Characteristics of Second Primary Breast Cancer after Ovarian Cancer: A Korea Central Cancer Registry retrospective study

Eun-Gyeong Lee National Cancer Center Jiwon Lim National Cancer Control Institute, National Cancer Center Hyeong In Ha Pusan National University Yangsan Hospital, Pusan National University School of Medicine Myong Cheol Lim National Cancer Center Yoon Jung Chang National Cancer Control Institute, National Cancer Center Young-Joo Won National Cancer Control Institute, National Cancer Center So-Youn Jung (  goje1@ncc.re.kr ) National Cancer Center

receive adjuvant radiotherapy (14.92% vs. 21.92%, p = 0.0228) or adjuvant chemotherapy (44.75% vs. 55.69%, p = 0.0031). Based on the age-standardized rate (ASR), the incidence of SPBC after OC was 293.58 per 100,000 ovarian patients and the incidence of PBC was 39.13 per 100,000 women. The 5-year OS rates were 72.88% and 89.37% for SPBC and PBC (p < 0.0001). The OS rate in SPBC decreased signi cantly with advanced stage and older age.
Conclusion: The incidence of breast cancer is about 1.27 times higher in ovarian cancer patients than in healthy people. The survival outcomes were worse for SPBC than for PBC and were related to older age and advanced stage. Active screening for breast cancer is necessary in ovarian cancer patients.

Background
Breast cancer is the most common female cancer and it is steadily increasing worldwide. [1] On the other hand, ovarian cancer has the highest mortality rate among gynecologic malignancies. [2] Korea has followed the global trend in this respect. According to 2016 nationwide cancer statistics in Korea, breast cancer had the highest incidence in women, with a crude incidence rate of 85.0 per 100,000; additionally, about 2,600 people were newly diagnosed with ovarian cancer, which caused an estimated 1,200 deaths in 2016. [3] Survivors of primary cancer are increasing with advances in diagnostic methods and treatments. Consequently, second primary cancer has become an important issue among survivors. Various studies on second primary breast cancer following ovarian cancer have reported that this cancer is related to genetic factors, such as BRCA mutations. [4][5][6] For these patients, the risk of breast cancer was reduced by treatment of ovarian cancer, which consists of salpingo-oophorectomy and platinum-based chemotherapy. [7,8] Some studies have reported differences in the clinical and survival outcomes and the risk of second primary breast cancer. [9][10][11] However, these have mainly originated from western countries, and reports from Asian countries have been limited.
This study aimed to determine the risk and survival outcomes for patients with second primary breast cancer (SPBC) diagnosed after ovarian cancer. We also aimed to identify differences in clinicopathologic outcomes between second primary breast cancer and primary breast cancer (PBC).

Study population
Using the population-based Korea Central Cancer Registry (KCCR) database, we searched all patients with breast cancer who were diagnosed with PBC and SPBC after ovarian cancer between 1999 and 2017. We excluded breast cancer with other secondary cancers from the analysis. The KCCR was established in 1999 and is a representative population registry that collects about 98% of cancer data in Korea.
The different types of breast cancer (C50) and ovarian cancer included the following: primary peritoneal cancer (C48), epithelial ovarian cancer (C56.9), and fallopian tube cancer (C57) which were all de ned based on the basis of the International Classi cation of Diseases for Oncology, 3rd edition (ICD-O-3). [12] Patients were grouped according to age (< 30 years, 30-39 years, 40-49 years, 50-59 years, 60-69 years, 70-79 years, and ≥ 80 years), date of diagnosis; Surveillance, Epidemiology, and End Results (SEER) stage; and the course of treatment, such as operation, radiation therapy, and chemotherapy within 4 months after the diagnosis of breast cancer.

Statistical analysis
The age-standardized rate (ASR) was calculated in patients diagnosed with breast cancer, using Segi's world standard population and was expressed per 100,000 people. The standardized incidence ratio (SIR) of subsequent breast cancer among patients with ovarian cancer was calculated to quantify relative risk compared to the general population. Survival curves were created using the Kaplan-Meier method and compared using the log-rank test, according to age, histological type, and SEER stage. All statistical tests were considered statistically signi cant at p-values of < 0.05. All statistical analyses were performed using SAS software (version 9.

Characteristics of second primary breast cancer after ovarian cancer
According to the KCCR database, 251,244 patients were newly diagnosed with breast cancer from 1999 to 2017, of whom 228,148 were PBC patients and 181 were patients with SPBC diagnosed with ovarian cancer. As shown in Table 1, the ASR for breast cancer was 39.1288 per 100,000 women. The ASR of SPBC was 0.0280 per 100,000 women and 293.58 per 100,000 after ovarian patients.   A total of 181 women diagnosed with SPBC were evaluated for a mean follow-up period of 8.95 years. The mean interval from the diagnosis of ovarian cancer to the diagnosis of SPBC was 5.05 years. In this group, the SIR between 1 and 4 years increased signi cantly to 1.34.

Survival outcomes
The 5-year OS rate from the onset of SPBC was 72.88% and that from the onset of PBC was 89.37% ( Figure 1). Compared by age, the 5-year OS rate of patients with SPBC was low, at 50.05%, in patients Among cases with NST histology, the 5-year OS rates were 72.07% in SPBC and 89.16% in PBC cases. When compared by stage, patients with SPBC had a signi cantly worse prognosis than those with PBC.

Discussion
In this study, we investigated differences in clinicopathologic outcomes between SPBC after ovarian cancer and PBC in Korea. We showed that the incidence of breast cancer is higher in patients with ovarian cancer than it is in healthy people and that survival outcomes were worse for SPBC than for PBC; increased mortality was related to older age and advanced cancer stage.
In the current study, SPBC after ovarian cancer accounted for only 0.07% of newly diagnosed breast cancers in Korea, based on KCCR data from a 19-year period. In a retrospective observational study using SEER data between 1973 and 2013, the incidence of SPBC in the ovarian cancer cohort was approximately 1.37% (1,821/133,149) and the incidence of SPBC decreased from 7.2% to 2.0% between 1973 and 2008 (P < 0.05). [13] From 1999 to 2017, the incidence of breast cancer continued to increase year by year. On the other hand, the incidence of SPBC after ovarian cancer did not remain constant. In this study, the incidence of SPBC after ovarian cancer increased about two-fold in 2016 and 2017 (Supplement 1). Increasing rates of SPBC may be due to interest in genetic testing and application of insurance reimbursement, which may have led to active screening for breast cancer.
Ovarian cancer and breast cancer are hereditary cancers, and BRCA1 and BRCA2 are well known as causative genes. [4] According to the National Comprehensive Cancer Network guideline, risk-reducing surgery is recommended for carriers of BRCA gene mutations at an appropriate time. [7] A previous metaanalysis reported that the risk of breast cancer was reduced by about 50% in carriers of BRCA1 and BRCA2 mutations who underwent risk-reducing bilateral salpingo-oophorectomy (RRSO).
[8] In our previous study about patterns of risk-reducing surgery in carriers of BRCA mutations, the rate of RRSO was 42.5%. After insurance reimbursement started in 2013, the rate of risk-reducing surgery was signi cantly higher (46.3% after 2013 vs. 31.6% before 2013, p < 0.001). [14] In the current study, the overall SIR for SPBC after ovarian cancer was 1.27 (95% CI, 1.09-1.46). In a study of invasive ovarian cancer, the SIR of breast cancer was 1.35 (95% CI, 0.85-2.05). [10] In another study on an ovarian cancer cohort from the Stockholm-Gotland Cancer Registry, the SIR of breast cancer was 1.41 (95% CI, 1.14-1.75). [9] We found that the SIR of SPBCS was signi cantly higher at 1.34 between 1 and 4 years after the initial diagnosis of ovarian cancer. Thus, patients with ovarian cancer require more active surveillance for SPBC during this period.
This study showed that patients with SPBC after ovarian cancer had a markedly poor survival.
Interestingly, when compared by age, our study con rmed that the survival rate of patients with PBC was relatively lower in the older age-group, whereas the survival rate of patients with SPBC was lower in the 40s age-group. Treatment of ovarian cancer with radiation therapy and chemotherapy may lead to aggressiveness of the second primary tumor. A previous study using the SEER program database showed that survival of patients with localized SPBC was similar to that of patients with PBC, while cases with advanced stage SPBC showed worse survival outcomes. [11] Our study showed similar results.

Conclusion
The present study con rmed that the incidence of SPBC in patients with ovarian cancer was higher than that observed in those with primary breast cancer, and the survival outcome was low. However, if it the cancer is detected in the early stages, it shows a survival rate similar to those with PBC. Hence, active screening for breast cancer is necessary in patients with ovarian cancer between 1 and 4 years after diagnosis of ovarian cancer. Figure 1 Survival outcomes of patients with breast cancer from the onset time of breast cancer diagnosis in Korea