2011;31(9) ( J South Med Univ ) Original Article Clinicopathological characteristics of male breast cancer: analysis of 25 cases at a single institution XIA Qing, SHI Yan-xia, LIU Dong-geng, JIANG Wen-qi Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China Abstract: Objective To investigate general and clinicopathological characteristics of male breast cancer and analyzed the factors affecting the outcomes of the patients based on the data from a single institution. Methods Twenty-five male breast cancer patients treated at Sun Yet-sen University Cancer Center between January 1, 2000 and April 30, 2011 were included into the study. The patients were followed up for 1 to 90 months with a median follow-up of 51 months. The general and clinicopathological characteristics including family history, age, smoking, alcohol drinking, site of tumor, location of tumor, histological type, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), Ki-67, vascular endothelial growth factor (VEGF), P53 expression, neoadjuvant chemotherapy, surgery, adjuvant chemotherapy, adjuvant radiotherapy, adjuvant endocrine therapy, tumor size, lymph node status, distant metastasis and TNM stage were investigated by univariate analysis to evaluate the impact of these factors on patient survival. Results The 5-year survival rate was 66.5% in these patients. Neoadjuvant chemotherapy, tumor size, lymph node status, distant metastasis and TNM stage were significant predictors for the overall survival. Patients receiving adjuvant endocrine therapy tended to have a better overall survival, though this was not supported statistically (P= 0.086). However, patients with neoadjuvant chemotherapy had a poorer overall survival than those without it (P=0.000). Patients in stages I and II had better overall survival than those in stages III and IV (P=0.000). Conclusion The 5-year survival rate was 66.5% in these male breast cancer patients. Neoadjuvant chemotherapy, tumor size, lymph node status, distant metastasis and TNM stage are significant predictors of the overall patient survival. Key words: breast cancer; male breast cancer; univariate analysis; prognosis Introduction Breast cancer in men is rare and only accounts for approximately 1% of all breast cancers [ 1 ] . Even with a significant raise in the incidence of male breast cancer over the last 25 years, it still remains a rare clinical entity, and the therapy is mainly based on what is known from female breast cancer. Despite the fact that randomized controlled prospective trials are not possible due to the low incidence, data obtained from retrospective analyses have clearly demonstrated that male breast cancer is not exactly the same entity as female breast cancer [ 2 ] . Male breast cancer patients tended to have higher estrogen receptor (ER) and progesterone receptor (PR) expressions [ 2-3 ] and the relationship of ER with the overall survival is uncertain [ 4-5 ] . The age of diagnosis is also older in male breast cancer patients than in female patients [ 2 ] . Male breast cancer exhibits more frequent lymph node involvement, presenting with a more advanced stage upon diagnosis and often showing a predominant proportion of invasive ductal carcinoma [ 2, 6 ] . Reports of male breast cancer cases in China are scarce. In this study, we conducted a long-term, longitudinal, follow-up study to investigate the general and clinicopathological characteristics of male breast cancer in a cohort of Chinese patients and analyze the factors that potentially affected the prognosis of the disease. Materials and Methods Patients This respective study was conducted among 25 male breast cancer patients treated in our hospital between January 1, 2000 and April 30, 2011. The general and clinicopathological characteristics analyzed included family history, age, smoking, alcohol drinking, site of tumor, location of tumor, histological type, ER and PR status, human epidermal growth factor receptor 2 (HER-2), Ki-67, vascular endothelial growth factor (VEGF), P53 expression, neoadjuvant chemotherapy, surgery, adjuvant chemotherapy, adjuvant radiotherapy, adjuvant endocrine therapy, tumor size, lymph node involvement, distant metastasis and TNM stage. The American Joint Committee on Cancer (AJCC, 6th edition) TNM classification system was used for staging of the tumors. The histopathologic diagnosis was established in line with the criteria postulated by the World Health Organization Classification of Tumors (IARC 2003 version). Follow-up study Received: 2011-06-13 Accepted: 2011-07-13 Supported by a Special Fund for National Eleventh Five-year Plan Key Sci-tech Project of New Drug Development (2008ZX09312-002) and by the Outstanding Young Researcher Program of Sun Yat-sen Cancer Center. Corresponding authors: LIU Dong-geng, Tel/Fax: 020-87343352, E-mail: [email protected]; JIANG Wen-qi, Tel/Fax: 020-87343352, E-mail: [email protected]. · ·1469
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Clinicopathological characteristics of male breast … Clinicopathological characteristics of male breast cancer (84.2%) and PR (84.2%) were significantly higher in male breast cancer
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2011;31(9) (J South Med Univ)
Original Article
Clinicopathological characteristics of male breast cancer:analysis of 25 cases at a single institution
XIA Qing, SHI Yan-xia, LIU Dong-geng, JIANG Wen-qi
Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
Abstract: Objective To investigate general and clinicopathological characteristics of male breast cancer and analyzed the factorsaffecting the outcomes of the patients based on the data from a single institution. Methods Twenty-five male breast cancer patientstreated at Sun Yet-sen University Cancer Center between January 1, 2000 and April 30, 2011 were included into the study. Thepatients were followed up for 1 to 90 months with a median follow-up of 51 months. The general and clinicopathologicalcharacteristics including family history, age, smoking, alcohol drinking, site of tumor, location of tumor, histological type, estrogenreceptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), Ki-67, vascular endothelial growthfactor (VEGF), P53 expression, neoadjuvant chemotherapy, surgery, adjuvant chemotherapy, adjuvant radiotherapy, adjuvantendocrine therapy, tumor size, lymph node status, distant metastasis and TNM stage were investigated by univariate analysis toevaluate the impact of these factors on patient survival. Results The 5-year survival rate was 66.5% in these patients. Neoadjuvantchemotherapy, tumor size, lymph node status, distant metastasis and TNM stage were significant predictors for the overall survival.Patients receiving adjuvant endocrine therapy tended to have a better overall survival, though this was not supported statistically (P=0.086). However, patients with neoadjuvant chemotherapy had a poorer overall survival than those without it (P=0.000). Patients instages I and II had better overall survival than those in stages III and IV (P=0.000). Conclusion The 5-year survival rate was 66.5%in these male breast cancer patients. Neoadjuvant chemotherapy, tumor size, lymph node status, distant metastasis and TNM stageare significant predictors of the overall patient survival.Key words: breast cancer; male breast cancer; univariate analysis; prognosis
Introduction
Breast cancer in men is rare and only accounts forapproximately 1% of all breast cancers[1]. Even with asignificant raise in the incidence of male breast cancerover the last 25 years, it still remains a rare clinicalentity, and the therapy is mainly based on what is knownfrom female breast cancer. Despite the fact thatrandomized controlled prospective trials are not possibledue to the low incidence, data obtained fromretrospective analyses have clearly demonstrated thatmale breast cancer is not exactly the same entity asfemale breast cancer [2]. Male breast cancer patientstended to have higher estrogen receptor (ER) andprogesterone receptor (PR) expressions [2-3] and therelationship of ER with the overall survival is uncertain[4-5]. The age of diagnosis is also older in male breastcancer patients than in female patients[2]. Male breastcancer exhibits more frequent lymph node involvement,presenting with a more advanced stage upon diagnosisand often showing a predominant proportion of invasiveductal carcinoma[2, 6]. Reports of male breast cancercases in China are scarce. In this study, we conducted a
long-term, longitudinal, follow-up study to investigatethe general and clinicopathological characteristics ofmale breast cancer in a cohort of Chinese patients andanalyze the factors that potentially affected the prognosisof the disease.Materials and Methods
Patients
This respective study was conducted among 25male breast cancer patients treated in our hospitalbetween January 1, 2000 and April 30, 2011. Thegeneral and clinicopathological characteristics analyzedincluded family history, age, smoking, alcohol drinking,site of tumor, location of tumor, histological type, ERand PR status, human epidermal growth factor receptor2 (HER-2), Ki-67, vascular endothelial growth factor(VEGF), P53 expression, neoadjuvant chemotherapy,surgery, adjuvant chemotherapy, adjuvant radiotherapy,adjuvant endocrine therapy, tumor size, lymph nodeinvolvement, distant metastasis and TNM stage. TheAmerican Joint Committee on Cancer (AJCC, 6thedition) TNM classification system was used for stagingof the tumors. The histopathologic diagnosis wasestablished in line with the criteria postulated by theWorld Health Organization Classification of Tumors(IARC 2003 version).Follow-up study
Received: 2011-06-13 Accepted: 2011-07-13Supported by a Special Fund for National Eleventh Five-year Plan KeySci-tech Project of New Drug Development (2008ZX09312-002) and bythe Outstanding Young Researcher Program of Sun Yat-sen Cancer Center.Corresponding authors: LIU Dong-geng, Tel/Fax: 020-87343352, E-mail:[email protected]; JIANG Wen-qi, Tel/Fax: 020-87343352, E-mail:[email protected].
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All the patients were followed at 3-month intervalsduring the first year, 6-month intervals in the secondyear, and once a year thereafter. The overall survival(OS) was defined as the time from diagnosis to death, orwas censored at the last known living data. Patientfollow-up was completed by April 30, 2011.Statistical analysis
Statistical analyses of the data were performedusing SPSS 13.0 software (SPSS Inc, Chicago, IL, USA).The relationship among various clinicopathologicalfactors and among different groups were analyzed usingChi-square tests, likelihood ratio, and linear-by-linearassociation as appropriate. The non-parametricWilcoxon Signed Ranks test and Kruskal-Wallis testwere used to evaluate the significance of the differencesof the mean ranks. Kaplan-Meier method was used todetermine the survival curves and the log-rank test wasused to investigate the differences between the lifetables. A two-tailed P<0.05 was considered statisticallysignificant.Results
General characteristics of patients
The general characteristics of the patients weresummarized in Tab.1. Of the 25 patients, 12 had afamily history of cancer including breast cancer (4cases) and other cancers (8 cases). The mean age atdiagnosis was 61 years, ranging from 32 to 80 years.Thirteen patients (52%) were diagnosed at an age olderthan 61 years and 12 (48% ) at younger ages. Thirteen(52% ) patients reported a history of smoking and 6(24%) had a history of alcohol drinking.
Clinicopathological characteristics of the tumor
As shown in Tab.2, cancer occurred in the leftbreast in 13 (52% ) cases and in the right breast in 12(48% ) cases. Six of the 16 patients with known tumor
location had cancer in the retroareolar area. The mostfrequent histological type was invasive ductal carcinoma(n=23), and only one case had mucinous carcinoma andanother had an unknown type. Among the 19 patientsavailable for hormone receptors assays, 16 were positivefor both ER and PR and only 2 were positive for HER-2.The data of Ki-67, VEGF and P53 were available in 16,17 and 16 patients, of whom 12 (75%), 10 (58.8%) and13 (81.2% ) were positive, respectively. Three patientsreceived neoadjuvant chemotherapy and 1 patient hadadjuvant radiotherapy. Thirteen patients receivedadjuvant chemotherapy and 7 received adjuvantendocrine therapy. The main chemotherapy regimen wasCAF/CEF (8 patients, with a median of 4 cycles), andother strategies included TAC, CMF, and AT. Onepatient underwent radiotherapy covering the primarylesion on the chest wall and the regional lymph nodes(supraclavicular, subaxillary and/or internal mammarylymph nodes). The drugs for endocrine therapy weretamoxifen and toremifen. Twenty patients underwenttotal mastectomy and 1 had lumpectomy. Thepercentage of T1 and T2 tumor size was 80%, with 50%of the patients had positive lymph nodes and 14.3% haddistant metastasis. According to the TNM stagingsystem, 4 (19.0%), 8 (38.1%), 6 (28.6%), and 3 (14.3%)patients were in stages I, II, III and IV, respectively.Nine patients had local recurrence at 1 to 80 monthsafter the treatment (median 33 months). Three patientswere found to have distant metastasis at 0 to 14 months,occurring in the bones in 1 case, in the liver in 1 case,and in the distant lymph nodes in 1 case.Univariate analysis
The results of univariate analysis are summarizedin Tab.3. The median follow-up was 51 months (range 1to 90 months). Eight patients died and the 5-year OSrate was 66.5%. Neoadjuvant chemotherapy, tumor size,lymph node status, distant metastasis and TNM stagewere significant predictors for OS. Although it was notsignificantly different, patients with adjuvant endocrinetherapy tended to have better OS (P=0.086). However,patients with neoadjuvant chemotherapy had poorer OSthan those without neoadjuvant chemotherapy (P=0.000)(Fig.1). Patients in stage I and II had better OS thanthose in stage III and IV (P=0.000) (Fig.2).Discussion
Due to the low incidence rate, studies of malebreast cancer remained scarce in China. In Westerncountries, male breast cancer was presented mostly inthe 60s of the patients[7-9], which was consistent with ourdata. A smoking history was not found to associate withthe occurrence of male breast cancer[8], nor was alcoholdrinking, which was contrary to the findings of Guénel etal[10]. Our study showed that the predominant histologicaltype was invasive ductal carcinoma, and no case wasfound to have invasive lobular type, similar to the resultsof previous studies [11-12]. The positivity rates of ER
Variable
Family history
Breast cancer
Other cancer
No cancer
Age (year)
<61
≥61
Smoking
Yes
No
Alcohol drinking
Yes
No
n
4
8
13
12
13
13
12
6
19
Percentage (%)
16
32
52
48
52
52
48
24
76
Tab.1 General characteristics of the patients withmale breast cancer
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Clinicopathological characteristics of male breast cancerNo.9
(84.2% ) and PR (84.2% ) were significantly higher inmale breast cancer patients than in female patients[13].We also investigated the expression of such cell cycleproteins as p53 and Ki-67. Mutations in the P53 tumorsuppressor gene are the most commonly observedoncogenic abnormalities in human malignancies [14-15].P53 expression has been detected in 0%-54% ofpatients with male breast cancer byimmunohistochemistry [16-17]. The significance of P53mutation in male breast cancer is unclear[18]. In ourpatients, 13 (81.2% ) were positive for P53, a ratesignificantly higher than that reported previously,though it did not seem to associate with the OS. Ki-67nuclear antigen is associated with cell proliferation andhas been recognized as a proliferation marker in breastcancer[19]. Twelve patients were Ki-67-positive in ourseries, but no significant correlations were foundbetween Ki-67 expression and the prognosis of thepatients, suggesting that Ki-67 did not play a dominantrole in the survival of male breast cancer patients.VEGF is a primary stimulant of angiogenesis to increasevascular permeability and promote metastasis[20], but wedid not find a correlation between VEGF positivity andprognosis in our series. Three patients with neoadjuvantchemotherapy had poorer OS than those without, but allthe patients receiving the therapy were in advanced
stages (2 in stage IV and 1 in stage IIIC).Several studies have demonstrated the benefits ofadjuvant chemotherapy[21] and radiotherapy[22], but ourresult did not provide any statistical support of thisnotion possibly due to the small sample size. Althoughadjuvant hormonal therapy and chemotherapy haveproven benefits in a subgroup of female breast cancerpatients, the value of adjuvant chemotherapy in malebreast cancer is less clear[3]. Our results indicated thatadjuvant chemotherapy was not associated with theprognosis, while patients receiving adjuvant endocrinetherapy tended to have a better OS (P=0.086), thoughnot statistically so. TNM stage is an important prognosticfactor affecting the outcomes of patients with malignanttumors, and male breast cancer is not an exception. Thepresent study showed that the tumor size, lymph nodeinvolvement and TNM stage were significantlycorrelated to the clinical outcomes of the patients. The5-year survival rate was 66.5% in our series, which washigher than that reported by Chung et al (57% ) twodecades ago[23], possibly due to technical improvement inthe early detection over the 20 years, advancedcomprehensive treatment and close follow-up.Considering the small sample size in the currentstudy, multivariate analysis was not done to explore theindependent effects of the prognostic factors. Future
Variable
Site of tumor
Left
Right
Location of tumor
Retroareolar
Other quadrant
Histological type
Invasive ductal carcinoma
Non-invasive ductal carcinoma
ER
Negative
Positive
PR
Negative
Positive
HER-2
Negative
Positive
Ki-67
Negative
Positive
VEGF
Negative
Positive
P53
Negative
Positive
Neoadjuvant chemotherapy
Yes
No
n
13
12
6
10
23
1
3
16
3
16
17
2
4
12
7
10
3
13
3
22
Percentage (%)
52
48
37.5
62.5
95.8
4.2
84.2
15.8
84.2
15.8
89.5
10.5
25.0
75.0
41.2
58.8
18.8
81.2
12.0
88.0
Variable
Surgery
Total mastectomy
Lumpectomy
No surgery
Adjuvant chemotherapy
Yes
No
Adjuvant radiotherapy
Yes
No
Adjuvant endocrine therapy
Yes
No
Tumor size
T1
T2
T3
T4
Lymph node status
N0
N1
N2
N3
Distant metastasis
M0
M1
TNM stage
I
II
III
IV
n
20
1
4
13
12
1
24
9
16
8
8
1
3
10
3
3
4
18
3
4
8
6
3
Percentage (%)
80.0
4.0
16.0
52.0
48.0
4.0
96.0
36.0
64.0
40.0
40.0
5.0
15.0
50.0
15.0
15.0
20.0
85.7
14.3
19.0
38.1
28.6
14.3
Tab.2 Clinicopathological characteristics of the patients with male breast cancer
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(J South Med Univ) Vol.31
research of the complex behavior of male breast cancerinvolving a larger sample size with longer follow-up mayprovide important new insights into both the biologicaland clinical factors of this rare malignancy.References
Variable*
Family history
Breast cancer
Other cancer
No cancer
Age (year)
< 61
≥61
Smoking
Yes
No
Alcohol drinking
Yes
No
Site of tumor
Left
Right
Location of tumor
Retroareolar
Other quadrant
ER
Negative
Positive
PR
Negative
Positive
HER-2
Negative
Positive
Ki-67
Negative
Positive
VEGF
Negative
Positive
n
4
8
13
12
13
13
12
6
19
13
12
6
10
3
16
3
16
17
2
4
12
7
10
P
0.506
0.420
0.846
0.910
0.686
0.971
0.522
0.342
0.081
0.780
0.537
Variable
P53
Negative
Positive
Neoadjuvant chemotherapy
Yes
No
Surgery
Total mastectomy+lumpectomy
No surgery
Adjuvant chemotherapy
Yes
No
Adjuvant radiotherapy
Yes
No
Adjuvant endocrine therapy
Yes
No
Tumor size
T1+T2
T3+T4
Lymph node status
N0+N1
N2+N3
Distant metastasis
M0
M1
TNM stage
I+II
III+IV
n
3
13
3
22
21
4
13
12
1
24
9
16
16
4
13
7
18
3
12
9
P
0.859
0.000
0.105
0.528
0.191
0.086
0.045
0.001
0.000
0.000
*Twenty-three cases had invasive ductal carcinoma, 1 had mucinous carcinoma and 1 had an unknown type, thus the histological type can
not be analyzed.
Tab.3 Univariate analysis for the overall survival in all the patients
Without neoadjuvant chemotherapy
Without neoadjuvant chemotherapy
P=0.000
Time since diagnosis (months)0 20 40 60 80 100
1.0
0.8
0.6
0.4
0.2
0.0
Ove
rall
surv
ival
(pro
babi
lity
)
Fig.1 Kaplan-Meier curves of overall survival byneoadjuvant chemotherapy.
PEG-mediated covalent binding of VEGF to decellularized aortic valves promotesadhesion and proliferation of endothelial progenitor cells
ZHOU Jian-liang1, ZOU Ming-hui1, CHEN Yi-chu1, LU Cui-fen2, SHI Jia-wei1, DONG Nian-guo1
1Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology,Wuhan 430022, China; 2College of Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, China
Abstract: Objective To improve the biological properties of decellularized aortic valves by polyethylene glycol(PEG)-mediated covalent incorporation of vascular endothelial growth factor (VEGF). Methods PEG crosslinking ofdecellularized aortic valves were completed via a Michael-type addition reaction, followed by covalent incorporationof VEGF through another Michael-type addition reaction between the unsaturated propylene acyl of PEG and thethiol groups on cysteine residues of VEGF. The effect of VEGF incorporation was evaluated by enzyme-linkedimmunosorbent assay (ELISA) and immune fluorescence assay. The endothelial progenitor cells (EPCs) were seededon decellularized aortic valves with or without these modifications, and after 10 days of culture, the valves wereexamined for DNA content and by hematoxylin-eosin staining and scanning electron microscopy. Results Immunefluorescence and ELISA showed that the maximal VEGF incorporation on the decellularized aortic valve reached908.94 ± 0.27 pg. Compared with the unmodified valves and the valves with PEG crosslinking, decellularized aorticvalves with covalent incorporation of VEGF significantly promoted the adhesion and proliferation of EPCs, whichformed a confluent cell monolayer on the valve surface. Conclusions PEG-mediated covalent incorporation of VEGFin the decellularized aortic valves improves the adhesion and proliferation of the seeded EPCs to facilitate theconstruction of tissue-engineered heart valves.Key words: decellularized aortic valves; polyethylene glycol; Michael-type addition reaction; vascular endothelialgrowth factor; endothelial progenitor cells
No.9 Clinicopathological characteristics of male breast cancer
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