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Characterization and prognosis of estrogen receptor-positive/progesterone receptor-negative male breast cancer: a population-based study

Contributed equally
World Journal of Surgical Oncology201816:236

https://doi.org/10.1186/s12957-018-1539-7

  • Received: 10 June 2018
  • Accepted: 4 December 2018
  • Published:

Abstract

Background

The aim of this study was to explore the characteristics and prognostic information of estrogen receptor-positive/progesterone receptor-negative (ER+/PR−) male breast cancer.

Methods

Using the US National Cancer Institute’s Surveillance, Epidemiology, and End Results database, we compared the demographics, clinical characteristics, and outcome of estrogen receptor-positive/progesterone receptor-positive (ER+/PR+) patients with ER+/PR− male breast cancer patients from 1990 to 2010. Two thousand three hundred twenty-two patients with ER+/PR+ tumors and 355 patients with ER+/PR− tumors were included in our study.

Results

ER+/PR− patients were younger (P = 0.008) and more likely to be African American (P < 0.001) while presented with higher histological grade (P < 0.001), larger tumor size (P = 0.010), and more invasion to the lymph nodes (P = 0.034) and distant sites (P < 0.001), thus later stage (P = 0.001). Despite higher chance of receiving chemotherapy (51.0% vs 36.5%, P < 0.001), ER+/PR− patients experienced significantly worse breast cancer-specific survival (BSCC) (P < 0.001) and shorter overall survival (OS) (P = 0.003). Multivariate Cox model confirmed that tumor size, lymph node invasion, metastasis, and surgery were independent prognostic factors of both BSCC and OS for ER+/PR− male breast cancer. Age at diagnosis and chemotherapy were significantly associated with OS but not with BSCC.

Conclusion

ER+/PR− male breast cancer was more aggressive and experienced shorter survival than ER+/PR+ patients. The prognosis was mainly associated with tumor size, lymph node invasion, metastasis, and surgery.

Keywords

  • Male breast cancer
  • Progesterone receptor
  • Estrogen receptor
  • Cancer-specific survival
  • Overall survival

Background

Male breast cancer (MBC) is an uncommon disease, accounting for less than 1% of all breast cancer diagnoses in the USA [1]. However, the annual incidence was reported to increase from 1.0 per 100,000/year in the late 1970s to 1.2 per 100,000/year in 2000–2004 [2]. Due to its rarity, the epidemiology, tumor behavior, treatment, and prognosis remain poorly understood. Current knowledge was mainly based on small series of studies, except for the advancement made by the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. The results of part 1, a retrospective joint central study of 1822 MBC patients, and part 2, a 30-month prospective registry of 557 cases, had been partially released lately [36]; thus, further analysis and prospective trials are still yet to be conducted.

Suffering from lack of clinical trials and knowledge on molecular biology, clinicians have to extrapolate treatment strategies for MBC from female breast cancer (FBC) data, despite differences at the protein, genetic, and epigenetic level [79]. Although several recent studies have assessed the prognostic factors of MBC, the conclusions are controversial and often blighted by the small number of patients [1012].

Testing for estrogen receptor (ER) and progesterone receptor (PR) markers has been recommended for all newly diagnosed breast cancer patients by the College of American Pathologists and American Society of Clinical Oncology [13]. Several studies have demonstrated high rates of ER positivity in MBC, for example, Cardoso et al. reported that up to 99.3% of tumors were ER-positive [3, 14, 15]. The range of PR expression is wider than ER among different published reports, from 58.8 to 96% [16]. In FBC, if human epidermal growth factor receptor 2 (HER-2) was negative, ER+/PR− and ER+/PR+ breast cancer would be categorized as luminal B subtype and luminal A subtype, respectively, with different prognosis. Given the fact that HER-2 was dominantly negative in MBC [3, 5, 17], we conducted this population-based study to compare ER+/PR− MBC with ER+/PR+ MBC and further investigate the clinical characterization and prognostic factors of ER+/PR− MBC.

Materials and methods

Data were obtained from the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database [18]. We selected patients diagnosed with breast cancer between 1990 and 2010 according to the following criteria: male, pathological diagnosis of invasive carcinoma, unilateral, ER-positive, and breast as the only primary site. Patients with unknown PR status were excluded. Data extraction was performed by SEER*Stat software version 8.3.2 based on the November 2015 data submission [19]. Marital status was divided into three categories: not married, married, and unknown, with the first one consisting of divorced, separated, single (never married), and widowed. The outcome of interests were breast cancer-specific survival (BCSS) and overall survival (OS). The former was calculated from the date of diagnosis to the date of breast cancer death, and OS was defined as the interval from diagnosis to the death from any cause.

Our study was approved by the ethics committee of our hospital, namely Northern Jiangsu People’s Hospital Ethics Committee. No informed patient consent was needed.

Statistical analyses

Patient characteristics were compared between ER+/PR+ and ER+/PR− subtypes using a chi-square test or Fisher’s exact test as appropriate. The Kaplan-Meier method was used to construct survival curves. The multivariate Cox regression models were built to assess the independent association of all the variables with BCSS and OS in the ER+/PR+ and ER+/PR− cohorts (forward: LR). Stage, which was defined by tumor size, lymph node invasion, and distant metastasis, was excluded from the model to avoid interference among the variables. Hazard ratios (HR) and their 95% confidence intervals (95% CI) were estimated using the Cox models. Statistical analyses were performed using SPSS 22.0 (Chicago, IL, USA). Two-sided P < 0.05 was considered statistically significant.

Results

Patient characteristics

A total of 2677 male patients with ER+ invasive carcinoma were included in this study. Two thousand three hundred twenty-two patients had ER+/PR+ tumors, and 355 patients had ER+/PR− tumors. Table 1 shows the demographic and clinical characteristics of patients according to PR status. Compared with PR-positive patients, PR-negative patients were younger (P = 0.008), more likely to be African American (P < 0.001). PR-negative tumors tended to present with higher grade (P < 0.001), larger tumor size (P = 0.010), and more invasion to the lymph nodes (P = 0.034) and distant sites (P < 0.001), thus later stage (P = 0.001). Fifty-one percent of PR-negative patients received chemotherapy, significantly higher than PR-positive patients (P = 0.001). There was no significant difference between ER+/PR+ and ER+/PR− MBC patients in terms of laterality, marital status, surgery, and radiation therapy (P = 0.910, 0.331, 0.623, and 0.089, respectively).
Table 1

Demographic and clinical characteristics

Characteristics

PR-positive

PR-negative

P value

N

%

N

%

Age at diagnosis

    

0.008

 ≤ 40

62

2.7

18

5.1

 

 41–55

501

21.6

89

25.1

 

 56–70

901

38.8

145

40.8

 

 71–85

722

31.1

89

25.1

 

 > 85

136

5.9

14

3.9

 

Race

    

< 0.001

 White

1901

81.9

273

76.9

 

 Black

266

11.5

70

19.7

 

 Other

144

6.2

11

3.1

 

 Unknown

11

0.5

1

0.3

 

Laterality

    

0.910

 Right

1211

52.2

184

51.8

 

 Left

1111

47.8

171

48.2

 

Marital status

    

0.331

 Married

1562

67.3

235

66.2

 

 Not married

662

28.5

110

31.0

 

 Unknown

98

4.2

10

2.8

 

Grade

    

< 0.001

 I

264

11.4

36

10.1

 

 II

1137

49.0

135

38.0

 

 III/IV

744

32.0

159

44.8

 

 Unknown

177

7.6

25

7.0

 

Tumor size

    

0.010

 T1

1110

47.8

146

41.1

 

 T2

906

39.0

149

42.0

 

 T3

96

4.1

21

5.9

 

 T4

145

6.2

34

9.6

 

 TX

65

2.8

5

1.4

 

Nodal status

    

0.034

 N0

1175

50.6

153

43.1

 

 N1

678

29.2

114

32.1

 

 N2

219

9.4

44

12.4

 

 N3

152

6.5

32

9.0

 

 NX

98

4.2

12

3.4

 

Metastasis

    

< 0.001

 M0

2172

93.5

311

87.6

 

 M1

150

6.5

44

12.4

 

Stage

    

< 0.001

 I

701

30.2

85

23.9

 

 II

968

41.7

137

38.6

 

 III

425

18.3

84

23.7

 

 IV

150

6.5

44

12.4

 

 Unknown

78

3.4

5

1.4

 

Surgery

    

0.623

 Done

2217

95.5

335

94.4

 

 Not

98

4.2

19

5.4

 

 Unknown

7

0.3

1

0.3

 

Radiation

    

0.089

 Done

613

26.4

109

30.7

 

 Not

1709

73.6

246

69.3

 

Chemotherapy

    

< 0.001

 Yes

848

36.5

181

51.0

 

 No/unknown

1474

63.5

174

49.0

 

Survival analysis

After a median follow-up of 82 months, 1313 deaths were reported among patients in this study, 625 of which were due to breast cancer. Compared with PR-positive patients, patients with PR-negative breast cancer experienced significantly worse BCSS (P < 0.001) and shorter OS (P = 0.003) (see Fig. 1).
Fig. 1
Fig. 1

Kaplan-Meier plots of the a overall survival and b breast cancer-specific survival according to PR status

In the PR-positive MBC cohort, laterality and radiation did not make it into the final Cox model (forward: LR) in the analysis of OS and BCSS. Race, age at diagnosis, marital status, histological grade, tumor size, lymph node status, metastasis, and surgery all exhibited independent prognostic significance. Chemotherapy could significantly improve OS (HR = 1.261, 95% CI 1.088–1.461, P = 0.002) but not BSCC, as shown in Table 2.
Table 2

Cox proportional hazards regression model multivariate analysis of the overall survival and breast cancer-specific survival in PR-positive cohort (forward: LR)

Variables

OS

BCSS

HR (95% CI)

P value

HR (95% CI)

P value

Age at diagnosis

 ≤ 40

Reference

 

Reference

 

 41–55

1.143 (0.729–1.791)

0.56

1.245 (0.761–2.035)

0.383

 56–70

1.633 (1.056–2.525)

0.027

1.245 (0.768–2.017)

0.374

 71–85

3.695 (2.391–5.709)

< 0.001

1.693 (1.032–2.776)

0.037

 > 85

7.501 (4.678–12.029)

< 0.001

2.167 (1.123–4.182)

0.021

Race

 White

Reference

 

Reference

 

 Black

1.290 (1.069–1.557)

0.008

1.453 (1.129–1.869)

0.004

 Other

0.874 (0.662–1.156)

0.346

0.959 (0.628–1.466)

0.848

 Unknown

0.862 (0.348–2.138)

0.749

0.000 (0.000–8.644E+62)

0.905

Marital status

 Married

Reference

 

Reference

 

 Not married

1.589 (1.397–1.808)

< 0.001

1.508 (1.243–1.829)

< 0.001

 Unknown

1.318 (0.957–1.814)

0.08

1.156 (0.690–1.938)

0.582

Grade

 I

Reference

 

Reference

 

 II

1.250 (0.996–1.568)

0.054

2.136 (1.297–3.519)

0.003

 III/IV

1.470 (1.162–1.858)

0.001

2.775 (1.675–4.596)

< 0.001

 Unknown

1.175 (0.875–1.578)

0.283

2.493 (1.412–4.401)

0.002

Tumor size

 T1

Reference

 

Reference

 

 T2

1.565 (1.450–1.911)

< 0.001

1.953 (1.567–2.435)

< 0.001

 T3

1.858 (1.395–2.475)

< 0.001

1.746 (1.161–2.626)

0.007

 T4

1.890 (1.490–2.397)

< 0.001

2.636 (1.863–3.728)

< 0.001

 TX

0.873 (0.588–1.296)

0.501

0.981 (0.549–1.753)

0.948

Nodal status

 N0

Reference

 

Reference

 

 N1

1.655 (1.426–1.922)

< 0.001

2.317 (1.829–2.935)

< 0.001

 N2

1.931 (1.558–2.395)

< 0.001

2.713 (2.002–3.677)

< 0.001

 N3

2.362 (1.879–2.968)

< 0.001

4.075 (3.022–5.495)

< 0.001

 NX

2.348 (1.741–3.168)

< 0.001

2.194 (1.355–3.553)

0.001

Metastasis

 M0

Reference

 

Reference

 

 M1

2.952 (2.348–3.713)

< 0.001

5.412 (4.075–7.189)

< 0.001

Surgery

 Done

Reference

 

Reference

 

 Not

2.350 (1.766–3.127)

< 0.001

2.623 (1.830–3.758)

< 0.001

 Unknown

1.580 (0.690–3.617)

0.279

1.692 (0.646–4.428)

0.284

Chemotherapy

 Yes

Reference

 

 No/unknown

1.261 (1.088–1.461)

0.002

In the PR-negative MBC cohort, laterality, radiation, race, marital status, and histological grade were not included in the final Cox model (forward: LR) in the analysis of OS and BCSS. Tumor size, lymph node invasion, metastasis, and surgery were independent prognostic factors. Age at diagnosis and chemotherapy were significantly associated with OS but not with BCSS. Chemotherapy could reduce the risk of dying from all causes (HR = 1.492, 95% CI 1.073–2.076, P = 0.017), as shown in Table 3.
Table 3

Cox proportional hazards regression model multivariate analysis of the overall survival and breast cancer-specific survival in PR-negative cohort (forward: LR)

Variables

OS

BCSS

HR (95% CI)

P value

HR (95% CI)

P value

Age at diagnosis

 ≤ 40

Reference

 

 41–55

0.795 (0.365–1.733)

0.564

 56–70

0.812 (0.387–1.705)

0.582

 71–85

1.485 (0.695–3.173)

0.308

 > 85

2.834 (1.087–7.389)

0.033

Tumor size

 T1

Reference

 

Reference

 

 T2

2.047 (1.443–2.902)

< 0.001

2.177 (1.379–3.436)

0.001

 T3

5.696 (3.107–10.444)

< 0.001

5.507 (2.749–11.034)

< 0.001

 T4

2.565 (1.567–4.201)

< 0.001

3.306 (1.825–5.989)

< 0.001

 TX

0.536 (0.143–2.013)

0.356

1.296 (0.365–4.598)

0.688

Nodal status

 N0

Reference

 

Reference

 

 N1

1.244 (0.864–1.791)

0.241

1.382 (0.869–2.199)

0.172

 N2

2.415 (1.544–3.779)

< 0.001

2.379 (1.381–4.098)

0.002

 N3

2.264 (1.605–4.290)

< 0.001

3.509 (1.993–6.181)

< 0.001

 NX

2.954 (1.212–7.201)

0.017

3.073 (1.163–8.120)

0.024

Metastasis

 M0

Reference

 

Reference

 

 M1

2.311 (1.452–3.677)

< 0.001

3.200 (1.902–5.383)

< 0.001

Surgery

 Done

Reference

 

Reference

 

 Not

2.143 (1.130–4.064)

0.020

3.120 (1.621–6.006)

0.001

 Unknown

2.629 (0.336–20.549)

0.357

1.683 (0.215–13.191)

0.62

Chemotherapy

 Yes

Reference

 

 No/unknown

1.492 (1.073–2.076)

0.017

As age at diagnosis was related to OS in both the PR-positive and PR-negative patients, we constructed the survival curves and conducted a pair-wise comparison among different age groups to further explore the difference between PR-positive and PR-negative MBC, as shown in Fig. 2 and Table 4. For PR-positive MBC, the OS of patients younger than 40 was not significantly different from patients aged 41 to 55 (P = 0.800) and 56 to 70 (P = 0.154) but better than patients aged 71 to 85 (P < 0.001) and older (P < 0.001). The OS of patients aged 41 to 55 was significantly better than the following groups (P = 0.010, P < 0.001, and P < 0.001, respectively). For PR-negative MBC, the OS of patients younger than 40, patients aged 41 to 55, and patients aged 56 to 70 did not change dramatically (P = 0.951, 0.772, and 0.738, respectively). Survival declined significantly with age after 70, as shown in Table 4.
Fig. 2
Fig. 2

Kaplan-Meier plots of the overall survival according to age groups within a PR-positive and b PR-negative cohorts

Table 4

Comparison of the overall survival among different age groups (log-rank)

PR status

Age at diagnosis

≤ 40

41–55

56–70

71–85

> 85

Survival months

P value

P value

P value

P value

P value

Mean ± SD

Positive

≤ 40

 

0.800

0.154

< 0.001

< 0.001

184.0 ± 14.3

41–55

0.800

 

0.010

< 0.001

< 0.001

193.7 ± 6.7

56–70

0.154

0.010

 

< 0.001

< 0.001

153.3 ± 4.9

71–85

< 0.001

< 0.001

< 0.001

 

< 0.001

91.2 ± 3.1

> 85

< 0.001

< 0.001

< 0.001

< 0.001

 

48.8 ± 3.3

Negative

≤ 40

 

0.951

0.772

0.088

0.024

164.7 ± 31.3

41–55

0.951

 

0.738

0.001

< 0.001

117.50 ± 8.0

56–70

0.772

0.738

 

< 0.001

< 0.001

129.2 ± 9.3

71–85

0.088

0.001

< 0.001

 

0.037

78.6 ± 6.4

> 85

0.024

< 0.001

< 0.001

0.037

 

44.4 ± 8.1

Discussion

MBC is substantially different from FBC, arising with increasing frequency due to BRCA2 mutations with differential effects by gender of single nucleotide polymorphisms (SNPs) [20]. The rarity of MBC resulted in difficulty in operating randomized, controlled clinical trials and limited prognostic information and suboptimal treatment. Only 3 out of the 12 breast cancer trials that included male patients are phase 3 clinical trials, and just 1 trial is actively recruiting [5]. The implications for PR positivity have long been a focus of debate. Some researchers recommended the elimination of PR testing from the routine diagnostic work-up of invasive breast cancer [13]. Other researchers advocated assessment of PR status to distinguish subsets of ER-positive and ER-negative tumors [21]. Also, PR status was suggested as a useful tool for selecting initial therapy, because ER+/PR− tumors might benefit more from initial treatment with an aromatase inhibitor [22]. However, tamoxifen is still the standard endocrine therapy in MBC patients [17]. In our study, we found that the clinical characteristics and prognosis of ER+/PR− MBC were different from ER+/PR+ MBC, the former being more aggressive and experiencing a much shorter OS and BCSS. Given the fact that normally endocrine therapy would be administered to both ER+/PR+ MBC and ER+/PR− MBC patients, the survival difference possibly lay more in tumor behavior than treatments. This verified the importance of PR testing. Besides, according to our study, the prognosis of ER+/PR− MBC patients was significantly related to tumor stage and surgery other than demographic factors like marital status and race; herein, early detection, diagnosis, and intervention were of great importance to improve the outcome of these patients.

The median age at diagnosis of MBC is 65–69 years old [3, 6, 2325] in the West counties and a little bit younger in Asia [26] and the Middle East [27]. Most literature has validated the prognostic role of age at diagnosis [12, 24, 26, 28, 29]. Our study was in agreement with the previous research. Nevertheless, we found different effect of age between the PR-positive and PR-negative MBC. OS dropped significantly for PR-positive patients older than 55 years, while patients younger than 70 years old experienced similar OS in PR-negative group. Furthermore, age was not independently related to BCSS in PR-negative MBC patients. The analysis of EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program partially supported our results [3]. Compared with patients diagnosed ≤ 40 years old, patients diagnosed ≥ 75 years old experienced a 25% higher mortality risk. Nonetheless, the authors did not conduct strata analysis according to breast cancer subtypes, and only deaths following a distant relapse were considered breast cancer mortality event. We assume that older onset of age with a high presence of comorbidities could explain the divergence between OS and BCSS. 32.6% of MBC patients were diagnosed with comorbidities, including hypertension, diabetes, and ischemic heart disease [26]. Nearly 40% of MBC patients died from causes unrelated to their breast cancer [24].

Histological grade is representative of the “aggressive potential” of the tumor and would be expected to predict the survival of MBC. Some literature did report that tumor grade was a predictor of OS and/or BCSS [25, 28, 30], so did our analysis of the PR-positive cohort. On the contrary, Vermeulen et al. [6] found that tumor grade was not independently associated with survival, so did our analysis of the PR-negative patients and some other research [3, 31]. Different “scoring systems” were applied for determining the grade of a breast cancer, including four-tier grading scheme and three-tier grading scheme, which undermined the comparison among different results. Also, the grading system that was initially developed for FBC may not be suitable in the MBC setting. Last, MBC could be a heterogenous disease with different subtypes exhibiting different prognostic patterns, as our work demonstrated.

Interestingly, chemotherapy was confirmed an independent prognostic factor in the multivariate Cox analyses of OS but did not reach significance with this test in BCSS, neither in ER+/PR+ nor ER+/PR− cohort, as shown in Tables 2 and 3. Since few studies analyzed OS and BCSS of MBC at the same time, our finding was not echoed. There might be some possibilities: first, the drugs somehow reduced the risk of dying from causes other than cancer; second, we did not use HER-2 status in the model, which was not available until 2010, so the conclusion might be partial. The application of the 21-gene breast recurrence score (RS) may shed some light on the option of chemotherapy. After testing 38 MBC patients, Turashvili et al. [32] found similar RS distribution in MBC and FBC patients. Besides, RS testing was declared to play a prognostic role in MBC [7]. Larger studies with different cohorts are needed to further identify the risk factors and optimize treatments for MBC patients.

We acknowledge some limitations to our study. We do not have the information regarding HER-2 status, as mentioned above. Also, as a retrospective analysis, our study may have introduced biases. Despite these limitations, our study, to our best knowledge, was the first to expound the characterizations and prognosis of PR-negative MBC. Also, our SEER-based study included the data on systemic treatments of this population, which was recently updated.

In conclusion, ER+/PR− MBC, compared with ER+/PR+ MBC, presented with more aggressive behavior and poorer survival. The prognosis was independently associated with stage and clinical intervention; thus, early diagnosis and individualized treatment were warranted to improve the outcome.

Notes

Abbreviations

BCSS: 

Breast cancer-specific survival

CI: 

Confidence intervals

ER: 

Estrogen receptor

FBC: 

Female breast cancer

HER-2: 

Human epidermal growth factor receptor 2

HR: 

Hazard ratios

MBC: 

Male breast cancer

OS: 

Overall survival

PR: 

Progesterone receptor

RS: 

Recurrence score

SNPs: 

Single nucleotide polymorphisms

Declarations

Acknowledgements

Not applicable.

Funding

Not applicable.

Availability of data and materials

The datasets generated during the current study are available on the following website: http://seer.cancer.gov/seerstat/. The corresponding author would provide the raw files analyzed via e-mail on reasonable request.

Authors’ contributions

WJ analyzed and interpreted the patient data. FD was a major contributor in writing the manuscript. ZJ conceived the idea. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Department of Thyroid and Breast Surgery, Clinical Medical College of Yangzhou University and Northern Jiangsu People’s Hospital, Yangzhou, China
(2)
Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

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