Abstract
Purpose. Male breast cancer (MBC) is an uncommon disease. In the absence of randomized studies, current guidelines are mainly based on data on the management of female breast cancer (FBC). In light of concerns regarding the quality and extent of management in men, the aim of the present study was to investigate whether there are differences in tumor characteristics, treatment and outcome in male compared with FBC patients. Methods. Cohorts of male and female breast cancer were retrospectively analyzed. All male patients diagnosed with invasive breast cancer between 1993 and 2007 were identified from the Regional Breast Cancer Register of the Uppsala-Örebro Region in Sweden. To increase the power of the study and obtain comparable cohorts we sampled four FBC patients (n = 396) for each MBC patient (n = 99) with similar age at diagnosis and time of diagnosis. Results. No differences were seen in stage at diagnosis between MBC and FBC. Men underwent mastectomy more often than women (92% vs. 44%, p < 0.001). Radiotherapy was delivered less often to MBC than FBC (44% vs. 56%, p = 0.034), but radiotherapy given after mastectomy (44% vs. 39%, p = 0.47) did not differ between the groups. No differences were found regarding adjuvant chemotherapy (16% vs. 21%; p = 0.31) or adjuvant endocrine therapy (59% vs. 52%, p = 0.24). Both overall survival (41% vs. 55%, p = 0.001) and relative survival (74% vs. 88%, p = 0.015) were inferior in MBC compared to FBC. Conclusion. Concerns regarding less extensive treatment in MBC patients were not supported by this study. Although no differences in the stage of the disease or treatment intensity could be demonstrated, outcome was inferior in the male group.
Male breast cancer (MBC) is a rare disease, representing 0.5% of all breast cancers.
The occurrence of MBC is increasing because of an ageing population [Citation1], while age-standardized incidence rates remain stable [Citation2,Citation3]. In female breast cancer (FBC), death rates have decreased during the last decades due to improvements in diagnostic procedures and treatment whereas death rates in MBC have remained essentially constant since 1975 [Citation4].
The incidence of MBC peaks at around 70 years, whereas in females it peaks bi-modally at 50 and 70 years [Citation2,Citation5]. MBC presents on average about 5–10 years later than FBC [Citation6,Citation7]. Differences in tumor stage and tumor biology have been described [Citation2,Citation6,Citation8]. MBC is often reported to be diagnosed at a more advanced stage than FBC [Citation6]. Whether this could be caused by a delay in diagnosis or differences in tumor biology is not yet known. MBC is more often estrogen (ER)- and progesterone (PgR) receptor positive than FBC and differences in histologic grade have been described [Citation2,Citation6].
Treatment recommendations for MBC are based mainly on data from FBC. Due to the rareness of MBC, prospective randomized studies have not been conducted and current knowledge is mostly derived from small descriptive studies based on few events or extractions from data bases. Some retrospective analyses indicate that adjuvant endocrine therapy improves the outcome in MBC and tamoxifen has often been recommended as the preferred choice of adjuvant treatment [Citation9–11]. On the other hand, other studies disagree [Citation4,Citation12]. There are no studies proving that adjuvant chemotherapy significantly increases survival in MBC, although retrospective reports estimate a benefit consistent with that seen in FBC [Citation10]. While current guidelines generally recommend that MBC should be managed in the same way as FBC, there are indications that MBC patients do not receive adjuvant treatment to the same extent as FBC patients [Citation11,Citation13]. However, in general MBC patients are older and have more co-morbidities, which can influence the choice of treatment [Citation14].
Reports on outcomes in MBC compared with FBC are conflicting. Some studies have reported a poorer overall survival [Citation8] or disease specific survival [Citation15] in MBC, whereas others indicate a similar or even better outcome in MBC [Citation11,Citation16,Citation17].
The aim of this study was to investigate whether there are differences in the primary treatment between male and female breast cancer and whether there are differences in outcome.
Material and methods
A population-based clinical breast cancer register for the Uppsala-Örebro region initiated in 1992 was used. The register covers a population of approximately 1.9 million in seven counties and was established to ensure that treatment is given according to regional treatment recommendations and to evaluate outcome. Since 1995 there are formal treatment guidelines for breast carcinoma to unify treatment in the region. These guidelines recommend the same treatment for male and female breast cancer. The register contains information on age at diagnosis, date of diagnosis, tumor stage, histopathology parameters (ER status, PgR status, histologic grade, proliferation and HER2 status) and planned primary treatment.
In this study, cohorts of male and female invasive breast cancer were analyzed retrospectively. A sampling procedure was used to achieve comparable groups. All men with invasive breast cancer diagnosed between 1993 and 2007 were retrieved from the register. For each case of male breast cancer four women with breast cancer were randomly sampled. Sampling was performed using age at diagnosis (< 49, 50–59, 60–69, 70–79, ≥ 80 years of age) and time of diagnosis (1993–1997, 1998–2002, 2003–2007). Finally, a cohort of 99 men with breast cancer was compared with a cohort of 396 women. Data on tumor size, lymph node status, hormone receptors, tumor grade, surgery, radiotherapy and adjuvant systemic treatment were collected from the register and updated information about the patients vital status was obtained from the National Population Register.
Of all female cases 64% were clinically detected and the rest diagnosed through screening mammography, whereas all MBC were clinically detected. In a separate step, comparisons were restricted to men and women with clinically detected disease.
The study was approved by the Regional Ethics Committee.
Statistical analyses
Differences in proportions between cohorts were tested with χ2 statistics. When appropriate the Fischer's exact test was used. Testing was done without regard to the initial sampling procedure.
Overall survival was analyzed using Kaplan-Meier. Differences in survival between genders were analyzed with Log-rank test.
Relative survival estimates the ratio of observed survival to the expected survival of comparable groups in the standard population. Relative survival has been estimated using the Hakulinen method in Stata. The standard population used was Sweden 2000. Differences in survival between genders were analyzed with a Poisson regression model [Citation18].
For statistical analyses SAS, Stata and R were used.
Results
See and and .
Figure 1. Overall survival in MBC patients (bottom line) and FBC patients (top line). MBC patients have a significantly worse overall survival at five years follow-up compared with FBC patients (p = 0.001). After five years results are uncertain due to few patients at risk.
Figure 2. Relative survival of MBC patients (bottom line) compared with FBC patients (top line). MBC patients have a significantly poorer relative survival at five years follow-up compared with FBC (p = 0.015). After five years results are uncertain due to few patients at risk.
Table I. Stage at diagnosis- MBC vs. FBC.
Table II. Histopathological characteristics- MBC vs. FBC.
Table III. Adjuvant treatment- MBC vs. FBC.
The mean age at diagnose in this study was 67.6 years (95% CI 40.2–95.0) for FBC and 68.1 years (95% CI 38.9–97.3) for MBC patients compared to 63.4 years (95% CI 36.2–90.5) for all FBC patients in the region (diagnosed 1993–2007). All MBC were clinically detected compared to 64% of FBC.
No differences in the distribution of stage at diagnosis were seen between the male and the female groups ().
Tumors in FBC more often lacked expression of ER and PgR (16% vs. 5%, p = 0.005 and 26% vs. 15%, p = 0.02, respectively). Hormone receptor status was not analyzed in 19% of the MBC patients compared with 8% of FBC patients (p = 0.001). Tumors in MBC were less often histologic grade I (11% vs. 20%, p = 0.04) and more often grade III (25% vs. 16%, p = 0.04) ().
Men underwent mastectomy more often than women (92% vs. 44%, p < 0.0001) and partial mastectomy/lumpectomy less often (4% vs. 50%, p < 0.0001). A significantly larger proportion of female cases received adjuvant radiotherapy (44% vs. 56%, p = 0.03), but no difference was seen regarding radiotherapy after mastectomy (44% vs. 39%, p = 0.47). There were no gender differences in the proportions of patients offered adjuvant chemotherapy (16% vs. 21%, p = 0.31) or endocrine treatment (59% vs. 52%, p = 0.24). In node positive patients up to 70 years of age, the proportions receiving adjuvant chemotherapy did not differ (MBC 68% vs. FBC 73%, p = 0.70) nor could any differences in endocrine treatment be observed in ER positive patients with localized disease (MBC 75% vs. FBC 68%, p = 0.24) ().
Subgroup analysis focusing on clinically detected disease did not change the above findings regarding stage, hormone receptors, surgery or systemic adjuvant treatment. However, the difference regarding radiotherapy was no longer seen (p = 0.68) and no differences were observed regarding histologic grade (p = 0.39 and 0.33, respectively).
Registered clinical follow-up was available more often for FBC than for MBC (87% vs. 77%; p = 0.01) with a median time of 4.2 years and 4.1 years, respectively. For calculations of overall and relative survival, follow-up times based on vital status was used with a median of 4.2 years for MBC and 5.9 years for FBC. Overall survival (41% vs. 55%, p = 0.001) and relative survival (74% vs. 88%, p = 0.015) at five years was poorer in the male group ( and ).
Discussion
The general opinion has been that MBC resembles postmenopausal FBC with tumors more frequently expressing hormone receptors and displaying a more indolent growth pattern [Citation2,Citation19]. However, several studies have reported a poorer outcome for MBC patients and it remains unknown whether this reflects their presenting at a higher stage, an older age, different tumor characteristics or sub-optimal adjuvant treatment. In our study, no differences regarding stage at presentation could be found, even when clinically detected tumors were compared in men and women. This finding contradicts several previous reports on MBC that show a more advanced stage at diagnosis [Citation6,Citation15,Citation19], which in turn is often explained by a low level of public awareness and a subsequent delay in diagnosis. Some investigators have reported that MBC tends to metastasize at an early stage to axillary lymph nodes. Cutuli et al. described pN2+ involvement in 10% of pT1 tumors [Citation14]. Our study could not support these findings. Our observation regarding stage is supported by a study from Australia, in which Wang et al. reported even slightly smaller tumor size in the male group compared with postmenopausal FBC [Citation13]. Some previous studies that report more advanced stages at diagnosis covered a long time-period and it seems plausible that awareness about MBC has increased during recent years.
Lack of hormone receptor expression was more frequently observed in FBC than MBC both regarding ER and PgR, as previously reported [Citation20]. Furthermore, we found significantly more high grade tumors and less grade I tumors in MBC as did Nahleh et al. [Citation8]. Other studies have reported MBC tumors to be of lower or equal grade, however in some of these studies samples size was small or there was a large proportion of missing cases [Citation6,Citation16,Citation17,Citation21]. We did not observe any differences in HER2 overexpression. Prior studies have reported highly varying results with both higher and lower frequencies compared with FBC [Citation22,Citation23]. With current available data, the extent of HER 2 overexpression in MBC still remains unclear.
In accordance with other reports, male patients underwent mastectomy more frequently and partial mastectomy less frequently than females. However, MBC and FBC patients underwent axillary surgery to the same extent. Males did not receive loco-regional radiotherapy as often as females, a fact also reported by Nahleh et al. [Citation8]. This finding seems reasonable, since the majority of MBC undergo mastectomy where only selected cases receive adjuvant radiotherapy. In the present study, no differences in adjuvant radiotherapy after mastectomy or after partial mastectomy were seen. In contrast to our findings, Scott-Connor reported that patients with MBC were more likely to receive radiotherapy after mastectomy but less likely to do so after lumpectomy [Citation11]. A possible explanation could be that some guidelines have recommended post-mastectomy radiotherapy on wider indications in MBC compared with their female counterparts; this could be due to anatomical differences and the fear of a higher risk for loco-regional recurrence [Citation24,Citation25].
No differences regarding adjuvant chemotherapy or endocrine therapy were found. Even when analyzing those patients most likely to receive adjuvant chemotherapy (< 70 years and node positive) no differences could be demonstrated. Our results support the findings of Marchal et al., who could not identify any differences in stage-specific treatment in an age- and stage-matched population [Citation16]. However, these data are in contrast to other reports [Citation8,Citation11,Citation13]. In studies which were not age-matched, less chemotherapy administration in men could be due to the higher age in the male study population. Wang et al. reported that men with known ER positive disease received less endocrine treatment than corresponding women [Citation13]. Furthermore, male patients on endocrine treatment received tamoxifen to a greater extent than women. This is consistent with the present study where nearly all males on endocrine treatment received tamoxifen, whereas females were treated with aromatase inhibitors (AI) more frequently. This finding may reflect that data on the efficacy of AI in MBC is uncertain [Citation7,Citation26].
We found that overall survival (OS) was significantly inferior in MBC compared with FBC (). This could be explained by a higher comorbidity burden and shorter life expectancy in the normal male population compared with the female population in this age group. To adjust for these differences, we also analyzed relative survival (the ratio of observed to expected survival), which was also significantly worse at five years in men, thus indicating a real difference in breast cancer associated survival (). In line with our findings, a Swedish study revealed a significantly inferior disease specific survival (DSS) at longer follow-up for MBC [Citation15]. Other studies have reported poorer OS but no differences in disease-specific or relative survival [Citation10,Citation11,Citation16]. Possible explanations as to why we found a difference in relative survival, whereas others did not, could be the way we designed the study, the relatively large sample size and access to high quality registers.
Even though no differences in treatment could be demonstrated, outcome was poorer in MBC. An explanation for this could be that the biology of MBC indeed differs from that of FBC. This is supported by recent findings on the molecular level suggesting different pathways for disease progression and treatment response. When classifying MBC tumors using array CGH (comparative genomic hybridization), a new subgroup was identified in MBC which has not been described in FBC [Citation27]. Furthermore, Callari et al. demonstrated differences in gene expression, suggesting that HER2 and PgR have a reduced relevance in MBC, whereas the role of the androgen receptor appears to be more important [Citation28]. Additional studies are required to further characterize MBC on a molecular level. Establishing biological differences between male and female breast cancer might have potential implications on future treatment strategies in MBC.
The main advantage of the present study is access to high quality register data. The Regional Breast Cancer Register has a 90% level of agreement on data regarding primary treatment and is known for a high level of completeness [Citation29]. When validated against the mandatory Swedish Cancer Register, the Regional Breast Cancer Register included 97% of all breast cancer cases and 100% of all MBC cases diagnosed in the region during this time period.
One limitation of the present study is its size. Even though it is large compared with several previously published studies, the number of events analyzed for outcome is small. To increase the power of the study, we sampled four FBC patients for each MBC patient. Another limitation is the absence of data on breast cancer deaths, preventing us from analyzing disease specific survival. Also, no data was available on the treatment of recurrent disease, and we cannot therefore comment on possible differences in treatment in that situation.
In conclusion, no difference in primary treatment intensity between male and female breast cancer patients could be seen in our region. At the time of diagnosis, men and women presented with a similar distribution of disease stage. Male patients were not subjected to as intensive a follow-up after adjuvant treatment as female breast cancer patients. Although no differences in stage or treatment could be observed, the male group had significantly inferior overall and relative survival.
Acknowledgements
We are grateful to the Regional Research Foundation in Uppsala-Örebro, the Lion's Cancer Foundation, University Hospital, Uppsala and Västmanlands Research Foundation for financial support. We also would like to acknowledge Professor Carl Blomqvist for skillful advice and Associate Professor Henry Letocha for skillful advice and language support.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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