A prior history of breast cancer is a risk factor for the subsequent development of primary peritoneal, epithelial ovarian, and fallopian tubal (POFT) cancers. This study aimed to estimate the incidence of secondary POFT malignancy in breast cancer patients and the clinical outcomes of primary and secondary POFT cancer.
We searched the Korea Central Cancer Registry to find patients with primary and secondary POFT cancer who had breast cancer in 1999–2017. The incidence rate and standardized incidence ratio were calculated. Additionally, we compared the overall survival of patients with primary and secondary POFT cancer.
Based on the age-standardized rate, the incidence of second primary POFT cancer after breast cancer was 0.0763 per 100,000 women, which increased in Korea between 1999 and 2017. Among the 30,366 POFT cancer patients, 25,721 were primary POFT cancer only, and 493 had secondary POFT cancer after a breast cancer diagnosis. Second primary POFT cancer patients were older at the time of diagnosis (55 vs. 53, p < 0.001) and had a larger proportion of serous histology (68.4% vs. 51.2%, p < 0.001) than patients with primary POFT. There were no differences between the two groups in tumor stage at diagnosis. The 5-year overall survival rates were 60.2% and 56.3% for primary and secondary POFT cancer, respectively (p=0.216).
The incidence of second primary POFT cancer after breast cancer increased in Korea between 1999 and 2017. Besides, second primary POFT cancer patients were diagnosed at older ages and had more serous histology.
Patients who have primary cancer often develop metachronous or synchronous multiple malignancies. In 2018, breast cancer was the most common cancer among women and accounted for 24.2% of the cases in women worldwide [
Survival rates for women with breast cancer have constantly improved; therefore, the risk of developing a subsequent primary malignancy such as ovarian cancer is renewed. Especially, in
Epithelial ovarian cancer is the second most common cause of gynecological cancer deaths, and it is also related to the
This study used data from patients enrolled in the Korea Central Cancer Registry (KCCR), which collects information regarding approximately 98% [
We grouped the patients according to their age at diagnosis with ovarian cancer (< 30 years, 30–39 years, 40–49 years, 50–59 years, 60–69 years, 70–79 years, and ≥ 80 years), the SEER summary stage [
The age-standardized incidence rate (ASR) was calculated in patients diagnosed with POFT cancer using Segi’s world standard population and was expressed per 100,000 people. The standardized incidence ratio (SIR) of subsequent POFT cancers among patients with breast cancer was calculated to quantify relative risk compared with those among the general population. The Kaplan-Meier method was used to create survival curves, and the log-rank test was used to compare the survival difference.
ASR and SIR were analyzed using SAS ver. 9.4 (SAS Institute, Inc., Cary, NC) and SEER*Stat 8.3.6 (National Cancer Institute, Bethesda, MD), respectively. Survival analysis was performed using Stata ver. 16 (StataCorp LLC, College Station, TX). All statistical tests were considered statistically significant for p < 0.05.
Between 1999 and 2017, the KCCR included 251,244 cases of breast cancer and 30,366 POFT cancer cases. Among the POFT cancer cases, 493 cases had second primary POFT cancer after primary breast cancer diagnosis. Based on the ASR, the incidence of total POFT cancer was 4.82 per 100,000 women. In addition, the incidence of second primary POFT cancers was 0.0763 per 100,000 women and that of second primary POFT cancer after breast cancer was 78.84 per 100,000 women in breast cancer survivors (
The overall incidence of POFT cancer has been observed to increase steadily. In addition, despite slight fluctuations, the incidence of second primary POFT cancer has also been observed to increase. In 1999, there were 958 primary POFT cancer patients and no second primary POFT cancer patients. On the other hand, there were 2,478 primary POFT cancer patients and 77 second primary POFT cancer patients in 2017 (
The median age of patients with primary and second primary POFT cancers was 53 years (range, 10 to 96 years) and 55 years (range, 35 to 87 years), respectively. In the case of second primary POFT cancer, the median age at diagnosis of breast cancer was 48 years (range, 25 to 80 years). Moreover, the median of the interval between previous breast cancer and second primary POFT cancer was 6.92 years (range, 0.17 to 18.00 years) (
With respect to the entire group of breast cancer survivors, higher rates of second primary POFT cancers were observed to occur than in the general female population in KCCR (SIR, 2.32; 95% confidence interval [CI], 2.12 to 2.53). According to the age at second primary POFT cancer diagnosis, the SIR in the patients whose age at second primary POFT cancer was between 30 and 39 years was 3.34 (95% CI, 1.83 to 5.61) and most prominent. The SIRs also increased in all age groups except in those aged 80 or older.
The distribution of the patients’ age at diagnosis differed between primary and second primary POFT cancers and was significant (p < 0.001). The most common age group at the second primary POFT cancer diagnosis was 50–59 years (38.7%). However, there were 14 patients in the range of 30–39 years, accounting for only 2.84% (
Depending on the histologic subtype, there were differences in the SIRs. In the serous type of POFT, the SIR was 2.77 (95% CI, 2.48 to 3.09). On the other hand, the SIR was 1.60 (95% CI, 1.07 to 2.29) in endometrioid type disease. The SIRs of clear cell type and mucinous type were 1.13 and 1.19, respectively, with no statistical significance.
By classifying the histologic subtype into serous, endometrioid, clear cell, mucinous, and others, the distribution pattern of each histologic subtype was significantly different between primary and second primary POFT cancers (p < 0.001). For instance, the differences stand out in serous cancer, in which the percentage of serous POFT cancers was 68.4% in second primary POFT cancers and 51.2% in primary POFT cancers.
In terms of the extent of the disease, there was no statistical difference in the disease stage distribution between primary and second primary POFT cancers (p=0.326). The SIRs were increased for the entire stage at diagnosis between 2006 and 2017. In the localized stage, the SIR was 1.61 (95% CI, 1.18 to 2.13). On the other hand, the SIR was 1.85 (95% CI, 1.53 to 2.20) in distant metastasis cases.
After the diagnosis of primary breast cancer, the SIRs for the occurrence of second primary POFT cancers were observed to increase with time. The SIRs of survivors for breast cancer were 1.70 (95% CI, 1.44 to 2.00), 2.72 (95% CI, 2.34 to 3.15), and 3.88 (95% CI, 3.26 to 4.59) in 1–4 years, 5–9 years, and over 10 years, respectively (
The median follow-up period of primary POFT cancer cases was 3.33 years, and that of second primary POFT cancer cases was 10.25 years from the breast cancer diagnosis, 2.22 years from the secondary POFT cancer diagnosis (
In the patients with only POFT cancer (
In the patients with second POFT cancer, the 5-year OS rate of patients with a serous histology was 55.7%, whereas the patients with endometrioid and clear cell histology had more favorable outcomes (66.6% and 69.7%, respectively), though not significant (p=0.112) (
This study reported that second primary POFT cancer accounted for 1.6% (493/30,366) of all newly diagnosed ovarian cancers in Korea, based on the KCCR data from 1999 to 2017. These patients have an increased risk compared to the patients without breast cancer. Moreover, we reported that the absolute number and the ratio of second primary POFT cancers to the total number of cancer cases are steadily increasing.
The incidence rates for second primary malignancies are usually expressed as a SIR, which is the ratio of the observed to expected malignancies. We reported higher rates of second primary POFT cancers (SIR, 2.32) in breast cancer. The increased overall SIR supports previous studies wherein elevated SIRs in ovarian cancer after primary breast cancer were found [
In this study, the incidence rate for second primary ovarian cancers increased in ASR from a low value of 0.0111 per 100,000 women in 2000 to a peak of 0.1801 per 100,000 women in 2017. It reflects the fact that the overall incidence of POFT cancer has steadily increased [
On the other hand, since it was in 1999 that we started thorough registration, for patients with secondary POFT after 1999 who were diagnosed with breast cancer before 1999, they might have not been included if the time since the breast cancer diagnosis had been too long.
In breast cancer patients, it can be inferred that the second primary POFT cancer is due largely to the
Individuals with a
We could not infer the exact prevalence of
Risk-reducing salpingo-oophorectomy (RRSO) can be used for overcoming the potential risk of secondary ovarian cancer, especially in
The peak age of breast cancer is 10 to 20 years younger in Korea than Western countries, where the incidence rate of breast cancer is the highest in the fifth decade, followed by the sixth and fourth decades [
This study had several strengths. We analyzed the incidence of POFT cancer after breast cancer diagnosis by utilizing the population-based cancer registry which contained approximately 98% of Korean cancer cases [
The overall incidence of second primary POFT cancer after breast cancer increased between 1999 and 2017 in Korea. In addition, second primary POFT cancer patients were diagnosed at older ages and had more serous histology. Secondary POFT cancer was associated with lower 5-year survival than primary POFT cancer; however, this was not statistically significant (56.3% vs. 60.2%, p=0.216).
This study was approved by the Institutional Review Board of the National Cancer Center, Korea (NCC2020-0176). The requirement for informed consent was waived because we analyzed de-identified data secondarily.
Conceived and designed the analysis: Won YJ, Lim MC.
Contributed data or analysis tools: Lim J, Won YJ.
Performed the analysis: Lim J.
Wrote the paper: Ha HI, Lee EG, Jung SY, Chang YJ, Won YJ, Lim MC.
Interpretation, review: Ha HI.
Review and comment: Lee EG, Jung SY, Chang YJ.
Conflict of interest relevant to this article was not reported.
This work was supported by the National Cancer Center Grant (NCC-1910132, 1911274).
Survival outcome of peritoneal, ovarian, and fallopian tube (POFT) cancer patients from the onset time of POFT cancer diagnosis in Korea.
Survival outcomes from the onset time of peritoneal, ovarian, and fallopian tube (POFT) cancer diagnosis according to clinicopathologic characteristics (age, type, Surveillance, Epidemiology, and End Results stage). Women with second POFT cancer after breast cancer by age (A), histological type (B), and stage (since 2006) (C) and women with primary POFT cancer by age (D), histological type (E), and stage (since 2006) (F).
Incidence of POFT cancer and breast cancer by year of diagnosis, 1999–2017
Year | POFT cancer | Breast cancer | Secondary POFT cancer after primary breast cancer | |||||||
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ASR |
% of cases | No. of cases | ASR |
% of cases | No. of cases | ASR |
ASR per 100,000 breast cancer patients | % of cases | No. of cases | |
1999 | 3.73 | 3.15 | 958 | 21.37 | 2.32 | 5,824 | 0.0000 | 0.00 | 0.00 | 0 |
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2000 | 3.70 | 3.24 | 984 | 21.53 | 2.39 | 6,010 | 0.0111 | 17.16 | 0.61 | 3 |
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2001 | 3.62 | 3.28 | 995 | 25.25 | 2.90 | 7,277 | 0.0080 | 10.65 | 0.41 | 2 |
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2002 | 3.78 | 3.51 | 1,065 | 27.83 | 3.27 | 8,225 | 0.0165 | 19.71 | 1.01 | 5 |
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2003 | 4.01 | 3.76 | 1,141 | 27.95 | 3.37 | 8,474 | 0.0141 | 24.30 | 0.81 | 4 |
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2004 | 4.01 | 3.91 | 1,188 | 29.50 | 3.65 | 9,175 | 0.0235 | 33.52 | 1.42 | 7 |
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2005 | 4.28 | 4.28 | 1,300 | 32.32 | 4.07 | 10,236 | 0.0330 | 38.51 | 2.03 | 10 |
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2006 | 4.36 | 4.49 | 1,362 | 33.64 | 4.34 | 10,898 | 0.0578 | 67.18 | 3.65 | 18 |
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2007 | 4.89 | 5.14 | 1,560 | 36.17 | 4.77 | 11,987 | 0.0313 | 42.31 | 2.03 | 10 |
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2008 | 4.63 | 5.04 | 1,530 | 37.77 | 5.09 | 12,791 | 0.0522 | 51.76 | 3.45 | 17 |
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2009 | 4.61 | 5.21 | 1,582 | 39.32 | 5.42 | 13,628 | 0.0506 | 45.76 | 3.65 | 18 |
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2010 | 5.04 | 5.72 | 1,738 | 41.38 | 5.83 | 14,636 | 0.0754 | 74.82 | 5.27 | 26 |
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2011 | 4.97 | 5.81 | 1,763 | 44.58 | 6.42 | 16,133 | 0.0715 | 70.47 | 5.48 | 27 |
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2012 | 5.27 | 6.37 | 1,933 | 45.39 | 6.66 | 16,728 | 0.0777 | 75.17 | 6.29 | 31 |
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2013 | 5.23 | 6.52 | 1,981 | 46.34 | 6.94 | 17,432 | 0.1049 | 90.96 | 8.32 | 41 |
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2014 | 5.67 | 7.10 | 2,156 | 48.02 | 7.34 | 18,436 | 0.1230 | 103.49 | 10.55 | 52 |
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2015 | 5.59 | 7.25 | 2,201 | 49.59 | 7.66 | 19,254 | 0.1725 | 139.59 | 14.40 | 71 |
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2016 | 6.15 | 8.07 | 2,451 | 55.41 | 8.68 | 21,805 | 0.1830 | 128.31 | 15.01 | 74 |
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2017 | 6.15 | 8.16 | 2,478 | 56.07 | 8.87 | 22,295 | 0.1801 | 126.25 | 15.62 | 77 |
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1999–2017 | 4.82 | 100 | 30,366 | 39.13 | 100 | 251,244 | 0.0763 | 78.84 | 100 | 493 |
ASR, age-standardized rate; POFT, primary peritoneal, ovarian, and fallopian tube.
ASR was calculated using Segi’s world standard population.
Clinicopathologic characteristics of patients with POFT cancer in Korea, 1999–2017
Characteristic | SIR | Secondary POFT cancer after primary breast cancer | Primary POFT cancer | p-value |
---|---|---|---|---|
2.32 |
493 | 25,721 | - | |
- | 10.25 (0.17–18.75) | 3.33 (0.00–18.75) | < 0.001 | |
Interval between 1st and 2nd cancers, median (range, yr) | - | 6.92 (0.17–18.00) | ||
Follow-up from secondary ovarian cancer diagnosis, median (range, yr) | - | 2.22 (0.02–16.14) | ||
55 (35–87) | 53 (10–96) | < 0.001 | ||
< 30 | 0 | 0 | 1,185 (4.6) | < 0.001 |
30–39 | 3.34 |
14 (2.8) | 2,405 (9.4) | |
40–49 | 2.58 |
124 (25.2) | 6,497 (25.3) | |
50–59 | 2.12 |
191 (38.8) | 7,374 (28.7) | |
60–69 | 2.39 |
115 (23.3) | 4,943 (19.2) | |
70–79 | 2.43 |
47 (9.5) | 2,731 (10.6) | |
≥ 80 | 0.77 | 2 (0.4) | 586 (2.3) | |
Mean±SD | - | 7.27±4.47 | - | - |
< 1 | 1.06 | 24 (4.9) | - | - |
1–4 | 1.70 |
149 (30.2) | - | - |
5–9 | 2.72 |
182 (36.9) | - | - |
≥ 10 | 3.88 |
138 (28.0) | - | - |
Serous | 2.77 |
337 (68.4) | 13,163 (51.2) | < 0.001 |
Endometrioid | 1.60 |
29 (5.9) | 2,248 (8.7) | |
Clear cell | 1.13 | 24 (4.9) | 2,410 (9.4) | |
Mucinous | 1.19 | 26 (5.3) | 3,911 (15.2) | |
Others | 2.60 |
77 (15.6) | 3,989 (15.5) | |
Local | 1.61 |
48 (20.9) | 5,009 (26.3) | 0.326 |
Regional | 1.80 |
46 (20.0) | 3,646 (19.1) | |
Distant | 1.85 |
122 (53.0) | 9,352 (49.0) | |
Unknown | 2.57 |
14 (6.1) | 1,067 (5.6) | |
Yes | 2.27 |
428 (86.8) | 22,580 (87.8) | 0.514 |
No | 2.67 |
65 (13.2) | 3,141 (12.2) | |
Yes | 1.26 | 4 (0.8) | 425 (1.7) | 0.145 |
No | 2.34 |
489 (99.2) | 25,296 (98.3) | |
Yes | 2.34 |
375 (76.1) | 18,340 (71.3) | 0.021 |
No | 2.26 |
118 (23.9) | 7,381 (28.7) |
Values are presented as number (%) unless otherwise indicated. POFT, peritoneal, ovarian, and fallopian tube; SD, standard deviation; SIR, standardized incidence ratio.
ANOVA tests and chi-square tests were performed to evaluate differences by factor for continuous variables and for categorical variables, respectively,
Significant at alpha=0.05.