The treatment of male breast cancer (MBC) has been extrapolated from female breast cancer (FBC) because of its rarity despite their different clinicopathologic characteristics. We aimed to investigate the distribution of intrinsic subtypes based on immunohistochemistry, their clinical impact, and treatment pattern in clinical practice through a multicenter study in Korea.
We retrospectively analyzed clinical data of 248 MBC patients from 18 institutions across the country from January 1995 to July 2016.
The median age of MBC patients was 63 years (range, 25 to 102 years). Among 148 intrinsic subtype classified patients, 61 (41.2%), 44 (29.7%), 29 (19.5%), and 14 (9.5%) were luminal A, luminal B, human epidermal growth factor receptor 2, and triple-negative breast cancer, respectively. Luminal A subtype showed trends for superior survival compared to other subtypes. Most hormone receptor-positive patients (166 patients, 82.6%) received adjuvant endocrine treatment. Five-year completion of adjuvant endocrine treatment was associated with superior disease-free survival (DFS) in patients classified with an intrinsic subtype (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04 to 0.49; p=0.002) and in all patients (HR, 0.16; 95% CI, 0.05 to 0.54; p=0.003).
Distribution of subtypes of MBC was similar to FBC and luminal type A was most common. Overall survival tended to be improved for luminal A subtype, although there was no statistical significance. Completion of adjuvant endocrine treatment was associated with prolonged DFS in intrinsic subtype classified patients. MBC patients tended to receive less treatment. MBC patients should receive standard treatment according to guidelines as FBC patients.
Male breast cancer (MBC) is an orphan disease that accounts for 1% of all breast cancers [
Although the incidence of MBC is rare, it is on the rise [
In FBC, treatment is individualized according to the intrinsic subtype, and tailored management, such as anti-HER2 agents and immune-checkpoint inhibitors, has improved survival outcomes. However, as previously mentioned, the treatment of MBC patients is not based on unique biological features and extrapolated from clinical trials of FBC. There are growing efforts to gather data and establish the characteristics of biological features, treatment guidelines, and survival outcomes in MBC [
In this study, we conducted a multicenter, retrospective analysis using patients’ baseline demographics and pathologic characteristics, including intrinsic subtype based on immunohistochemical stain, detailed treatment pattern, and clinical outcomes of MBC patients from 18 institutions in Korea during a 21-year period.
This retrospective, multicenter study was conducted by the Breast Cancer Division of the Korean Cancer Study Group (KCSG). From January 1995 to July 2016, the medical records of male patients with histologically confirmed breast cancer were retrospectively reviewed. Two-hundred and forty-eight patients primarily diagnosed as MBC were enrolled, and subtypes were able to be analyzed for 148 patients whose data of Ki-67 was available (
Estrogen receptor (ER) and progesterone receptor (PR) positivity was defined by American Society of Clinical Oncology/College of American Pathologists guideline (ASCO/CAP guideline) [
Disease-free survival (DFS) was defined as the period from the time of primary treatment, such as surgical resection, to the date of disease recurrence or death from any cause. Overall survival (OS) was described as the period between the date of the first pathologic diagnosis and death or last follow-up. Continuous variables are presented as median values, and categorical variables are presented as percentages. Continuous variables were compared using the Mann-Whitney U test, while categorical variables were compared using the chi-square test and Fisher exact test. Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Hazard ratios for DFS and OS were estimated using the Cox proportional hazards model with a 95% confidence interval (CI). Two-sided p-values are presented for all analyses with p < 0.05, considered to be statistically significant. R ver. 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) was used for all statistical analyses.
During the 21-year follow-up, 248 male patients with breast cancer were enrolled in the study. Baseline patient characteristics are described in
The histopathology and intrinsic subtype of enrolled patients were analyzed (
Upfront surgery was performed without neoadjuvant chemotherapy in the majority of patients. Most patients underwent modified radical mastectomy (MRM; 165 patients, 72.1%) as surgical treatment. Anthracycline and taxane-based regimen was administered for patients who received neoadjuvant chemotherapy. Adjuvant chemotherapy was delivered to approximately half of the total surgically resected patients, which is a lower rate than that of FBC patients. Anthracycline-based adjuvant chemotherapy was most commonly administered, and approximately one-third of patients received taxane during adjuvant treatment. Few patients received trastuzumab as adjuvant treatment (
Adjuvant radiation therapy was administered to fewer patients (24% of the 218 operable patients). When analyzed according to the administration of adjuvant radiation therapy, patients with nodal involvement and with higher histologic tumor grade received adjuvant radiation, similar to the adjuvant chemotherapy group. More patients underwent axillary lymph node dissection and neoadjuvant or adjuvant chemotherapy compared with patients who did not receive adjuvant radiation therapy (
Adjuvant endocrine treatment was administered to 166 patients of 200 patients (83%), and approximately 90% of patients received tamoxifen as adjuvant endocrine treatment (
Median OS of the total number of treated patients was 60.7 months (range, 1.2 to 230.4 months) and 5-year OS rate was 95.2% (95% CI, 0.921 to 0.984) (
Cox regression analysis was performed for an in-depth analysis of the relationship between clinicopathological variables and survival outcomes (DFS and OS). Completion of adjuvant endocrine treatment was associated with prolonged DFS and OS in patients with MBC (hazard ratio [HR], 0.15; 95% CI, 0.07 to 0.33; p < 0.001; OS: HR, 0.32; 95% CI, 0.09 to 1.11; p=0.073) (
In 148 patients who were evaluable for intrinsic subtype classification, 5 years of adjuvant endocrine treatment was still associated with superior DFS (HR, 0.22; 95% CI, 0.07 to 0.63; p=0.004). When adjusted for stage, subtype, adjuvant chemotherapy, and radiotherapy, completion of adjuvant endocrine treatment remained to be associated with prolonged DFS in the group of patients that were classified according to the intrinsic subtype (HR, 0.15; 95% CI, 0.04 to 0.49; p=0.002) (
During a median follow-up of 59.6 months, 51 patients (22.2%) experienced disease recurrence. Nineteen patients (7.7%) were diagnosed with
Among the 56 patients who were hormone receptor-positive, 35 (62.5%) received palliative endocrine treatment. Tamoxifen was the most frequently used endocrine treatment in MBC patients as a first-line treatment. Aromatase inhibitors were administered as first-line or above in patients, but few patients received concurrent gonadotropin-releasing hormone (GnRH) agonists during treatment. Although BOLERO-2 [
In this study, we intensively reviewed the medical records of each enrolled patient from multiple tertiary medical centers who were qualified for breast cancer treatment. Based on the data collection over more than 20 years, we analyzed the clinicopathological characteristics, including intrinsic subtype, pattern of treatment during adjuvant and palliative setting, and survival outcome.
The median age of the total patient population was 63 years, similar to previous Korean Central Cancer Registry data and the Western registry data [
Considering that most patients with early-stage MBC are diagnosed as hormone receptor–positive, adjuvant endocrine treatment may have an important role in extending survival. In our study more than 80% of hormone receptor positive patients started adjuvant endocrine treatment but less than half of patients have completed 5 years of treatment. Considering the side effects of adjuvant endocrine treatment, long-term compliance has always been an issue in the treatment of MBC [
In MBC patients, neoadjuvant chemotherapy, adjuvant chemotherapy and adjuvant radiation treatment were not performed as often as in FBC. This result is in agreement with the Korea Central Cancer Registry data [
Excluding MBC patients in various pivotal phase 3 trials has resulted in a relative lack of evidence when establishing treatment guidelines in various countries [
In our analysis, the 5-year OS was estimated to be over 90%, which is superior to previously published literature ranging from 77% to 87% [
The strength of this study is the long-term follow-up data that were collected in multiple institutions, spanning more than 20 years with detailed medical records of enrolled patients, although it was based on retrospective analysis. To the best of our knowledge, this is the first report analyzing the intrinsic subtype based on IHC for the Asian patients with MBC. Intrinsic subtype is originally defined after gene expression profiling, but the classification of intrinsic subtype was based only on IHC performed at each institution without central review. Gene expression profiling was not conducted due to lack of archival tumor tissues and poor quality of long-term stored formalin fixed paraffin embedded tissues. Although investigators have reviewed the medical records of each enrolled patient, pathological characteristics, such as Ki-67 index, were omitted or not analyzed in some patients that were diagnosed in the nineties or the early 2000s. Therefore, approximately half of the patients could not be classified for subtype analysis. Additionally, most patients did not undergo a germline
To conclude, this was the first study analyzing subtypes of Korean MBC patients based on a multicenter study. The luminal A subtype was the most common, and completion of adjuvant endocrine treatment in patients that were classified based on the subtype was associated with prolonged DFS. Completion of adjuvant endocrine treatment was also the most important factor for prolonged DFS and OS in hormone receptor-positive MBC. Known prognostic factors were adjusted during analysis of relationship between prognostic factors and DFS or OS. Although statistically non-significant due to small number of patients, intrinsic subtype showed trend with improved survival for luminal A subtype. The incidence of MBC patients has increased recently, and appropriate treatment is this patient group is warranted. To improve survival of MBC patients, they should receive standard treatment according to guidelines as FBC patients.
Supplementary materials are available at Cancer Research and Treatment website (
This study was approved by the institutional review board of each participating institution. The requirement for informed consent was waived because of the retrospective nature of this study.
Conceived and designed the analysis: Woo IS.
Collected the data: Lee J, Lee KS, Sim SH, Chae H, Sohn J, Kim GM, Lee KH, Kang SH, Jung KH, Jeong JH, Byun JH, Koh SJ, Lee KE, Lim S, Kim HJ, Park HS, Lee GJ, Hong S, Baek SK, Lee SI, Choi MY, Woo IS.
Contributed data or analysis tools: Lee J, Lee KS, Sim SH, Chae H, Sohn J, Kim GM, Lee KH, Kang SH, Jung KH, Jeong JH, Byun JH, Koh SJ, Lee KE, Lim S, Kim HJ, Won HS, Park HS, Lee GJ, Hong S, Baek SK, Lee SI, Choi MY, Woo IS.
Performed the analysis: Lee J.
Wrote the paper: Lee J, Woo IS.
Conflict of interest relevant to this article was not reported.
Flow diagram of enrolled patients. HER2, human epidermal growth factor receptor 2.
Survival outcomes in treated patients: (A) in all treated patients, (B) overall survival according to age, and (C) overall survival according to stage. CI, confidence interval; HR, hazard ratio; mOS, median overall survival; NA, not available; OS, overall survival.
Survival outcomes according to subtypes. (A) Comparison of OS between luminal and non-luminal subtypes. (B) Comparison of OS between luminal A and other subtypes (n=148). CI, confidence interval; HR, hazard ratio; OS, overall survival.
Survival outcomes according to completion of adjuvant endocrine treatment in hormone receptor–positive subgroup. (A) DFS according to completion of adjuvant endocrine treatment. (B) OS according to completion of adjuvant endocrine treatment. CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; NA, not available; OS, overall survival.
Baseline patient characteristics
No. (%) | |
---|---|
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248 |
|
|
Median (range) | 63.0 (25–102) |
≤ 65 | 134 (54.0) |
> 65 | 112 (45.2) |
Not assessed | 2 (0.8) |
|
|
1995–1999 | 17 (6.9) |
2000–2004 | 44 (17.7) |
2005–2009 | 62 (25) |
2010–2014 | 79 (31.9) |
2015–2016 | 46 (18.5) |
|
|
Palpable breast mass | 184 (74.2) |
Nipple discharge | 10 (4.0) |
Nipple retraction | 1 (0.4) |
Breast pain | 7 (2.8) |
Gynecomastia | 3 (1.2) |
Axillary mass | 6 (2.4) |
Chest wall mass | 1 (0.4) |
Bleeding | 3 (1.2) |
Skin ulceration | 3 (1.2) |
Back pain | 3 (1.2) |
Abnormal physical examination | 3 (1.2) |
Not assessed | 24 (9.7) |
|
|
Median (range) | 6.0 (0.2–96) |
|
|
Unilateral, right | 113 (45.6) |
Unilateral, left | 115 (46.4) |
Bilateral | 1 (0.4) |
Not assessed | 19 (7.7) |
|
|
No | 203 (81.9) |
Yes | 12 (4.8) |
Not assessed | 33 (13.3) |
|
|
0 | 81 (32.7) |
1 | 115 (46.4) |
2 | 5 (2.0) |
3 | 2 (0.8) |
Not assessed | 45 (18.1) |
|
|
I | 70 (28.2) |
II | 101 (40.7) |
III | 41 (16.5) |
IV | 19 (7.7) |
Not assessed | 17 (6.9) |
ECOG PS, Eastern Cooperative Oncology Group performance status.
Based on American Joint Committee on Cancer 7th guideline.
Histopathologic characteristics of patient population
No. (%) (n=248) | |
---|---|
|
|
Invasive ductal carcinoma | 192 (77.4) |
Invasive lobular carcinoma | 1 (0.4) |
Mucinous carcinoma | 9 (3.6) |
Papillary carcinoma | 13 (5.2) |
Cribriform carcinoma | 4 (1.6) |
Sarcoma | 4 (1.6) |
Carcinoma | 6 (2.4) |
Other | 5 (2.0) |
Not assessed | 14 (5.6) |
|
|
Grade 1 | 36 (14.5) |
Grade 2 | 102 (41.1) |
Grade 3 | 39 (15.7) |
Not assessed | 71 (28.6) |
|
|
No | 99 (39.9) |
Yes | 72 (29.0) |
Not assessed | 77 (31.0) |
|
|
No | 125 (50.4) |
Yes | 44 (17.7) |
Not assessed | 79 (31.9) |
|
|
No | 119 (48.0) |
Yes | 14 (5.6) |
Not assessed | 115 (46.4) |
|
|
Negative | 18 (7.3) |
Positive | 200 (80.6) |
Not assessed | 30 (12.1) |
|
|
Negative | 40 (16.1) |
Positive | 176 (71.0) |
Not assessed | 32 (12.9) |
|
|
Negative | 184 (74.2) |
Positive | 29 (11.7) |
Not assessed | 35 (14.1) |
|
|
Luminal A | 61 (41.2) |
Luminal B | 44 (29.7) |
HER2 enriched | 29 (19.6) |
TNBC | 14 (9.5) |
|
18.5 (2–80) |
HER2, human epidermal growth factor receptor 2; TNBC, triple-negative breast cancer.
Treatment patterns in operable patients
No. (%) | |
---|---|
|
|
Modified radical mastectomy | 165 (72.1) |
Total mastectomy | 43 (18.9) |
Breast conserving surgery | 11 (4.8) |
Node excision | 2 (0.9) |
Not done | 6 (2.6) |
Not assessed | 1 (0.4) |
|
|
ALND | 135 (61.1) |
SLNB | 53 (24.0) |
Not done | 16 (7.2) |
Not assessed | 17 (7.7) |
|
|
No | 212 (95.9) |
Yes | 9 (4.1) |
AC followed by taxane | 5 (2.3) |
DA | 2 (0.9) |
Others | 2 (0.9) |
|
|
Yes | 108 (48.6) |
AC followed by taxane | 32 (14.5) |
AC or EC | 30 (13.6) |
CMF | 14 (6.3) |
FAC or FEC | 13 (5.9) |
TAC | 4 (1.8) |
AC followed by taxane with trastuzumab | 3 (1.4) |
TC | 2 (0.9) |
AC followed by trastuzumab | 1 (0.5) |
Others | 7 (3.2) |
Not assessed | 2 (0.9) |
Completion of chemotherapy | |
Yes | 86 (38.9) |
No | 15 (6.8) |
Not assessed | 6 (2.7) |
No | 107 (48.2) |
Not assessed | 6 (3.2) |
|
|
Yes | 166 (83.0) |
Tamoxifen | 150 (75.0) |
Toremifen | 9 (4.5) |
Aromatase inhibitor | 2 (1.0) |
Others | 5 (2.5) |
Total duration of treatment, median (range, mo) | 48.5 (1.0–87) |
Completion of treatment | |
Yes | 68 (34.0) |
No | 63 (31.5) |
Ongoing | 23 (11.5) |
Not assessed | 12 (6.0) |
No | 25 (12.5) |
Not assessed | 9 (4.5) |
|
|
No | 157 (71.9) |
Yes | 52 (24.0) |
Not assessed | 9 (4.1) |
AC, adriamycin-cyclophosphamide; ALND, axillary lymph node dissection; CMF, cyclophosphamide-methotrexate-5-fluorouracil; DA, docetaxel-adriamycin; EC, epirubicin-cyclophosphamide; FAC, 5-fluorouracil-adriamycin-cyclophosphamide; FEC, 5-fluorouracil-epirubicin-cyclophosphamide; SLNB, sentinel lymph node biopsy; TAC, docetaxel-adriamycin-cyclophosphamide; TC, docetaxel-cyclophosphamide.
Univariate and multivariate Cox regression analysis for DFS and OS in total patient population
Characteristic | DFS | OS | ||||||
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Univariate analysis | Multivariate analysis | Univariate analysis | Multivariate analysis | |||||
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HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | |
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> 65 vs. ≤ 65 | 0.77 (0.43–1.39) | 0.394 | - | - | 2.42 (1.13–5.16) | 0.023 | 4.91 (1.06–22.76) | 0.042 |
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II vs. I | 3.56 (1.44–8.76) | 0.005 | 1.39 (0.23–8.29) | 0.715 | 2.46 (0.65–9.32) | 0.186 | 1.17 (0.18–7.38) | 0.866 |
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III vs. I | 6.32 (2.48–16.16) | < 0.001 | 2.46 (0.32–18.76) | 0.384 | 4.40 (1.13–17.11) | 0.032 | 1.04 (0.09–11.61) | 0.969 |
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IV vs. I | - | - | - | - | 112.69 (21.15–600.53) | < 0.001 | - | - |
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HER2 vs. hormone receptor (+) | 1.27 (0.28–2.21) | 0.648 | - | - | 1.416 (0.41–4.91) | 0.584 | - | - |
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TNBC vs. hormone receptor (+) | 2.41 (0.10–1.79) | 0.238 | - | - | 1.769 (0.49–6.41) | 0.381 | - | - |
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Yes vs. no | 0.15 (0.07–0.33) | < 0.001 | 0.16 (0.05–0.54) | 0.003 | 0.32 (0.09–1.11) | 0.073 | 0.16 (0.04–0.73) | 0.018 |
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Yes vs. no | 2.69 (1.42–5.10) | 0.002 | 2.42 (0.52–11.29) | 0.262 | 2.15 (0.83–5.61) | 0.116 | - | - |
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Yes vs. no | 3.52 (1.92–6.44) | < 0.001 | 2.09 (0.46–9.52) | 0.337 | 3.02 (1.21–7.52) | 0.018 | 4.33 (0.65–29.16) | 0.131 |
CI, confidence interval; DFS, disease-free survival; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; OS, overall survival; RT, radiation therapy; TNBC, triple-negative breast cancer.
Univariate and multivariate Cox regression analysis for DFS and OS in intrinsic subtype classified patients
Characteristic | DFS | OS | ||||||
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Univariate analysis | Multivariate analysis | Univariate analysis | Multivariate analysis | |||||
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HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | |
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> 65 vs. ≤ 65 | 0.49 (0.19–1.25) | 0.137 | - | - | 3.47 (1.05–11.44) | 0.041 | 2.88 (0.73–11.35) | 0.130 |
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II vs. I | 3.03 (0.84–10.91) | 0.089 | 1.52 (0.26–8.97) | 0.643 | 3.30 (0.37–29.65) | 0.286 | 4.91 (0.51–47.54) | 0.169 |
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III vs. I | 6.54 (1.72–24.85) | 0.005 | 2.67 (0.36–19.64) | 0.334 | 7.20 (0.80–64.80) | 0.078 | 7.04 (0.74–66.05) | 0.088 |
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IV vs. I | - | - | - | - | 57.09 (4.22–771.95) | 0.002 | 66.23 (4.28–1,023.5) | 0.003 |
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Non-luminal vs. luminal | 0.77 (0.29–1.98) | 0.583 | 2.05 (0.53–7.90) | 0.295 | 1.52 (0.49–4.73) | 0.465 | 2.02 (0.54–7.52) | 0.294 |
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LumB vs. LumA | 2.69 (0.94–7.72) | 0.065 | - | - | 2.33 (0.49–11.07) | 0.288 | - | - |
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HER2(+) vs. LumA | 1.40 (0.43–4.57) | 0.528 | - | - | 1.72 (0.38–7.71) | 0.481 | - | - |
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TNBC vs. LumA | 1.67 (0.12–2.84) | 0.516 | - | - | 2.36 (0.49–11.56) | 0.283 | - | - |
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Yes vs. no | 0.22 (0.07–0.63) | 0.004 | 0.15 (0.04–0.49) | 0.002 | 0.34 (0.06–2.09) | 0.244 | - | - |
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Yes vs. no | 5.74 (1.69–19.45) | 0.004 | 2.44 (0.53–11.24) | 0.254 | 1.24 (0.36–4.29) | 0.729 | - | - |
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Yes vs. no | 3.43 (1.44–8.14) | 0.005 | 2.29 (0.51–10.28) | 0.278 | 1.75 (0.48–6.38) | 0.394 | - | - |
CI, confidence interval; DFS, disease-free survival; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; LumA, luminal A; LumB, luminal B; OS, overall survival; RT, radiation therapy; TNBC, triple-negative breast cancer.