Selected features of breast and peritoneal cancers diagnosed in BRCA1 carriers after risk-reducing salpingo-oophorectomy

Background Since more than two decades Risk-reducing salpingo-oophorectomy (RRSO) is recommended and widely accepted by BRCA1/2 carriers as a method reducing ovarian cancer risk and improving survival rate. After RRSO, there remains a risk of breast cancer and peritoneal cancer. The characteristics of these neoplasms are not well known. In this study, we determined the selected parameters such as age at cancer diagnosis, time from RRSO to the diagnosis of cancer, and significance of BRCA1 mutation type in patients diagnosed with breast or peritoneal cancer during postoperative follow-up. Methods The material comprised of 195 BRCA1 carriers who performed RRSO between years 1999–2012. In this period, 16 patients developed cancer (6-primary breast cancer, 3-contralateral breast cancer, 5-relapse of breast cancer, 2-peritoneal cancer). They were subject of the further analysis. Results During the follow-up period mean age of patients after RRSO at the time of cancer diagnosis was 53.19. The mean age of patients diagnosed with primary breast cancer was 50, contralateral breast cancer – 58.67, recurrence of breast cancer - 51 and peritoneal cancer 60. The mean time periods from RRSO to the diagnosis of primary, contralateral, recurrence breast cancer were 53, 58.67 and 25,4 months respectively and of peritoneal cancer 46 months. BRCA1 c.5266dupC mutation carriers demonstrated significantly shorter time of cancer development compared to patients carrying c.181T > G and c.4035delA mutations. Peritoneal cancer was only observed in two c.181T > G BRCA1 mutation carriers. Conclusions The mean age of cancer diagnosis and the mean time periods from RRSO to the diagnosis of cancer are similar to those observed by other researchers. The carriers of c.181T > G and c.5266dupC BRCA1 mutation should be the subject further studies in context of breast and peritoneal cancer risk or time of cancer development after RRSO, respectively.


Introduction
It was shown that diagnostic methods for ovarian cancer early-stage detection are ineffective [1]. Intensive screening tests in groups with the highest risk of ovarian cancer, such as carriers of the BRCA1 and BRCA2 mutations, have also low efficacy [1][2][3][4][5][6]. For these reasons, patients who are carriers of the BRCA1/2 mutation are offered risk-reducing salpingo-oophorectomies (RRSO), which is widely accepted by BRCA1/2 carriers and have been performed for decades in hospitals and gynecological clinics all around the world. At the moment, such management is considered the best possible option for reducing ovarian cancer risk and improving the survival rate [1,7,8]. However, after this surgery, there remains a risk of breast cancer and risk of peritoneal cancer. Data about characteristics of these cancers developing after RRSO are pure. In this study, we analyzed characteristics of breast or peritoneal cancer after RRSO. Follow-up was conducted over the course of 12 years. The analysis included: age at cancer diagnosis, time from RRSO to the diagnosis of cancer, significance of BRCA1 mutation type in patients diagnosed with breast or peritoneal cancer during postoperative follow-up.

Material and methods
The material comprised of 195 BRCA1 carriers from the West Pomeranian Voivodship in Poland who performed RRSO between 15.09.1999-31.12.2012 at the Department of Gynecological Surgery and Oncology of Adults and Adolescents of the Pomeranian Medical University in Szczecin. No malignancy was found in the histopathological examination of the excised material. 80 of 195 (41.03%) patients were treated for breast cancer before risk-reducing surgery. All patients carried one of three BRCA1 mutations most commonly occurring in the Polish population (c.5266dupC -128 patients, c.4035delA -19 patients and c.181T > G -48 patients) [9]. Median follow-up time for the group of 195 patients amounted to 80 months.
At the time of observation 16 out of 195 patients were diagnosed with cancer. 6 (3.1%) cases with primary breast cancer (PBC); 3 (1.5%) cases contralateral primary breast cancer (CPBC); 5 (2.56%) cases with cancer cells diagnosed in a scar after mastectomy defined as relapse of breast cancer (RBC); 2 (1.03%) cases with peritoneal cancer. The detailed characteristics of 16 patients from the study group are shown in Table 1. Ten (62.5%) of these patients had been treated for breast cancer also before the RRSO. The median age of affected patients (n = 16) at the time of RRSO was 46.5 years (36-63 years), which did not deviate from median age for the whole group (n = 195) -47 years (31-78 years).
Histopathological examination of tissues excised during RRSO was performed with extraordinary caution in order to rule out the presence of cancerous foci in the ovary or the salpinx, which have been described in the literature and could have been missed in the primary histopathological assessment [10,11]. Repeated histopathological examination of excised material failed to reveal micro-invasive foci in both of our patients diagnosed with primary peritoneal cancer during the follow-up period.
The patient analysis included: age at cancer diagnosis, time from RRSO to the diagnosis of cancer, significance of BRCA1 mutation type in patients diagnosed with breast or peritoneal cancer during postoperative follow-up. The data has been subjected to statistical analysis.

Statistical analysis
All variables were checked for normal distribution using the Shapiro-Wilk test. They were described as means, standard deviations, medians, quartiles, as well as minimal and maximal values. We checked for statistically significant differences in quantitative variables using Student's t-test or Mann-Whitney test and Fisher's exact test were used in order to calculate differences in proportions. For all tests, the differences were considered statistically significant at p-value < 0.05. Statistical analyses were performed using STATA 11 software (license no. 30110532736).

Results
Summary of selected features of BRCA1 carriers diagnosed with cancer during the follow-up period is shown in Table 2. The mean age of cancer diagnosis in 16 patients who were subject of the study, was 53.19. Peritoneal cancer observed in two patients was diagnosed significantly later at a mean age of 60. Both patients were previously treated (before RRSO) due to breast cancer. With regards to breast cancer, the PBC was diagnosed in 6, CPBC in 3 and RBC in 5 out of 16 cases. The peritoneal cancer was diagnosed almost 7 months earlier than PBC (46 months vs. 53 months), but this difference was not statistically significant. Breast cancer recurrence was diagnosed almost twice as fast as primary breast cancer and peritoneal cancer (25.4 vs. 53 months), but this difference was also not statistically significant.
Peritoneal cancers diagnosed during the follow-up period were observed only in two c.181T > G BRCA1 mutation carriers. We performed a statistical analysis of the frequency of peritoneal cancer in c.181T > G BRCA1 mutation carriers in comparison to other mutation carriers. Statistical significant differences were observed for this characteristic (p = 0.0392; OR = 29.00; 95% CI: 1.048-802.64).
The time to any cancer diagnosis after RRSO was significantly shorter for c.5266dupC mutation carriers compared to c.181T > G and c.4035delA mutation carriers (30.45 vs. 75.6 months; p = 0.021).

Discussion
In our material, we observed relatively advanced age of cancer diagnosis among BRCA1 carriers after RRSO. It is most likely associated with particularly late age of undergoing this surgery. In our study, the average age of undergoing such an operation is 46-49 years [12][13][14]. The reason for delayed RRSO was that, in a significant number of breast cancer patients, BRCA1 mutation was diagnosed after diagnosis of breast cancer. In our study group, 62.5% of patients had been previously treated due to breast cancer. As indicated in our previous studies, patients treated for breast cancer undergo RRSO at a later age compared to patients without the diagnosis of breast cancer (50 vs. 46 years; p = 0.0003) [13]. In our study, we found that the mean age at diagnosis of any breast cancer was similar to those observed by Ramon  Finch et al. showed that mean time to development of peritoneal cancer among BRCA1 carriers after RRSO amounted to 63.6 months, although they emphasize that in three cases the diagnosis was made before the end of three years. The mean age of those patients at the time of diagnosis equalled 51.5 years [18], which approximates our data. In another study, Finch et al. reported similar mean age at diagnosis of peritoneal cancer -51.6 years, but the mean time to diagnosis extended to 73.2 months. Possibly, prolonged time to the diagnosis of peritoneal cancer might have been influenced by the inclusion of four patients with BRCA2 mutation into the study group of 32 patients [19]. In case of particularly short time to diagnosis of peritoneal cancer after RRSO, one should very carefully assess the excised material in order to rule out micro-invasive foci, which is described in the literature [10,11]. Rhiem [17]. The diagnosis was made as early as a year after the procedure [24]. In our material, the mean age of patients diagnosed with peritoneal cancer was 60 and the mean time from RRSO to the diagnosis of peritoneal cancer amounted to 46 months.
Influence of particular BRCA1 gene mutation on studied characteristics is a very difficult topic to discuss. Although c.5266dupC, the most common mutation in the Polish population, is also often identified in the Ashkenazi Jewish population [25], available literature lacks data for discussion. The frequency of particular BRCA1 mutations observed between carriers who were diagnosed with any cancer reflects the frequency of these mutations in the Polish population. However, we found peritoneal cancer in two BRCA1 carriers with c.181T > G mutation, only. These two patients also developed breast cancer before RRSO. We observed that the time to any cancer diagnosis after RRSO was significantly shorter for c.5266dupC BRCA1 mutation carriers. We think that these are interesting observations important for future analyses on significance of particular BRCA1 gene mutation, however, for more general conclusions studies on larger groups should be performed.

Conclusions
The mean age of cancer diagnosis and the mean time periods from RRSO to the diagnosis of cancer are similar to those observed by other researchers. The carriers of c.181T > G and c.5266dupC BRCA1 mutation should be the subject further studies in context of breast and peritoneal cancer risk or time of cancer development after RRSO, respectively.