Poorer Survival of Male Breast Cancer Compared with Female Breast Cancer Patients May Be Due to Biological Differences

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<ul><li><p>Original Articles</p><p>Poorer Survival of Male Breast Cancer Compared with Female BreastCancer Patients May Be Due to Biological Differences</p><p>Xingyu Chen1,2, Xiaodong Liu1,2, Li Zhang1,2, Shufen Li1,2, Yehui Shi1,2 and Zhongsheng Tong1,2,*</p><p>1Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Breast,Tianjin and 2Department of Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China</p><p>*For reprints and all correspondence: Zhongsheng Tong, Department of Breast Oncology, Tianjin Medical UniversityCancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin 300060, China. E-mail: 18622221181@163.com</p><p>Received June 6, 2013; accepted July 21, 2013</p><p>Objective: The objective of the study was to compare disease-free survival and overall survivalin a group of matched males and females with breast cancer, and to analyze possible treat-ment- and gender-related differences.Methods:We retrospectively analyzed the data of 150 operable male breast cancer patientstreated in our hospital from December 1980 to June 2012. Each male breast cancer patientrecorded in the database was matched with two female breast cancer patients of equal stage.Prognosis in terms of disease-free survival and overall survival was evaluated.Results: The mean age at diagnosis was 58.6+9.7 years for males and 57.2+10.3 years forfemales. The median follow-up was 69 months for males and 81 months for females.Significant differences were identified for tumor location, hormone receptor status, molecularsubtypes and hormone therapy between the two groups. Monofactorial analysis demonstratedthat tumor size, lymph node state, American Joint Committee on Cancer stage, molecular sub-types and adjuvant chemotherapy treatment were prognostic factors in male breast cancerpatients. The 5- and 10-year disease-free survival rates were 65.6 and 40.1% for males, and74.9 and 51.5% for females, respectively. The 5- and 10-year overall survival rates were 72.9and 53.9% for males, and 83.2 and 68.5% for females, respectively. There was significantlydifference in disease-free survival and overall survival between the two matched groups(P 0.002).Conclusions:Male breast cancer patients had inferior outcome despite of equal stage in com-parison with matched female breast cancer patients, which demonstrates that biological differ-ences may contribute to the worse prognosis.</p><p>Key words: male breast cancer female breast cancer prognosis</p><p>INTRODUCTION</p><p>Male breast cancer (MBC) is a rare and often overlooked</p><p>disease accounting for ,1% of all breast cancer cases (1).However, the incidence of MBC has been steadily increasing</p><p>along with the increasing incidence of female breast cancer</p><p>(FBC) over the past three decades (2). The reason for the in-</p><p>creasing incidence of MBC is likely due to several factors, in-</p><p>cluding longer lifespan, increased public awareness and rising</p><p>levels of obesity in the male population (3). This increasing</p><p>trend highlights the importance of understanding MBC and</p><p>whether it differs from FBC.</p><p>Because of its low incidence, MBC has not been studied as</p><p>extensively as FBC. Its rarity has precluded prospective rando-</p><p>mized controlled trials and only data from retrospective and</p><p>often small series are available. Few retrospective studies have</p><p>included more than 100 cases. Appropriate management</p><p>guidelines for MBC have not yet been clearly established, and</p><p>limited information is available regarding the epidemiology,</p><p># The Author 2013. Published by Oxford University Press. All rights reserved.For Permissions, please email: journals.permissions@oup.com</p><p>Jpn J Clin Oncol 2013;43(10)954963</p><p>doi:10.1093/jjco/hyt116</p><p>Advance Access Publication 9 August 2013</p><p> at Belgorod State U</p><p>niversity on February 8, 2014http://jjco.oxfordjournals.org/</p><p>Dow</p><p>nloaded from </p></li><li><p>treatment and prognosis of the disease (4). Therefore, despite</p><p>possible differences in pathogenesis, biology and genetics</p><p>between both the sexes, the treatment strategies for MBC have</p><p>been extrapolated from the data based on the FBC (5). As</p><p>more data on the tumor biology of MBC emerge, it is becom-</p><p>ing clear that MBC is a unique disease requiring its own trials</p><p>and treatment guidelines.</p><p>In the past two decades, several retrospective studies have</p><p>described the epidemiology and biological characteristics of</p><p>MBC and its prognosis compared with FBC, with inconsistent</p><p>results. It has been assumed that MBC carried a worse progno-</p><p>sis compared with FBC, which has mainly been attributed to</p><p>delays in diagnosis, more advanced stage at diagnosis, older</p><p>age at diagnosis and a higher incidence of lymph node metas-</p><p>tases in males with breast cancer (612). However, recent</p><p>studies revealed that MBC and FBC patients have a similar</p><p>prognosis (1315). One study showed that although overall</p><p>survival (OS) was equivalent between both the sexes, disease-</p><p>specic survival was signicantly better in MBC than in FBC</p><p>(16). Thus, there is no consensus on the relationship between</p><p>the patients sex and prognosis in breast cancer. Therefore, the</p><p>aim of the present study was to compare the survival in a</p><p>group of carefully matched males and females with breast</p><p>cancer, and to retrospectively analyze disease characteristics</p><p>of MBC in a Chinese population over the past 32 years. In this</p><p>regard, clinicopathological features, treatment patterns and</p><p>survival were investigated, and prognosis in terms of OS and</p><p>disease-free survival (DFS) was evaluated.</p><p>PATIENTS ANDMETHODS</p><p>PATIENT CHARACTERISTICS</p><p>We retrospectively reviewed the medical records of 150 MBC</p><p>patients who had been treated at the Cancer Institute and</p><p>Hospital of Tianjin Medical University, China, between</p><p>December 1980 and June 2012. To be included in this retro-</p><p>spective analysis, the following conditions had to be fullled:</p><p>all men had to suffer from invasive breast cancer curatively</p><p>treated with mastectomy, and had well-documented clinical</p><p>information and accurate TNM stage. Patients presenting with</p><p>metastatic lesions or second cancers at initial diagnosis were</p><p>excluded. Each male fullling the criteria was recorded in the</p><p>database and carefully matched with two females. Matching</p><p>criteria included the main potential prognostic factors such as</p><p>pathology of invasive ductal carcinoma in MBC and FBC, age</p><p>at diagnosis (+5 years), date of diagnosis (+5 years) (17)and identical clinical stage of the primary cancer at diagnosis.</p><p>The females were selected from a total of 27 314 consecutive</p><p>patients whose data were recorded in the same database and</p><p>who underwent treatment at our institution during the same</p><p>period. When more than two females met the matching</p><p>criteria, the female patients whose date of diagnosis was</p><p>closer to the male patients were chosen (13). A total of 150</p><p>MBC patients and 300 matched FBC patients were enrolled in</p><p>the study.</p><p>The database was reviewed to obtain the demographic in-</p><p>formation, clinical history, tumor characteristics and treatment</p><p>characteristics. Follow-up information was obtained from the</p><p>database, the medical records and contact with the patients or</p><p>their family. Mortality due to breast cancer, second primary</p><p>cancer and other causes were the end points considered.</p><p>According to the standard of Perou (18) and Carey (19),</p><p>breast cancer molecular subtypes were classied according to</p><p>the immunohistochemical panel expression prole as follows:</p><p>ER positive and/or PR positive and HER2 negative for</p><p>Luminal A; ER positive and/or PR positive and HER2 positive</p><p>for Luminal B; ER and PR negative and HER2 positive for</p><p>HER2 over-expressed; ER, PR and HER2 all negative for</p><p>basal-like (triple negative).</p><p>STATISTICAL ANALYSES</p><p>We determined and compared the 5- and 10-year DFS time</p><p>and OS time for male- and female-matched groups. DFS was</p><p>dened as the time from the surgery until disease progression</p><p>or death by any cause on the date of the last follow-up. OS</p><p>was dened as the time from the surgery until death by any</p><p>cause. A statistical comparison of female-matched pair sur-</p><p>vival data was performed with the paired t-test. DFS and OS</p><p>were calculated using the KaplanMeier method from the</p><p>time of diagnosis (20). The log-rank test was used to assess</p><p>survival difference between the groups. Actuarial curves</p><p>were compared by the two-tailed log-rank test. The statistical</p><p>analysis was performed using SPSS software version 17.0.</p><p>A P value of, 0.05 was considered signicant for both tests.</p><p>RESULTS</p><p>CLINICAL MATERIALS</p><p>The 150 cases of MBC patients were matched with 300 FBC</p><p>patients during the same period. Table 1 displays the matching</p><p>information and demographic data of the matched male and</p><p>female breast cancer (FBC) patients. The mean age at diagno-</p><p>sis was similar for the two matched groups: 58.6+ 9.7 years(range, 2683) for males and 57.2+ 10.3 years (range,2281) for females. The mean follow-up time for the 32-year</p><p>study period was 85.8+ 49.7 months (range, 9298) formales and was 90.2+ 49.2 months (range, 12287) forfemales. Invasive ductal carcinoma was the pathological type</p><p>of all cases.</p><p>The clinicopathological characteristics of both male and</p><p>female patients are described in Table 2. Signicant differ-</p><p>ences were identied for tumor location (P, 0.01), hormonereceptor status (P, 0.01), molecular subtypes (P 0.005)and hormone therapy between male and female patients.</p><p>Males were more likely to have an unknown hormone receptor</p><p>and HER2 status (20.7%, 35.3%) compared with females</p><p>(17.3%, 24.3%). 99 cases of MBC patients had positive ER/</p><p>PR and 26 cases had positive HER2 expression, and 147 cases</p><p>of FBC patients had positive ER/PR and 62 cases had positive</p><p>Jpn J Clin Oncol 2013;43(10) 955</p><p> at Belgorod State U</p><p>niversity on February 8, 2014http://jjco.oxfordjournals.org/</p><p>Dow</p><p>nloaded from </p></li><li><p>HER2 expression. Among the patients who examined for</p><p>HER2 detection, the distribution of tumor molecular sub-</p><p>types was 59 (39.3%) Luminal A, 22 (14.7%) Luminal B, 4</p><p>(2.7%) HER2 over-expressed and 12 (8.0%) basal-like for</p><p>male patients, and 103 (34.3%) Luminal A, 42 (14.0%)</p><p>Luminal B, 20 (6.7%) HER2 over-expressed and 62</p><p>(20.7%) basal-like for female patients, respectively. A lower</p><p>number of male patients underwent endocrine therapy (58</p><p>cases, 38.7%) in comparison to female patients (146 cases,</p><p>48.7%) (P 0.045). Adjuvant endocrine therapy of men wasmainly performed with tamoxifen alone (n 47). Fewermale patients received aromatase inhibitors (n 8) or aswitch from tamoxifen to an aromatase inhibitor (n 3) thanfemale patients (n 49 and 12). Stage-specic treatmentand use of multimodality therapy (surgery, chemotherapy</p><p>and radiotherapy) did not differ between the two matched</p><p>groups. There was no signicant difference in chemotherapy</p><p>regimens between the two groups. Four different schedules</p><p>were administered: CMF (cyclophosphamide, methotrexate,</p><p>uorouracil), CAF/CEF (cyclophosphamide, doxorubicin,</p><p>uorouracil/cyclophosphamide, epirubicin, uorouracil), AT</p><p>(paclitaxel and doxorubicin), TAC/TEC (docetaxel,</p><p>doxorubicin, cyclophosphamide/docetaxel, epirubicin and</p><p>cyclophosphamide).</p><p>MONOFACTORIAL ANALYSIS OF PROGNOSIS</p><p>To further investigate relevance of tumor- and treatment-</p><p>related factors of MBC on survival rate, the following subana-</p><p>lyses were performed. Univariate analysis revealed that</p><p>impact of tumor size, lymph node state, American Joint</p><p>Committee on Cancer (AJCC stage, molecular subtypes and</p><p>adjuvant chemotherapy treatment on OS rate were signicant</p><p>for MBC and FBC (P, 0.05). Moreover, hormonal treatmentand adjuvant chemotherapy regimens were prognostic factors</p><p>of FBC, the impact of different chemotherapy regimens on</p><p>survival was not signicant for MBC (Tables 3 and 4).</p><p>Estimated 5-year OS for male patients with tumor</p><p>size 5 cm and .5 cm were 81.8 and 33.3%, respectively(P, 0.05, Fig. 1a). Presence of node-negative diseaseresulted in an estimated 5-year OS of 84.7 versus 58.5% for</p><p>node-positive breast cancer (P 0.002, Fig. 1b). Due to thevery low incidence of HER2 over-expressed and basal-like</p><p>group, we only compared the 5-year OS of luminal A and</p><p>luminal B subtypes. There were no signicant differences</p><p>between Luminal A and B groups by KaplanMeier survival</p><p>curves (5-year OS was 83.1 versus 78.9%, P 0.761,Fig. 1c). Given chemotherapy was associated with 80.4%</p><p>5-year OS compared with 60.5% without chemotherapy reach-</p><p>ing a trend with P 0.041 (Fig. 1d). In contrast, administra-tion of adjuvant hormonal treatment (AHT) had no impact on</p><p>5-year OS with 74.1 versus 62.0% (P 0.164, Fig. 1e).</p><p>SURVIVAL ANALYSIS AND COMPARISON OF MATCHED PAIRS</p><p>To evaluate whether MBC and FBC had a similar outcome,</p><p>matched pairs of males with females were generated. Five-</p><p>and 10-year DFS and OS of the two groups were calculated.</p><p>The KaplanMeier curves for DFS and OS (Figs. 2 and 3)</p><p>demonstrated signicant difference between the male and the</p><p>matched female patients (P 0.006 and 0.002, log-rank test).The 5- and 10-year DFS rates were 65.6 and 40.1% for males,</p><p>and 74.9 and 51.5% for females, respectively. The 5- and</p><p>10-year OS rates were 72.9 and 53.9% for males, and 83.2 and</p><p>68.5% for females, respectively.</p><p>DISCUSSION</p><p>The relationship between the patients sex and prognosis in</p><p>breast cancer is always controversial, since there are so many</p><p>differences between MBC and FBC (21). Some studies</p><p>observed similar predictors of outcome for men and women</p><p>with breast cancer, and suggested that the sex of the patient</p><p>did not inuence mortality (2224). Other studies showed</p><p>that the outcome of the present male cohort of breast cancer</p><p>patients was inferior to females (25), which was conrmed by</p><p>our matched pair analysis with females.</p><p>Table 1. Characteristics of patients</p><p>Characteristics Male (%) Female (%) P value</p><p>Sample size (n) 150 300</p><p>Age (years)</p><p>Mean+SD 58.6+9.7 57.2+10.3 0.107</p><p>Median (range) 59 (2683) 57 (2281)</p><p>Year of diagnosis (n)</p><p>198089 25 (16.6) 50 (16.6) 1.000</p><p>199099 43 (28.7) 86 (28.7)</p><p>200012 82 (54.7) 164 (54.7)</p><p>AJCC stage (n)</p><p>I 31 (20.7) 62 (20.7) 1.000</p><p>II 76 (50.7) 152 (50.7)</p><p>III 43 (28.6) 86 (28.6)</p><p>Follow-up time (months)</p><p>Mean+SD 85.8+49.7 90.2+49.2 0.372</p><p>Median (range) 69 (9298) 81 (12287)</p><p>Recurrence during follow-up (n)</p><p>No 63 (42.0) 136 (45.3) 0.502</p><p>Yes 87 (58.0) 164 (54.7)</p><p>Cause of mortality (n)</p><p>Breast cancer 39 (51.3) 91 (72.8) 0.002*</p><p>Second primary cancer 15 (19.7) 8 (6.4)</p><p>Other causes 22 (29.0) 26 (20.8)</p><p>SD, standard deviation; AJCC, American Joint Committee on Cancer.*P, 0.01.</p><p>956 Poorer survival of MBC due to biological differences</p><p> at Belgorod State U</p><p>niversity on February 8, 2014http://jjco.oxfordjournals.org/</p><p>Dow</p><p>nloaded from </p></li><li><p>Table 2. Comparison of clinical and pathological characteristics between MBC and FBC patients</p><p>Characteristics Male, n 150 (%) Female, n 300 (%) x2 P value</p><p>Laterality</p><p>Right 78 (52.0) 148 (49.3) 0.733 0.392</p><p>Left 72 (48.0) 162 (50.7)</p><p>Tumor location</p><p>Central 46 (30.7) 16 (5.3) 54.734 0.000**</p><p>Peripheral quadrant 104 (69.3) 287 (94.7)</p><p>SBR tumor grade</p><p>1 34 (22.7) 75 (25.0) 0.306 0.858</p><p>2 98 (65.3) 191 (63.7)</p><p>3 18 (1...</p></li></ul>

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