Prevalence of BRCA1 and BRCA2 mutations in non-familial breast cancer patients with high risks in Korea: The Korean Hereditary Breast Cancer (KOHBRA) Study

Overall mutation of BRCA1 and BRCA2 genes in high-risk breast cancer patients without family history of breast or ovarian cancer in this study was 8.6% (BRCA1: 3.3%, BRCA2: 5.3%). The prevalence of genetic BRCA1/2 mutation among non-familial patients with high-risk factors in this study was more than three times higher than the 2.6% prevalence observed for BRCA1/2 mutations in sporadic breast cancer patients in Korea [25, 27, 28]. Genetic counseling and testing for BRCA1 and BRCA2 gene mutation has become an integral part of high-risk patient evaluation and management for hereditary breast ovarian cancer [11, 33]. Guideline organizations, including NCCN and ASCO, have advised targeting BRCA1 and BRCA2 testing to probands whose probability of mutation carriage is approximately 10% or greater. However, there might be variation in BRCA1/2 mutation prevalence across race and ethnicity for breast cancer patients with high-risk factors, although the prevalence of BRCA1/2 mutations is comparable among sporadic breast cancer patients of African, Asian, White, and Hispanic descent: approximately 1–4% per gene, with the exception of Ashkenazi Jewish and Icelandic patients [33, 34]. There is a question of whether ethnic differences in genetic, reproductive, or environmental exposures might alter mutation penetrance, which could have significant implications for clinical practice. Therefore, large data collection of BRCA1/2 mutation prevalence and penetrance in individual ethnic groups is necessary for applying individualized guideline for genetic counseling and testing, and management in clinical practice.

This KOHBRA study showed the prevalence of BRCA1/2 mutations in high-risk breast cancer patients without family history of breast or ovarian cancer via a large multicenter nationwide cohort study. Previous reports of BRCA1/2 mutations in Korean breast cancer patients were limited by small sample sizes, and the studies were performed individually at various sites with different screening methods. Overall mutation of BRCA1/2 genes in high-risk breast cancer patients without family history of breast or ovarian cancer in this study was 8.6%. On the other hand, the prevalence of BRCA1/2 mutations among breast cancer patients with family history of breast or ovarian cancers was 24.8% in the KOHBRA study interim report [32]. Notably, BRCA2 mutation was more common than BRCA1 mutation in our study, compared with previous small clinic-based studies [25‐27]. This finding is consistent with other studies showing BRCA2 mutations appear as or more commonly than BRCA1 mutations in clinic-based Asians, a difference from other ethnic groups [34].

According to high-risk groups in this study, mutation of BRCA1/2 genes were identified in 8.5% among early onset patients, in 17.7% among bilateral breast cancer, in 50.0% among patients with both breast and ovarian cancer, in 5.9% among male breast cancer patients, in 7.6% among patients with cancer of multiple organs, and in 27.1% among patients having two or more of these high-risk factors. There are few previous smaller studies of Korean patients which report BRCA mutations by individual risk category and several of these include patients with family history [24, 27]. BRCA1/2 mutations in Korean patients with early onset regardless of family history were detected in 10.4–18.3% in the previous studies (Table 7) [23, 26, 32]. The wide variation in reported prevalence of BRCA1/2 mutation in patients with early onset could be related to variation in number with family history of breast cancer in these studies. When the group of early onset patients under 35 years was considered, we found prevalence of 10% for BRCA1/2 mutations with no other risk factor. The mutation rate increased up to 25.9% for the early onset patients with other risk factor. Therefore, additional risk factors increase the likelihood of BRCA1/2 mutation among young patients.

Two studies reviewed the prevalence of BRCA1/2 mutations in breast cancer patients in terms of ethnic difference, finding that those diagnosed at a younger age (mostly under 35 to 45-year old) had prevalence of 5–10% among various races [24, 34]. On the other hand, the prevalence of BRCA1 mutation was particularly high in African-American patients diagnosed before age 35 years (16.7%), compared with young Hispanics (8.9%), non-white Hispanics without Ashkenazi Jewish ancestry (7.2%), and Asian-Americans (2.4%) [35].

Family structure can affect BRCA gene mutation rate and the accuracy of mutation probability models. BRCA1/2 mutations were detected in 13.7% of the limited family structure and in 5.2% of the adequate family structure. Family structure was a significant predictor of mutation status [18]. However, there was no significant difference of BRCA gene mutations between family structures in our study.

The prevalence of BRCA1/2 mutations in bilateral breast cancer patients in Korea was 17.7% in our study and was higher than 15.4% prevalence in a previous small study [27]. BRCA1/2 mutations of bilateral breast cancer in other ethnic countries showed both 29.6% in high-risk Jewish families and in Polish patients with having 46.9–82.4% positive familial history [36, 37].

There is a lack of studies about the prevalence of BRCA1/2 mutations in male breast cancer in Korea. Two (25%) BRCA2 mutations and no BRCA1 mutation were reported among eight male breast cancer patients in a small study [27]. However, the patients with mutation also had familial breast cancer history. Our study had a small number of male breast cancer patients and BRCA2 mutation was detected in only one (5.9%) patients. The BRCA mutations in male breast cancer without familial breast cancer history are usually undetected and if detected, it is almost always in BRCA2 gene.

The prevalence of BRCA2 mutation in male breast cancer varies from 4 to 40% according to racial differences. This variance might be related to the different rates of familial breast cancer history [38‐43]. On the other hand, a recently published study accounted for 16% BRCA2 mutation of 115 male breast cancer cases from the United States, including 40% for breast cancer families and 13% for non-familial breast cancer. The study suggested that family history is not a strong predictor of carrying a mutation in males and males who develop breast cancer should be screened for mutations in BRCA2 [44].

The prevalence of BRCA1/2 in multiple organ cancer cases in our study (7.6%) was lower than previously reported (9.1%) for cases without familial history in a previous small study, which also showed 50% with BRCA1/2 mutations in cases with familial breast cancer history [27]. In our study, the other primary cancer sites in breast cancer patients were 46 thyroid cancers, 6 uterine cancers, 5 kidney cancers, 2 stomach cancers, 2 rectal cancers, 2 tongue cancers, 1 liver cancer, 1 pancreatic cancer, and 1 bone cancer. Five BRCA1/2 mutations were detected in 2 thyroid cancers, 2 kidney cancers, and 1 bone cancer, respectively (Table 8). It would seem that genetic testing should be considered whether or not a specific primary cancer is genetically related to breast cancer. For example, the International Consensus Conference on Breast Cancer Risk, Genetics, and Risk Management suggested as candidates for genetic counseling and testing for breast cancer, any patient who has had a family history of prostate cancer, thyroid cancer, sarcoma, endometrial cancer, adrenocortical cancer, brain cancer, or pancreatic cancer—although these involve less strict criteria [1].

A study reported that the germline mutation rate in BRCA1 was 2.7% in 37 Korean sporadic ovarian cancer patients unselected for family history, which was slightly lower than rates obtained in other countries [45]. The prevalence of BRCA1/2 mutations in patients with both breast and ovarian cancer in our study was 50% and higher than that in Myriad data (20%), although the number of cases were small [46]. This high prevalence supports current practice guidelines of genetic testing for all patients with breast and ovarian cancers, regardless of age or family cancer history [11].

Although germline mutations were scattered through the BRCA1 and BRCA2 genes, the BRCA1, 509C>A gene which was identified separately in four unrelated patients, and the BRCA2, 7708C>T gene which was identified separately in six unrelated patients, are the most frequent mutation in either genes and accounted for 16 and 15% of mutations detected in BRCA1 and BRCA2 respectively in this study of Korean women. 509C>A gene was also detected in Asian population and 5615del11insA were detected in only Korean patients in the BIC database. The BRCA2, 7708C>T gene was detected in Asian and West European population and detected frequently in Korean patients in the previous studies [23‐25, 27‐29]. These genes would be possible candidates for founder mutations of BRCA1/2 in high-risk Korean breast cancer patients. However, defining founder genes in Korean breast cancer patients should be approached carefully, because there is no data of mutation frequency in the Korean general population and additional data about BRCA mutations is required even though the KOHBRA study was a nationwide multicenter study.

The selection of genetic testing criteria would be clinically important because the mutation result might affect the decision-making for operation method and follow-up method. Although widely accepted clinical criteria for referral are usually suggested, genetic testing criteria may differ between countries based on mutation prevalence because the prevalence of BRCA1/2 mutations varies considerably among ethnic groups and geographical areas [12]. As the NCCN guideline currently recommends genetic counseling and genetic testing for any patient with high risk 10% or more of mutation, the prevalence of BRCA1/2 mutations in high-risk breast cancer patients without family history of breast or ovarian cancer—noted in this study—may play a key role for genetic testing criteria in Korean breast cancer patients with high risk of mutation. BRCAPRO and Myriad II, two of the most commonly used computer predictive models on clinical expertise, show accuracy of approximately 80% for whites with strong personal and/or familial history of breast, ovarian, and/or male breast cancer. However since these models show underestimation of Asian mutation carriers because of their differences in performance by race/ethnicity, using these models to predict the BRCA1/2 mutation probability among Korean patients may result in inaccuracies [34]. Therefore, large nationwide trials like the KOHBRA study are needed to continue developing the appropriate guidelines for genetic counseling, genetic testing, and management as well as the suitable predictive model for BRCA1/2 mutation patients or carriers in Korea. It is important to evaluate whether the difference of BRCA1/2 mutation prevalence exists between Koreans and other races. Identifying racial differences in genetic or lifestyle factors, which may modify the cancer risk of BRCA1/2 mutations, is also a priority for future research. So far, the management for BRCA1/2 mutation patients or carriers in Korea is recommending that application is individually based on the prevalence data of BRCA1/2 mutation of the KOHBRA study, as well as the worldwide guidelines such as the NCCN guideline or the International Consensus Conference guideline.

Our study has some limitations despite being a large multicenter nationwide study. Three different screening methods for testing BRCA1/2 mutations were performed although most patients were tested with the F-CSGE method. This heterogeneous screening method might affect the prevalence of BRCA mutation. Also, the number of patients varied according to risk groups. For instance, the prevalence of BRCA1/2 mutations in male breast cancer patients as well as in patients with breast and ovarian cancer in this study must be interpreted with caution due to the very small number of subjects. Another limitation involves the various additional primary organ sites for patients with multiple organ cancers. Additional primary cancer sites in breast cancer patients in our study were thyroid, uterus, kidney, stomach, tongue, rectum, liver, bone, and pancreas. Whether cancers from these organs are genetically related to breast cancer or BRCA1/2 mutation requires confirmation. Besides the differences in number of cases with familial breast cancer history, the different sites of multiple-organ cancers might affect the many discrepancies in the prevalence of BRCA1/2 in multiple organ cancers cases between our study and the previous smaller study [27].

In conclusion, BRCA1 and BRCA2 mutations were detected at higher frequency than reported for Korean sporadic breast cancer patients in those patients with no family history of breast or ovarian cancer but with other risk factors of genetic disease. In particular, the patients with early onset of less than 35 years of age, bilateral breast cancer, and personal history of breast and ovarian cancer had greater than 10% prevalence of BRCA1/2 mutations. Genetic testing may be indicated for these high-risk patient groups.