With more than 180,000 U.S. women diagnosed with breast cancer annually,29
the magnitude of the burden related to the risk of second primary breast cancer is substantial. Increasingly, women with breast cancer, particularly younger cases including those without a positive family history, are likely to be referred for genetic testing and, thus, there is a growing need for information regarding CBC risk in mutation carriers. Here, we present population-based estimates of the risk of CBC in BRCA1
mutation carriers derived from a large study of 2,103 women with UBC or CBC, all of whom were diagnosed with a first invasive breast cancer before age 55 years.
Overall, carrying a mutation in either gene was associated with a four-fold increased relative risk of CBC. A woman with breast cancer before age 55 who carried a BRCA1
mutation was estimated to have a 20% or 15% probability, respectively, of developing CBC within 10 years. Risks were substantially greater for women diagnosed with their first cancer at younger ages and, as in other studies,30–34
mutations were more common in patients with younger age at diagnosis.
A number of past studies,11–22,24
most including small numbers of CBCs and none of which was population-based, have assessed the risk of CBC in mutation carriers. Most of these studies involved retrospective case ascertainment from high-risk cancer genetics clinics,13–15,17,19,21,22,35
the three largest of which we review here. One study included 336 breast cancer cases from families with one or more confirmed mutation carriers, all ascertained through genetics clinics and 97 of whom had CBC.19
The 10-year cumulative CBC rate was 29.5% (BRCA1
, 32%; BRCA2
, 24.5%), 31% in women diagnosed before age 50 versus 23.5% in women diagnosed at age 50 to 64 years. Another study examined CBC risk in 160 mutation-positive breast cancer cases ascertained through high-risk clinics and a comparison group of 445 sporadic cases with minimal or no family history of breast cancer and no family history of ovarian cancer.21
The 12 and 36 CBCs among sporadic and mutation-carrying cases, respectively, translated into a 10-fold increased risk of CBC associated with carrying a mutation in either gene and 10-year CBC rates of 26% and 3% in mutation-carrying and sporadic cases, respectively. A third study22
accrued 326 breast cancer cases through a high-risk genetics clinic from families with a known BRCA1/BRCA2
mutation-carrying member, 311 cases from high-risk type families who tested negative for BRCA1/BRCA2
, and a comparison series with minimal or no family history. Eighty-six CBC cases were observed, yielding 10-year cumulative CBC risk estimates of 25% and 20% in BRCA1
mutation–associated cases, respectively, 6% in cases from BRCA1/BRCA2
-negative families, and 5% in the comparison series. Compared with the comparison series, BRCA1
- and BRCA2
-associated cases had 5.8-fold and 6.1-fold increased risks of CBC, respectively.
Overall, these studies produced risk estimates approximately 10% to 15% higher than those in our study. Although these studies had a powerful design for accruing large proportions of mutation carriers and generating suitable estimates for high-risk families or patients in similar clinic settings, results from these studies may not extrapolate reliably to the broader spectrum of breast cancers in the general population. In addition, as noted by others,19,22,24
there is potential for ascertainment bias within some high-risk clinic studies which could yield inflated CBC rate estimates. In general, high-risk clinic studies have reported the highest estimates of CBC risk in mutation carriers, with 10-year cumulative risks approaching 30% to 40%. To reduce ascertainment bias potential within the high-risk setting, a recent study assessed CBC risk in 1,042 women with breast cancer selected from families with a known mutation-carrying index case and reported some of the lowest CBC risk estimates to date.36
The 10-year cumulative CBC risks for women from families with BRCA1
mutations were 18.5% and 13.2%, respectively. As the authors noted, the absence of genotype information on 83% of the 1,042 women indicates that some noncarriers were included, which would reduce risk estimates since mutation noncarriers have a lower CBC risk than carriers.
Several investigators have sought to minimize selection bias potential through retrospective ascertainment of cases from hospitals, unselected on family history, age, or survival, and enrolled on the basis of Ashkenazi Jewish ethnicity and the availability of pathology tissue for testing the three Jewish founder mutations.10,12,23,24
The largest of these included 496 Ashkenazi cases who received breast-conserving surgery at either of two hospitals,12,37
observed a BRCA1/BRCA2
mutation prevalence of 11.3%, and found mutation carriers were significantly more likely to develop CBC in 10 years (27%) than noncarriers (8%).24
These studies, by not selecting cases on the basis of family history and instead by including all cases in an institution, accrued series with less extreme familial risk profiles than in high-risk clinic populations. It is notable that the mutation prevalence in cases appears somewhat high, reflecting the increased mutation prevalence in Ashkenazi Jewish populations.
Our study differed from previous studies by using a population-based design to investigate the relationship between BRCA1/BRCA2 mutations and CBC risk. This design involves systematic case ascertainment, regardless of family history or treatment facility, in well-defined geographic catchment areas and temporal periods and circumvents the ascertainment complexities of previous studies. Our nested case-control design within a population-based cohort of breast cancer cases allowed the accrual of a well-defined study population, the largest number of CBC cases to date, and substantial numbers of women without a first-degree family history. It is conceivable that differences in design contribute to the lower prevalence of mutations and somewhat lower risks of CBC observed in our study compared with most prior studies. For example, 5.2% of the UBC cases in our study carried a mutation in BRCA1/BRCA2, a much lower prevalence than observed in high-risk clinic and hospital-based studies of Ashkenazi Jews. Similarly, the 15% to 20% 10-year cumulative risks of CBC in mutation carriers in our study of a younger age group, in which genetic factors would be expected to have strong effects, are lower than those in previous studies. Nonetheless, the magnitude of these risks remains quite substantive, four-fold higher for carriers versus noncarriers of mutations, and warrants consideration by women with breast cancer and their clinicians.
Cumulative 5- and 10-year risks of CBC are provided as a general guideline for clinicians and patients regarding subsequent risk. These estimates were anchored on CBC rates in the national SEER cancer registry system, which includes a large number of cases and provides better precision for estimating the population risk of CBC than is possible in any individual study. However, this approach precluded us from examining whether cumulative risk profiles are modulated by other factors besides carrier status, such as treatment. The models underlying these results have not been validated for calibration in an independent data set, a step precluded by the unavailability of other population-based studies with sufficient numbers of CBC cases.
Strengths of our study include the comprehensive, centralized mutation detection approach used. Denaturing high-performance liquid chromatography followed by sequencing has been demonstrated to have high sensitivity and specificity and was the only method to detect all BRCA1
mutations in a validation study.38
Despite stringent quality control, the presence of undetected mutations, including large deletions, cannot be ruled out. Another strength is the population-based design, which offers maximum efficiency for accruing large numbers of CBC patients without regard to family history and facilitates extrapolation to the general population. However, because our study excluded synchronous cancers and women with prophylactic contralateral mastectomy, results may underestimate mutation prevalence. Similarly, because our study was limited to women who survived breast cancer(s), we cannot exclude the possibility that findings might differ if otherwise eligible deceased women were included. Nevertheless, our design allowed us to address the single most relevant clinical question, since the estimation of future risk of CBC is of little relevance to patients with synchronous breast cancer or to those who have had a prophylactic contralateral mastectomy.
In summary, we provide population-based estimates of the risk of CBC following an invasive breast cancer diagnosis before age 55 years in women with mutations in the BRCA1 or BRCA2 genes. These findings have important clinical implications in terms of the potential value of BRCA1/BRCA2 testing in patients with early-onset breast cancer as well as therapeutic, preventive, and surveillance considerations for patients found to carry a mutation.