Genetic variants related to specific cancer risk have been well established, including in BRCA1 or BRCA2-related ovarian cancer [1]. In the Korean population, germline mutations have been identified in 23.8%-25.7% of peritoneal, ovarian, or fallopian tube (POFT) cancer cases [2,3]. Meanwhile, 16% of patients with epithelial ovarian cancer have a family history of cancer. Among them, 74% of patients undergo genetic testing. Germline BRCA1 or BRCA2 mutations have been confirmed in 33% of tested patients [2].

The BRCA1 or BRCA2 gene is transmitted in an autosomal dominant fashion [4]. Therefore, familial genetic testing is recommended to first-degree relatives such as children, siblings, and parents of patients with BRCA1 or BRCA2 mutation. The National Comprehensive Cancer Network (NCCN) guidelines and Position Statement of Korean Society of Gynecologic Oncology recommend genetic testing to families of patients with BRCA1 or BRCA2 mutation [5,6]. However, among patients with ovarian cancer, previous studies have reported that only 20% of eligible individuals had taken advantage of a family-specific variant (FSM) genetic test [7]. Overall, where FSM was identified in a relative, the uptake of risk-reducing salpingo-oophorectomy was approximately 52% [8]. Nevertheless, to-date, the uptake rate of FSM testing among relatives of patients with BRCA1 or BRCA2 mutation has not been investigated in Korea. Therefore, the aim of this study was to examine the uptake rate of FSM testing and influencing factors among relatives of patients with a POFT cancer and a BRCA1 or BRCA2 germline mutation.

We identified a total of 392 patients with POFT cancer who underwent genetic counseling/testing at the National Cancer Center of Korea between April 2016 and February 2019. All of these patients underwent BRCA1 or BRCA2 germline mutation genetic testing and provided a pedigree.

Outpatient genetic counseling by gynecologic oncologists and nursing staff have been conducted with 392 patients with POFT cancer (April 25, 2016-Febraury 28, 2019). Information about hereditary POFT cancer patterns, penetration of the cancer, cost of genetic tests, advantages and limitations of genetic tests, as well as potential psychosocial impact of genetic testing were explained to the patients. Patients were asked to provide a family pedigree up to three generations. Among 392 women with POFT cancer undergoing genetic counseling/testing, 129 women had a confirmed BRCA1 or BRCA2 germline mutation.

Baseline demographic and clinical characteristics, including age, type of cancer, and pedigree information of 129 patients with a BRCA1 or BRCA2 germline mutation were collected and analyzed. Relatives of these patients were invited for FSM testing, and their baseline and clinical characteristics were examined. In particular, the characteristics of the ‘uptake of FSM group and non-uptake of FSM group were compared.

In statistical analysis, comparisons were made with the Student t test, Wilcoxon test, chi-square test, and Fisher method. Univariate and multivariate Cox regression analysis was performed to identify factors affecting the uptake of FSM testing. A p-value < 0.05 was considered statistically significant.

In this study, among 392 women with POFT cancers undergoing genetic counseling/testing, 129 women had a BRCA1 or BRCA2 germline mutation.

The average time from confirmation of a pathogenic variant in a patient with ovarian cancer to the first FSM test of a relative was 168 days (range, 23 to 618 days).

Among 129 patients with BRCA1 and BRCA2 mutation, FSM testing was performed within families of 69 patients (53.5%). Overall, the number of families who needed testing was 423, while the uptake of FSM testing was 129 familial members (30.5%). Half of familial members (50.7%, 77/152) have the FSM (Table 1).

There were no statistically significant differences in characteristics between patients’ relatives in the uptake of FSM group and non-uptake FSM group, including in frequency of POFT cancers being diagnosed within the family (Table 2). We compared the between the’ uptake of FSM testing’ and the ‘non-uptake of FSM testing’ groups. (Table 3) The median surviving family number did not differ significantly between the two groups (median [range], 8 [3-15] in the uptake of FSM testing group, 8 [4-17] in the non-uptake of FSM testing group). However, the rate of FSM testing was higher within families with living fathers (33.8% vs. 13.3%, p=0.007) or daughters (79.4% vs. 60.3%, p= 0.019) (Table 3).

Comparisons between persons of different sex within a generation, for example, father vs. mother, brother vs. sister, and son vs. daughter, revealed that the uptake of FSM testing was higher among female relatives of cancer patients than among male relatives (40.9% vs. 17.6%, p < 0.001) (Table 4). None of the fathers included in the present study had undergone FSM testing. Sisters were more likely to be tested than were brothers (29.9% vs. 9.3%, p < 0.001). Daughters were more likely to be tested than were sons (67.8% vs. 39.7%, p=0.001).

Genetic testing of patients with ovarian cancer is important for appropriate treatment of the patient and for managing cancer risk within the patient’s family. Despite this recommendation, not all eligible candidates undergo genetic testing [9]. In the present study, we classified patients with ovarian cancer with BRCA1 or BRCA2 mutation into two groups, FSM uptake group vs. FSM non-uptake group and compared their characteristics.

In the present study, the uptake rate of FSM testing was higher among individuals whose fathers were alive. Previous studies have suggested that larger families (which are more likely to include a living father) with close relationships, good communication, and forward-thinking attitudes tend to share health information and treatment plan, when required [10,11]. The larger the number of living relatives, including a living father, the more likely the family is to undergo genetic testing as a result of good communication among family members. It is likely that communication among family members might be facilitated when a father is alive.

Concurrently, the uptake of FSM testing was higher among female relatives of cancer patients than among male relatives (40.9% vs. 17.6%, p < 0.001). The uptake of FSM testing was higher among families with a sister that among families with a brother (29.9% vs. 9.3%, p < 0.001). Among patients’ children, the proportion of daughters who received a genetic test was higher than the proportion of sons (67.8% vs. 39.7%, p=0.001).

Meanwhile, although men should undergo FSM testing, they are not commonly tested due to a misconception that they are not vulnerable to these kinds of cancer, such as ovarian or breast cancer, which are considered “female” cancers. Patients need to be informed that the BRCA gene is inherited in the autosomal dominant rather than a sex-chromosomal recessive pattern [4,12]. Indeed, BRCA1 and BRCA2 mutations are associated with male hereditary cancers, such as male breast cancer, pancreatic cancer, and prostate cancer [13]. Men can be carriers of the mutated gene; therefore, within families at risk, it is as important to test men, as it is to test women [14,15].

To-date, several studies on the importance of genetic testing in various cancer-related fields have been published [16]. Meticulous pre-test counseling is important to improve patients’ understanding of disease and increase the number of proband relatives undergoing testing aimed at detecting autosomal dominant cancer syndrome.

The present study has some limitations. This was a single institutional study with a limited number of patients (n=129). This was a retrospective study, resulting in missing information regarding some clinical characteristics of the included patients and their relatives. As a result, we considered only basic rather than comprehensive clinical factors.

Once a diagnosis was reached based on the results of the genetic test, all relatives of patients all relative of patients with a BRCA1 or BRCA2 genetic mutation were encouraged to be tested at our center. However, it was impossible to confirm whether the patient explained the information to all relatives, which could have resulted in selection bias.

There are some strengths to this study. First, this is the first study on family screening among patients with ovarian cancer with BRCA1 or BRCA2 mutation in Korea. Second, a single nurse certified in genetic counseling was consistently responsible for all patient interaction, including data collection, which was unlikely to bias the findings.

Further prospective studies are needed to understand factors that increase the uptake rate of FSM testing. Genetic testing might help reduce the rate of cancer within family units and reduce national health care costs [17]. Finally, information and awareness campaigns are required to educate the public about the importance of genetic testing to increase the number of patients’ relatives undergoing testing.