Comparison of Clinicopathologic Features and Outcomes Between Synchronous and Metachronous Bilateral Breast Cancer

Jun Hyung Kim; Tae Wan Won

doi:10.14449/jbd.2023.11.1.21

Journal of Breast Disease > Volume 11(1); 2023 > Article

Kim and Won: Comparison of Clinicopathologic Features and Outcomes Between Synchronous and Metachronous Bilateral Breast Cancer

Original Article

Journal of Breast Disease 2023; 11(1): 21-29.

Published online: June 30, 2023

DOI: https://doi.org/10.14449/jbd.2023.11.1.21

Comparison of Clinicopathologic Features and Outcomes Between Synchronous and Metachronous Bilateral Breast Cancer

Jun Hyung Kim, M.D., Ph.D., Tae Wan Won, M.D., Ph.D.

Department of Surgery, Wonkwang University School of Medicine, Iksan, Korea

Correspondence: Tae Wan Won, M.D., Ph.D. Department of Surgery, Wonkwang University School of Medicine, 859 Muwangro, Iksan 54538, Korea Tel: +82-63-859-1490, Fax: +82-63-855-2386, E-mail: furufuru79@naver.com

This paper was supported by Wonkwang University in 2022.

Received September 26, 2022 Revised October 31, 2022 Accepted November 24, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

Bilateral breast cancer (BBC) can be divided into two concurrent lesions, depending on the time of occurrence of primary cancer and secondary tumors after treatment of the primary cancer. This study aimed to compare the clinicopathological characteristics and results of synchronous BBC (SBBC) and metachronous BBC (MBBC).

Methods

Data of patients diagnosed with breast cancer at Wonkwang university Hospital between October 1991 and October 2021 were retrospectively reviewed. Data of 3,259 patients who were diagnosed with malignant neoplasm of the right or left breast were reviewed. The tumor was defined as SBBC when another cancer was identified as BBC simultaneously or within six months after the primary breast cancer, and as MBBC when another cancer was identified after six months. Among patients with BBC, 31 had SBBC and 32 had MBBC.

Results

In SBBC patients, the median age was 59.9 years, and the condition was diagnosed 3.3 years later compared with MBBC. The primary and secondary tumors of SBBC had lower disease stage, even when diagnosed late. Except for tumor, node, and metastasis stage, MBBC showed more invasive ductal carcinoma, while SBBC showed relatively more ductal carcinoma in situ in both primary and secondary tumors compared with MBBC. In addition, SBBC showed lower hormone receptor positivity rates and Ki-67 levels compared with MBBC. MBBC patients showed a higher survival rate compared with SBBC patients. MBBC is associated with higher overall survival rate compared with SBBC, and its prognosis is not worse compared with that of unilateral breast cancer. In the case of secondary tumor that develops in the contralateral breast without evidence of metastasis, the survival rate is similar to that of unilateral breast cancer, while the treatment is similar to that of primary tumor.

Conclusion

As those with SBBC have a worse survival, these patients will require more medical attention; meanwhile, MBBC requires an active treatment approach that is equivalent to that for unilateral breast cancer.

Keywords: Bilateral breast cancer; Metachronous bilateral breast cancer; Synchronous bilateral breast

INTRODUCTION

Breast cancer is the most common cancer among Korean women and the second most common cancer worldwide [1]. In particular, the incidence of breast cancer is 3–4 times higher than that of primary breast tumors. Moreover, the incidence of secondary breast cancer in women is increasing owing to the increased incidence of breast cancer, breast cancer survival, and life expectancy. Accordingly, awareness of the importance of bilateral breast cancer (BBC) has also increased.

Primary breast cancer treatment is important owing to its effect on patient’s survival. BBC or contralateral breast cancer is the most common type after primary cancer. BBC accounts for nearly 1%–12% of all breast malignancies. It is classified as synchronous BBC (SBBC), in which two simultaneous lesions occur, and metachronous BBC (MBBC), in which neoplastic cancer develops on the contralateral side after treatment of primary cancer or with recurrence and metastasis. Many studies have reported diverse criteria for diagnosing BBC.

This is because each study divided the criteria for diagnosing secondary breast cancer based on the period of onset: 3,6,9, and 12 months.

In this study, a tumor was defined as SBBC when another cancer was identified simultaneously or within six months after the primary breast cancer, and as MBBC when another cancer was identified after six months. Few studies have investigated the risk factors for BBC. The breast cancer risk factors, such as familial history, mutant genes, breast cancer (BRCA)- 1 and 2 genes, and an initial diagnosis at a young age (<40 years), were also associated with the development of SBBC and MBBC. In the 1980s, some studies reported a particular histological lobular type of primary breast cancer in BBC. However, recent studies have found no difference in the histological type of primary cancer [2-7].

The distribution of the breast cancer subtypes varies according to ethnicity. The features of breast cancer subtypes should be identified to optimize the treatment of patients with BBC. This study aimed to evaluate the characteristics of breast cancer subtypes in Korean patients with SBBC or MBBC and to suggest an optimal breast cancer treatment method.

METHODS

This study was approved by the Institutional Review Board of Wonkwang University Hospital (IRB No. 2021-10-016-002). Patients diagnosed with breast cancer between October 1991 and October 2021 were included in the study.

A total of 3,259 patients were diagnosed with breast cancer in this hospital, of whom 63 developed cancer in the right and left breasts. Of them, 31 patients had SBBC, while 32 patients had MBBC. Simultaneous surgery was defined as surgery for cancer in both breasts or surgery for cancer in the contralateral breast within six months after diagnosis; patients who underwent this type of surgery were classified as having concurrent BBC (SBBC). Cancer that developed on the other breast six months after performing breast cancer surgery was defined as MBBC. In both cases, it was assumed that there was no evidence of distant metastasis from the primary tumor.

The expression patterns of biomarkers, including estrogen receptor (ER), progesterone receptor (PR), C-erbB-2, and Ki-67 in 38 patients with BBC, and the demographic characteristics were evaluated.

Breast cancer staging was performed according to the American Joint Committee of Cancer, 7th Edition.

To compare the prognosis of SBBC and MBBC, the disease-free and overall survival rates were compared between the groups by examining the period of recurrence and death of each patient. The SPSS software for Windows version 25 (IBM Corp., Armonk, USA) was used to perform all statistical analyses, the Kaplan-Meier method was used for survival rate analysis, and the log-rank test was used to calculate the differences in survival rates. A p-value of less than 0.05 was considered significant.

RESULTS

Demographic data

Of the 3,259 total breast cancer patients who were treated at Wonkwang University Hospital, 63 (1.9%) had SBBC or MBBC. Among them, 31 had SBBC and 32 had MBBC. The median ages of onset were 59.9 years for SBBC and 56.6 years for MBBC. Among those with simultaneous breast cancer, three patients were aged < 50 years, while 28 patients were aged >50 years. The p-value at the initial diagnosis age was 0.26, which was not significant; however, this may be due to the small sample size.

For MBBC, nine patients were aged < 50 years, while 23 patients were aged >50 years. In MBBC, the average period from the onset of the primary cancer to the onset of the second breast cancer was 76.6 months. The follow-up period was determined from the date of outpatient examination at the hospital until the date of death or transfer to another hospital. The median follow-up times were 2.6 years for both SBBC and MBBC patients and 6.4 years for MBBC patients alone. The follow-up time of SBBC patients is shorter as magnetic resonance imaging (MRI) examinations have been covered by the national insurance in Korea since 2019, thus allowing the performance of repeat scans. As MBBC patients may also develop smaller lesions, they may benefit from the expanded insurance coverage for repeat MRI examinations.

This study utilized the medical records to review the patients’ previous history of other malignancies, family history of cancer, and menopausal status. Of the patients with SBBC, 15 were in premenopausal stage and 15 were in postmenopausal stage, except for one patient who had male breast cancer. Fifteen MBBC patients were in the menopausal stage, while seventeen patients were in the post-menopausal stage. Seven patients with SBBC and thirteen patients with MBBC had a family history of cancer. One patient in each group was previously diagnosed with cancer.

The p-value for menopausal status, family history of cancer, and previous cancer was > 0.05, thus indicating no significance (Table 1).

Pathological findings

The results of pathological test of breast tumors obtained from each patient were collected. The collected data included pathological tumor, nodal status, and metastatic status(Table 2).

Invasive ductal carcinoma (IDC) is the most common (25 cases) subtype of SBBC. Five individuals had ductal carcinoma in situ (DCIS), while one had invasive lobular carcinoma (ILC). The second most common subtype of SBBC was DCIS (16 cases), followed by IDC (15 cases). The DCIS ratio of primary tumor increased compared with that of secondary tumor. In the MBBC group, 27 patients had IDC, while five had DCIS. Only six patients with secondary tumor had DCIS. The histological similarities between SBBC and MBBC were higher. A total of 18 patients had concordant with primary and secondary tumors of SBBC. Moreover, 27 patients showed characteristics concordant with those of primary and secondary tumors of MBBC (Table 3).

In both SBBC and MBBC groups, the primary cancer showed a low tumor grade, while the secondary cancer showed a high tumor grade (Table 2).

Tumor, node, metastasis (TNM) staging

For SBBC, only 10 patients (29%) had a similar TNM staging for both primary and secondary tumors. Of the 32 MBBC patients, only 11 (34%) had the same TNM staging for both primary and secondary tumors. One patient with stage IV SBBC was excluded from this study. When the primary cancer stages of SBBC and MBBC were compared, 4 (13%), 14 (45%), 10 (32%), 2 (6%), and 1 (3%) SBBC patients had stages 0, I, II, III, and IV, respectively, while 4 (13%), 11 (34%), 7 (22%), and 10 (31%) MBBC patients had stages I, II, III, and IV, respectively. The TNM stages for secondary breast cancer are shown in Table 2. The secondary cancer had lower TNM stages compared with that of the primary cancer. The primary cancer had relatively larger tumor size and higher risk of lymph node metastasis compared with the secondary cancer.

Biological markers

The pathological findings and levels of biological markers (ER, PR, and human epidermal growth factor receptor-2 [HER2]) were investigated.

ER or PR positivity was defined as an Allred score of 3–8 on immunohistochemistry (IHC). Based on the IHC status, breast cancers were divided into the following subtypes: (1) ER+ and/or PR+, HER2- (luminal A); (2) ER+ and/or PR+, HER2+ (luminal B HER2+); (3) ER-, PR-, and HER2+ (HER2 enriched); and (4) ER-, PR-, and HER2- (triple negative, TN) (Table 2). Tumors with ER, PR, and HER2 overexpression were classified as luminal B type according to the Allred score. ER-negative and PR-positive tumors were classified as luminal A and B types according to the HER2 status. Subtype concordance was defined when two tumors from the same patient were classified into the same subtype. In cases of SBBC, the biological markers were identical when divided by luminal type in 31 patients who underwent the ER, PR, and c-erbB-2 tests.

When the hormone receptors in the SBBC group were evaluated, 29 patients were identified to have a luminal type, while two had a triple-negative cancer. In the MBBC group, no difference was observed between the primary and secondary cancers. Among those with primary cancer, 21 patients had a luminal type, six patients had an HER2-positive type, and five patients had a triple-negative type. Among those with secondary cancer, 22 patients had a luminal type, six patients had an HER2-positive type, and four patients had a triple-negative type (Table 2).

With regard to the biomarkers, the ER and PR expression levels were identically concordant in 17 and 16 SBBC patients, respectively. The expression levels of C-erbB-2 was identical in 17 patients. The MBBC showed a similar pattern. In terms of Ki-67 levels, the primary and secondary tumors of SBBC showed a similar pattern. In the MBBC group, the Ki-67 expression levels were >14% in those with primary and secondary tumors (Table 2). The cutoff value for Ki-67 was set at 14% to increase the patients’ probability of receiving more aggressive treatment [8].

Treatment

In accordance with the National Comprehensive Cancer Network guidelines, the patients underwent curative surgery and adjuvant or neoadjuvant therapy. Either breast-conserving surgery or mastectomy was performed based on the surgeon’s discretion.

For axillary lymph nodes, the treatment included sentinel lymph node biopsy (SLNBx) alone, SLNBx followed by axillary lymph node dissection (ALND), or ALND alone. Postmastectomy radiotherapy was administered in patients with a tumor size of >5 cm or with > 4 metastatic axillary lymph nodes. Chemotherapy was continued, but only the period with presence or absence of treatment was recorded in the table. The different chemotherapy regimens used for adjuvant or neo-adjuvant treatment were as follows: doxorubicin and cyclophosphamide (AC); AC followed by paclitaxel or docetaxel, cyclophosphamide, methotrexate, and 5-fluorouracil; 5-fluorouracil, adriamycin, and cyclophosphamide; and 5-fluorouracil, epirubicin, and cyclophosphamide. Adjuvant endocrine therapy was indicated in patients with hormone receptor-positive breast cancer. These patients were divided into four groups based on the agents used for endocrine therapy (tamoxifen alone group, tamoxifen and GnRH agonist combination group, aromatase inhibitor alone group, or tamoxifen combined with aromatase inhibitor group). Patients with HER2-overexpressing breast cancer received anti-HER2 agents. Table 4 presents the patients’ treatment charts.

Prognosis

The follow-up periods were 31 months for SBBC and 77 months for MBBC (p = 0.05), which was of ambiguous significance. The SBBC and MBBC groups had the same proportion of pre- and post-menopausal individuals, with a p-value of greater than 0.05, thus indicating that it had no significant influence on the incidence of SBBC and MBBC. In the SBBC group, recurrence occurred in only one patient, who showed multiple metastases to the sternum, liver, and lungs. This patient eventually died. In the MBBC group, four patients showed metastasis, of whom two had tumor metastasis to the chest wall and two had multiple bone metastases.

Various studies have compared the prognosis of one-sided breast cancer with that of BBC; however, BBC had a higher recurrence rate compared with one-sided breast cancer [9]. When the survival rates were compared, MBBC had a higher survival rate compared with SBBC, as demonstrated in previous studies. In this study, SBBC initially had a high survival rate, but the survival rate of MBBC increased over time (Figure 1).

DISCUSSION

This study aimed to present the management and treatment of BBC based on the characteristics of SBBC and MBBC. Simultaneous surgery was defined as surgery for cancer in both breasts or surgery for cancer in the contralateral breast performed within six months after diagnosis. A cancer detected simultaneously in both breasts in the same patient was defined as concurrent BBC or SBBC. A cancer detected in the other breast six months after breast cancer surgery was classified as MBBC. The incidence of BBC varies depending on the research method, composition of the target group, and the follow-up period. However, the incidence of BBC is approximately 3.7%. The incidence of SBBC is 0.1%–2%, while that of MBBC is 1%–12% [10]. In this study, the incidence of BBC was 2.0% (SBBC: 1.0% and MBBC: 1.0%). When classifying SBBC and MBBC, the period from the onset of cancer in a unilateral breast to the onset of cancer in the contralateral breast is broadly defined as six months to five years, although the period of onset differs between studies [7].

In this study, SBBC and MBBC were classified based on an interval of six months, and the average period from the onset of the primary cancer to the onset of the second cancer was 72 months (3–301 months). A total of 63 patients were diagnosed with BBC, excluding those who were considered to have BBC due to recurrence.

In BBC, contralateral cancer may develop in the contralateral breast itself or may metastasize to the contralateral breast via the lymphatic system or through the bloodstream. Contralateral breast cancer was initially described as a second primary tumor in 1921. The risk of developing a second primary contralateral breast cancer in women diagnosed with breast cancer is higher than the risk of developing a primary breast cancer in the general population [11].

Generally, the risk factors for BBC are a familial history of breast cancer, multiple lesions, and a diagnosis of intraepidermal cancer at a young age. Some studies have reported the associations between BRCA 1 and BRCA 2 genes. Patients diagnosed with breast cancer in the 1990s and the early 2000s, before genetic testing became common due to increased awareness of hereditary breast cancer, were also included in this study. Genetic testing was not performed in patients with BBC [12,13]. In MBBC, a family history was the primary risk factor. In SBBC, the histological type of lobular epithelial carcinoma, absence of axillary lymph node metastasis, and history of estrogen use were the primary risk factors.

The average age of onset for SBBC was 59.9 years, while that for MBBC was 56.6 years. Nine patients with MBBC developed primary cancer before the age of 50 years. The average period of onset from the primary cancer to the second cancer was 76.6 months. This period was shorter compared with the 60.2 months in those aged < 50 years, but the onset period for those aged >50 years was longer.

According to histological classification, 18 of 31 SBBC patients showed the same findings on the histological examination. Five patients had DCIS, 25 patients had IDC, and one patient had ILC. One patient with a terminal-stage breast cancer was not tested. In the MBBC group, 27 patients had IDC primary cancer and five had DCIS primary cancer. In addition, IDC was the most common subtype, which was detected in 26 patients with secondary cancer. The other six patients had DCIS. In the MBBC group, secondary cancer developed at an earlier stage compared with primary cancer in 15 of 32 patients. The same stage was detected in 10 patients, possibly due to the periodic performance of mammographic and ultrasonographic examinations in breast cancer patients.

With regard to the biological markers, HER2 was overexpressed in approximately 50% of patients with primary and secondary tumors of SBBC and MBBC. However, this finding was not significant (Table 4).

Hormone receptor expression differed between the SBBC and MBBC patients. The ER and PR expression rates were 94% (29/31) in SBBC and 66% in MBBC (21/32). The low levels of hormone receptors in MBBC were presumed to be related to the effect of tamoxifen administered as systemic adjuvant therapy after surgery for patients with hormone receptor-positive cancer; however, additional research is needed to confirm this finding. Other studies have shown consistent results for SBBC, ER, PR, and HER2. For the MBBC group, no significant difference was observed between patients with secondary cancer and those with primary cancer [14-16]. To clarify whether hormone receptor negativity is a risk factor for breast cancer, Sandberg et al. [17] performed a population-based cohort study; this study reported that patients with ER-negative primary cancer had an increased risk of developing ER-negative contralateral breast cancer.

This study has some limitations. When SBBC and MBBC were compared, no significant differences were observed in the age and menopausal status, but follow-up time showed significant results. In addition, statistical testing is difficult to perform owing to the low incidence of SBBC and MBBC. The number of MBBC patient may have been underestimated.

The prevalence of MBBC has been reported to be 1%–12% in previous studies [9]. In a recent study analyzing the National Cancer Institute’s Surveillance, Epidemiology, and End Results database, the 10- year cumulative incidence of MBBC was 4.6% [18,19]. This study found that the incidence of MBBC was 0.74% in the study cohort. Compared with other studies, the prevalence of MBBC in our study was lower. Unlike the data used in previous population-based studies, the patients’ data in our study were obtained from a single hospital database.

In another study, a comparison of survival rates for unilateral breast cancer and BBC showed that patients with BBC have high risk of distant metastasis, with 5-year and 10-year survival rates of 82.1% and 41%, respectively. Meanwhile, unilateral breast cancer had 5-year and 10-year survival rates of 91.4% and 84%, respectively [3].

When the survival rates of unilateral and BBCs were compared, according to Jobsen et al. [20], distant metastasis was more common in patients with BBC; the 5-year and 10-year survival rates were 82.1% and 41% in BBC and 91.4% and 84% in unilateral breast cancer, respectively. Some studies indicated that SBBC is associated with a worse prognosis [21-24], while others stated that SBBC has a similar or even better prognosis compared with MBBC [25,26].

However, in this study, a comparison of SBBC and MBBC revealed that the mortality and recurrence rates of MBBC were lower than those of SBBC, and the prognosis of MBBC was better than that of general unilateral breast cancer. Patients with MBBC had a higher survival rate compared with those with SBBC. This finding suggests that MBBC has a higher disease-free survival from the onset of the primary cancer until the onset of the second cancer, which increases the overall survival rate.

Therefore, in the case of secondary cancer that develops without local or regional recurrence or distant metastasis after the onset of primary cancer, the survival rate will be similar to that of unilateral breast cancer and the treatment is similar to that of primary cancer. In the case of SBBC, the follow-up time is short; therefore, the patients’ data may not be accurate compared with those of MBBC patients. The fact that the incidence of SBBC increased compared with that of the MBBC after MRI augmentation may indicate a less accurate survival rate or prognosis of SBBC. In addition, several patients at risk of developing MBBC were lost to follow-up, thereby lowering its incidence in this study.

The expression rate of hormone receptors was lower in the MBBC group compared with that in the SBBC group, which was likely due to the effect of tamoxifen treatment in those with primary cancer. No other differences were observed in the HER2 expression and histological grade between SBBC and MBBC. This study indicated that hormone positivity can affect the breast cancer prognosis and TNM staging. Hormone therapy is important in the treatment of breast cancer. MBBC showed a higher overall survival rate compared with SBBC, and its prognosis was not worse compared with that of unilateral breast cancer.

For cases of second breast cancer that developed in the contralateral breast without evidence of metastasis after breast cancer onset, the survival rate and treatment are similar to those of unilateral breast cancer.

Because SBBC has a worse prognosis compared with MBBC, these patients require more medical attention. The disease-free survival and overall survival rates were higher in MBBC compared with that in SBBC. Therefore, in the case of MBBC without evidence of recurrence or metastasis after the onset of breast cancer, the survival rate is similar to that of unilateral breast cancer with the same treatment as the primary cancer. However, because survival rates demonstrate a worse prognosis in SBBC, these patients require more medical attention.

MBBC requires an active treatment approach that is equivalent to the unilateral breast cancer treatment.

CONFLICT OF INTEREST

The authors declare that they have no competing interests.

Figure 1.

Overall survival rate of synchronous and metachronous bilateral breast cancer. The SBBC has a high survival rate at first, but after eight years, MBBC has a higher survival rate. SBBC = synchronous bilateral breast cancer; MBBC = metachronous bilateral breast cancer.

Table 1.

Patient demographics of synchronous and metachronous bilateral breast cancer

Characteristic	SBBC (n=31)	MBBC (n = 32)	Total (n = 63)	p-value
Characteristic	No. (%)	No. (%)	No. (%)	p-value
Initial diagnosis age (yr)	59.9 (46−86)	56.6 (31−81)	58.2 (31−86)	0.26
Age at diagnosis of primary cancer (yr)
< 50	3 (9.6)	9 (29.0)	12 (19.0)
≥ 50	28 (90.4)	23 (71.0)	51 (81.0)
Follow-up time (yr)				0.05
	2.6 (0.2−12.6)	6.4 (0.5−35)	6.0 (0.2−35)
Menopausal status				0.57
Pre	15 (48.4)	15 (46.9)	30 (47.6)
Post	15 (48.4)	17 (53.1)	32 (50.8)
Non-menopause	1 (male), (3.2)	0	1 (1.6)
Familial history of cancer				0.12
Yes	7 (22.6)	13 (40.6)	20 (31.7)
No	24 (77.4)	19 (59.4)	43 (68.3)
Previous cancer				0.74
Yes	1 (3.2)	1 (3.1)	2 (3.2)
No	30 (96.8)	31 (96.9)	61 (96.8)

Values are presented as the median (range) or number (%).

SBBC=synchronous bilateral breast cancer; MBBC=metachronous bilateral breast cancer.

Table 2.

TNM stage and histological patterns of synchronous and metachronous bilateral breast cancer

Characteristic		SBBC (n=31)		MBBC (n=32)		Total (n = 63)
		No. (%)		No. (%)		No. (%)
		Primary	Second	Primary	Second	Primary	Second
Pt. overall stage at diagnosis
	0	4 (12.9)	15 (48.4)	4 (12.5)	7 (21.9)	8 (12.7)	22 (34.9)
	1	14 (45.2)	11 (35.5)	11 (34.3)	17 (53.1)	25 (39.7)	28 (44.4)
	2	10 (32.2)	3 (9.7)	7 (21.9)	5 (15.6)	17 (27.0)	8 (12.7)
	3	2 (6.5)	1 (3.2)	10 (31.3)	3 (9.4)	12 (19.0)	4 (6.3)
	4	1 (3.2)	1 (3.2)	0	0	1 (1.6)	1 (1.6)
Tumor stage
	Tis	4 (12.9)	15 (48.4)	4 (12.5)	6 (18.8)	8 (12.7)	21 (33.3)
	T1	17 (54.8)	12 (38.7)	13 (40.6)	20 (62.5)	30 (47.6)	32 (50.8)
	T2	8 (25.8)	4 (12.9)	8 (25.0)	6 (18.8)	16 (25.4)	10 (15.9)
	T3	0	0	5 (15.6)	0	5 (7.9)	0
	T4	2 (6.5)	0	2 (6.3)	0	4 (6.3)	0
Tumor grade
	Low	9 (29.0)	7 (22.6)	8 (25.0)	9 (28.1)	17 (27.0)	16 (25.4)
	Intermediate	18 (58.0)	15 (48.4)	8 (25.0)	9 (28.1)	26 (41.3)	24 (38.1)
	High	2 (6.5)	5 (16.1)	11 (34.3)	12 (37.5)	13 (20.6)	17 (27.0)
	Unknown	2 (6.5)	4 (12.9)	5 (15.6)	2 (6.3)	7 (11.1)	6 (9.5)
Nodal status
	N0	23 (74.2)	26 (83.9)	19 (59.3)	25 (78.0)	42 (66.7)	51 (81.0)
	N1	6 (19.4)	4 (12.9)	7 (21.9)	3 (9.4)	13 (20.6)	7 (11.1)
	N2	2 (6.5)	0	3 (9.4)	2 (6.3)	5 (7.9)	2 (3.1)
	N3	0	1 (3.2)	3 (9.4)	2 (6.3)	3 (4.8)	3 (4.8)
Metastatic status
	M0	30 (96.8)	31 (100)	32 (100)	31 (96.9)	62 (98.4)	62 (98.4)
	M1	1 (3.2)	0	0	1 (3.1)	1 (1.6)	1 (1.6)
	DCIS	5 (16.1)	16 (51.6)	5 (15.6)	6 (18.8)	10 (15.9)	22 (34.9)
	IDC	25 (80.6)	15 (48.4)	27 (84.4)	26 (81.2)	52 (82.5)	41 (65.1)
	ILC	1 (3.2)	0	0	0	1 (1.6)	0
	Other	0	0	0	0	0	0
Hormone receptor status
	ER and/or PR+	29 (93.5)	29 (93.5)	21 (65.6)	22 (68.7)	50 (79.4)	51 (81.0)
	HER2+	0	0	6 (18.8)	6 (18.8)	6 (9.5)	6 (9.5)
	ER-PR-HER2-	2 (6.5)	2 (6.5)	5 (15.6)	4 (12.5)	7 (11.1)	6 (9.5)
Ki-67
	< 14%	16 (51.6)	18 (58.1)	10 (31.3)	5 (15.6)	26 (41.3)	23 (36.5)
	≥ 14%	15 (48.4)	13 (41.9)	22 (68.7)	27 (84.4)	37 (58.7)	40 (63.5)

Pt.=patient; TNM=tumor, node, metastasis; SBBC=synchronous bilateral breast cancer; MBBC=metachronous bilateral breast cancer; ER=estrogen receptor; PR=progesterone receptor; HER2=human epidermal growth factor receptor-2; DCIS=Ductal Carcinoma in situ; IDC=Invasive ductal carcinoma; ILC=Invasive lobular carcinoma.

Table 3.

Pathologic similarities of synchronous and metachronous breast cancer

Pathologic factor	SBBC (n = 31)	MBBC (n = 32)
Pathologic factor	No. (%)	No. (%)
Histological type
Concordant	18 (58.1)	27 (84.4)
Discordant	12 (38.7)	5 (15.6)
Unknown	1 (Stage 4), (3.2)	0
Histological grade
Concordant	21 (67.7)	15 (46.9)
Discordant	6 (19.4)	11 (34.3)
Unknown	4 (12.9)	6 (18.8)
Estrogen receptor
Concordant	17 (54.8)	17 (53.1)
Discordant	14 (45.2)	15 (46.9)
Progesterone receptor
Concordant	16 (51.6)	18 (56.3)
Discordant	15 (48.4)	14 (43.7)
HER2
Concordant	17 (54.8)	16 (50.0)
Discordant	14 (45.2)	16 (50.0)

SBBC=synchronous bilateral breast cancer; MBBC=metachronous bilateral breast cancer; HER2=human epidermal growth factor receptor-2.

Table 4.

Treatment of synchronous and metachronous bilateral breast cancer

Treatment	SBBC (n = 31)	MBBC (n = 32)	p-value
Treatment	No. (%)	No. (%)	p-value
Mastectomy			0.82
Total	11/9^*	13/10^*
Partial	19/21^*	18/20^*
None	1/1^*	1/2^*
Chemotherapy			0.17
None	17 (54.8)	12 (37.5)
Use	14 (45.2)	20 (62.5)
Radiotherapy			0.14
None	11 (35.5)	6 (18.8)
Use	20 (64.5)	26 (81.2)
Endocrine therapy			0.25
None	3 (9.7)	6 (18.8)
Tamoxifen alone	10 (32.3)	12 (37.5)
Tamoxifen + AI	5 (16.0)	9 (28.1)
Tamoxifen + GnRH	3 (9.7)	3 (9.4)
AI alone	10 (32.3)	2 (6.3)
Anti-HER2 agent			0.63
None	27 (87.1)	28 (87.5)
Use	4 (12.9)	4 (12.5)

SBBC=synchronous bilateral breast cancer; MBBC=metachronous bilateral breast cancer; AI=aromatase inhibitor; GnRH=gonadotropin-releasing hormone; HER2=human epidermal growth factor receptor-2.

^* Primary/Second.

REFERENCES

1. Korea Central Cancer Registry; National Cancer Center. Annual report of cancer statistics in Korea in 2018. Seoul: Ministry of Health and Welfare; 2020.

2. Dixon JM, Anderson TJ, Page DL, Lee D, Duffy SW, Stewart HJ. Infiltrating lobular carcinoma of the breast: an evaluation of the incidence and consequence of bilateral disease. Br J Surg 1983;70:513-6.

3. Fisher ER, Fisher B, Sass R, Wickerham L. Pathologic findings from the national surgical adjuvant breast project: XI. Bilateral breast cancer. Cancer 54:3002-11.

4. Hislop TG, Elwood JM, Coldman AJ, Spinelli JJ, Worth AJ, Ellison LG. Second primary cancers of the breast: incidence and risk factors. Br J Cancer 1984;49:79-85.

5. Horn PL, Thompson WD. Risk of contralateral breast cancer. Associations with histologic, clinical, and therapeutic factors. Cancer 1988;62:412-24.

6. Karakas Y, Kertmen N, Lacin S, Aslan A, Demir M, Ates O, et al. Comparison of prognosis and clinical features between synchronous bilateral and unilateral breast cancers. J BUON 2017;22:623-7.

7. Shi YX, Xia Q, Peng RJ, Yuan ZY, Wang SS, An X, et al. Comparison of clinicopathological characteristics and prognoses between bilateral and unilateral breast cancer. J Cancer Res Clin Oncol 2012;138:705-14.

8. Soliman NA, Yussif SM. Ki-67 as a prognostic marker according to breast cancer molecular subtype. Cancer Biol Med 2016;13:496-504.

9. Lee CH, Lee JE, Lee JH, Ahn TS, Son MW, Han SW, et al. Clinical characteristics of metachronous contralateral breast cancer following diagnosis interval. Korean J Clin Oncol 2015;11:43-50.

10. Bland KI, Copeland EM, Klimberg VS, Gradishar WJ. Bilateral breast cancer. In: Barrio AV, Cody III HS, editors. The breast: comprehensive management of benign and malignant diseases. 5th ed. Amsterdam: Elsevier; 2018. p. 967-73.e2.

11. Kilgore AR. The incidence of cancer in the second breast: after radical removal of one breast for cancer. J Am Med Assoc 1921;77:454-7.

12. Bernstein JL, Thompson WD, Risch N, Holdford TR. Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer. Am J Epidemiol 1992;136:925-36.

13. Rhiem K, Engel C, Graeser M, Zachariae S, Kast K, Kiechle M, et al. The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study. Breast Cancer Res 2012;14:R156.

14. Jeon MH, Kim BS, Kang SH, Lee DS, Lee NH, Lee SJ, et al. Clinical review of bilateral breast cancer. J Breast Cancer 2005;8:128-33.

15. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010;28:2784-95.

16. Wolff AC, Hammond ME, Schwartz JN, Hagerty KA, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007;25:118-45.

17. Sandberg ME, Hall P, Hartman M, Johansson ALV, Eloranta S, Ploner A, et al. Estrogen receptor status in relation to risk of contralateral breast cancer—A population-based cohort study. PLoS One 2012;7:e46535.

18. Abo-Madyan Y, Aziz MH, Aly MM, Schneider F, Sperk E, Clausen S, et al. Second cancer risk after 3D-CRT, IMRT and VMAT for breast cancer. Radiother Oncol 2014;110:471-6.

19. Mezencev R, Svajdler Jr. Hormone receptor status of contralateral breast cancers: analysis of data from the US SEER population-based registries. Breast Cancer 2017;24:400-10.

20. Jobsen JJ, Cander Palen, Meerwaldt JH. Synchronous bilateral breast cancer: prognostic value and incidence. Breast 2003;12:83-8.

21. Jobsen JJ, van der, Ong F, Riemersma S, Struikmans H. Bilateral breast cancer, synchronous and metachronous; differences and outcome. Breast Cancer Res Treat 2015;153:277-83.

22. Kheirelseid EA, Jumustafa H, Miller N, Curran C, Sweeney K, Malone C, et al. Bilateral breast cancer: analysis of incidence, outcome, survival and disease characteristics. Breast Cancer Res Treat 2011;126:131-40.

23. Holm M, Tjonneland A, Balslev E, Kroman N. Prognosis of synchronous bilateral breast cancer: a review and meta-analysis of observational studies. Breast Cancer Res Treat 2014;146:461-75.

24. Vichapat V, Garmo H, Holmqvist M, Liljegren G, Wa¨rnberg F, Lambe M, et al. Tumor stage affects risk and prognosis of contralateral breast cancer: results from a large Swedish-population-based study. J Clin Oncol 2012;30:3478-85.

25. Beckmann KR, Buckingham J, Craft P, Dahlstrom JE, Zhang Y, Roder D, et al. Clinical characteristics and outcomes of bilateral breast cancer in an Australian cohort. Breast 2011;20:158-64.

26. Shen K, Yao L, Wei J, Luo Z, Yu W, Zhai H, et al. Worse characteristics can predict survival effectively in bilateral primary breast cancer: a competing risk nomogram using the SEER database. Cancer Med 2019;8:7890-902.