are accepted methods of deriving these parameters, but the need to estimate key terms makes well-described sensitivity analysis key to acceptance of the results. It is also important to consider the potential impact of missing data on the robustness of the conclusions. It is likely that a number of first-degree relatives of affected women did not participate in the study that formed the basis for the Kurian analysis, and it is plausible that participation was correlated with cancer occurrence (ie, first-degree relatives may not have been missing at random). This could have impacted the accuracy of the genotype imputation for nonparticipants, and hence the true-negative classification of participants who had not been tested. It would have been helpful to have had a clearer exposition of the extent and distribution of the missing data as well as of certain aspects of the study population, such as the actual number of carriers and noncarriers in the data set and their ages. One element of the segregation analysis that may be particularly confusing to nonspecialists is the description of a so-called latent gene that confers a relative risk of 13.4. It is well known that most familial Editorials