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A Comparison Outcome of Male Breast Cancer with Female Breast Cancer

Peter C. Willsher, FRACS, lain H. Leach, DM, Ian 0. Ellis, MRCPath, Jim B. Bourke, FRCS, Roger W. Blarney, FRCS, John F.R. Robertson, FRCS, Nottingham, United Kingdom

BACKGROUND: It is unclear whether breast cancer has a similar prognosis in males and females.

METHODS: A 20-year retrospective study of all male breast cancer patients in our region was undertaken. We compared this series with a group of females matched for the major prognostic factors and an unmatched series of female patients treated over the same period.

RESULTS: Forty-one patients with invasive cancer and 2 with ductal carcinoma in situ were identified. One invasive cancer was treated with radiotherapy, 40 had surgery. Local recurrence occurred in 23% and axillary recurrence in 40% of cases. Male and female patients (n = 123) matched for the major prognostic factors showed a similar outcome for disease-free interval (P = 0.90) and survival (P = 0.27). However, both the above groups had a significantly worse outcome than the unmatched series of female patients with breast cancer.

CONCLUSIONS: When prognostic factors are allowed for, male and female breast cancer patients have a similar outcome. This suggests that such features should be taken into account when determining management for males with breast cancer just as they are in females. Am J Surg. 1997;173:135-139. 0 1997 by Excerpta Medica, Inc.

I t would appear that much of the management of male breast cancer is based on clinical experience gained from treating females with breast cancer.‘-’ However, reports

in the literature are conflicting as to whether male breast cancer has a prognosis and clinical course similar to female breast cancer. We have undertaken a retrospective study of a series of male patients with breast cancer and compared the outcome with a group of matched female breast cancer patients.

METHODS Patients

Male patients who presented with breast cancer to any of the general surgeons at the three major hospitals in Not-

From the Professorial Unit of Surgery and Department of His- topathology, City Hospital and Department of Surgery, University Hospital, Nottingham, United Kingdom.

Requests for reprints should be addressed to Peter C. Willsher, FRACS, Professorial Unit of Surgery, City Hospital, Hucknall Road, Nottingham NG5 1 PB, United Kingdom.

Manuscript submitted October 4, 1995 and accepted in revised form March 25, 1996.

tingham during the 20-year period prior to June 1994 were identified in the following manner. All consultant surgeons were written to request permission to gather information on their patients, and were asked for details of male breast cancer patients they could recall treating. All consultants re- plied, providing an initial list of patients. Following this, the Trent Regional Cancer Registry provided a list of all male breast cancer patients listed for each general surgeon in Nottingham over the previous 20 years. Finally, a review of the records of the hospital pathology departments was undertaken. A total of 43 male patients with a histological diagnosis of breast cancer were identified. The case notes of all patients were reviewed, and the clinical data obtained.

Matching of Male and Female Patients For each of the 41 male patients with invasive cancer, 3

female breast cancer patients (n = 123) were matched to allow comparison of disease-free interval and survival. The female patients were obtained from a computerized database of over 3,000 patients treated in our unit over a 20-year period. Patients were matched for age, pathological size and grade of primary tumor, and pathological lymph node status (Table I). The groups were well matched for these factors apart from the lymph node status, since this was unknown in a large proportion of male patients. The matched female patients were diagnosed not more than 12 months from the date of diagnosis of each correspondmg male patient.

Statistical Analyses All analyses were performed with the SPSS-X data anal-

ysis program (SPSS UK Ltd.). Fisher’s exact test (two tailed) was used to assess for differences in proportions. Dis- ease-free interval and survival curves were compared with the Lee-Desu statistic using Gehan’s modification of the generalized Wilcoxon test. Degrees of freedom was n - 1 for all analyses.

RESULTS Clinical Features

The 43 patients in the study comprised 2 with ductal carcinoma in situ and 41 with invasive breast cancer. Of the 41 invasive cancers, 24 were in the left breast and 17 in the right. Patients had experienced symptoms for an average of 6 months prior to presentation (range 1 week to 3 years). For the patients with invasive cancer, 88% (36 of 41) complained of a lump at the time of presentation. Three reported a serosanguineous nipple discharge alone, 1 had pain only, and 1 patient with Paget’s disease complained of nipple deformity only. On examination 950/o (39 of 41) of patients had a palpable lump, the retnaining 2 had a nipple discharge only detected. Five patients had palpable axillary

% 1997 by Excerpta Medica, Inc. 0002-961 O/97/$1 7.00 185 All rights reserved. PII SOOO2-9610(97)00009-3

IALE AND FEMALE BREAST CANCER OUTCOMEMllLLSHER ET AL 1 1 TABLE I

Characteristics of Matched Male and Female Patients

Male Patients (n = 41)

Female Patients In = 123)

Mean age (range) Mean pathological

size (range) Pathological grade

II Ill

Axillaty node status

Positive Negative Unknown

63 years (32-96) 61 years (29-85)

24 mm (l-110) 25 mm (2-80)

1 (2%) 11 (27%) 29 (70%)

10 (24%) 8 (20%)

23 (56%)

3 (2%)

32 (26%)

88 (71%)

34 (28%)

76 (62%)

13 (10%)

TABLE II

Local Recurrence in Operable Patients (n = 40)

Recurrence Recurrence Rate After Rate Without

Type of Operation Radiotherapy Radiotherapy

Local excision (n = 4)

Simple mastectomy (n = 18)

Simple mastectomy and excision of axillaty nodes (n = 18)

Total (n = 40)

0% (O/2) 0% (O/2)

33% (l/3) 20% (3/15)

0% (Oh) 38% (5/13) 10% (l/10) 27% (8/30)

TABLE Ill

lpsilateral Axillaty Node Recurrence in Operable Patients (n = 40)

Recurrence Recurrence Rate After Rate Without

Radiotherapy Radiotherapy

Pathological node positive (n = 10) 0% (O/2) 75% (6/8)

Pathological node negative (n = 8) 0% (O/2) 50% (3/6)

Nodes not sampled (n = 22) 33% (2/6) 38% (5/16)

Total (n = 40) 20% (2/l 0) 47% (14/30)

nodes, and no patient had distant metastases detected at the time of presentation.

Initial Treatment and Clinical Outcome Of the 2 patients with ductal carcinoma in situ, 1 had a

mastectomy and the other a local excision of the palpable lump. Of the 41 patients with invasive cancer, 1 had a locally advanced tumor (11 cm diameter) and was initially treated with radiotherapy. The remaining 40 patients un- derwent surgery; 4 had lumpectomy alone, 18 simple mastectomy, and 18 mastectomy with excision of axillary nodes. The mean number of nodes removed was 2.8 (range 1 to 7). Of the 40 patients with operable tumors, 11 re-

1

0.3 1 1 0 12 24 36 46 60 72

Months from Diagnosis

Figure 1. Comparison of disease-free interval for male and matched female patients with breast cancer showing no significant difference (Lee Desu statistic = 0.02, P = 0.90). Compared with an unmatched female series, both the male patients (statistic = 4.3, P = 0.04) and matched female patients (statistic = 10.4, P = 0.001) have a worse outcome.

ceived adjuvant therapy (7 local flap and ipsilateral axillary radiotherapy, 3 tamoxifen and radiotherapy, and 1 tamoxifen only). Adjuvant tamoxifen was given to only 3 of the 10 patients with pathological axillary node involvement. No patient was given adjuvant systemic chemotherapy.

Neither patient with ductal carcinoma in situ had recurrence of their disease after 1 and 5 years of follow-up. For the 40 patients with operable invasive cancer, local recurrence after surgery occurred in 23%) (9 of 40) at a mean of 15 months (range 6 to 35). Table II shows the local recurrence rate for each type of operation. Local recurrence was more common for histological grade 3 cancers (grade 3, 8 of 29; grade 1 or 2, 1 of II), but this difference wds not si@ficant (P = 0.40). Tumor size larger than 2 cm in diameter (>2 cm 6 of 28, <2 cm 3 of 12; P = 0.80) and the presence of vascular invasion (VI positive 1 of 11, VI negative 7 of 29; P = 0.41) were not predictive of local recurrence.

Ipsilateral axillary node recurrence developed in 40% (16 of 40) patients at a mean of 16 months (range 2 to 45). Regional recurrence was significantly associated with higher grade tumors (grades 1 and 2, 1 of 11; grade 3 15 of 29; P = 0.03). The relationship between regional recurrence, pathological node involvement, ,md adjuvant radiotherapy is shown in Table III. Radiotherapy resulted in a reduction of the regional recurrence rate hut this was not statistically significant (P = 0.26). There was no significant difference in local recurrence rates if radiotherapy was given (Table II, P = 0.40). Thirty-four percent (14 of 41) of patients subsequently developed metastatic disease at a mean of 18 months (range 7 to 76). Metastaaes occurred in the following sites: hone = 8, lung = 9, visceral = 2, and skin = 1. Axillary node status did not show any relationship to survival outcome; however, it was only known for 18 patients (P = 0.45, curve not shown).

Comparison of Outcome for Male and Female Breast Cancer Patients

At a median follow-up of 42 months for Inale patients and 50 months for female, the analyses did not demonstrate any significant difference between the groups for disease-free interval (Figure 1) or survival (Figure 2). For comparison,

186 THE AMERICAN JOURNAL OF SURGERY@ VOLUME 173 MARCH 1997

/ MALE AND FEMALE BREAST CANCER OUTCOME/‘WlLLSHER ET AL

Figure 2. Survival curves for male and matched female patients with breast cancer showing no significant difference (Lee Desu statistic = 1.24, P = 0.27). Compared with an unmatched female series, both the male patients (statistic = 8.6, P = 0.0003) and matched female patients (statistic = 7.7, P = 0.006) have a worse outcome.

the outcome of the entire female series (n = 3,085, median follow-up 40 months) treated during the same period and in the same region as the male series is shown in Figures 1 and 2. This shows that both the male and matched female groups have a worse outcome than the female series as a whole.

COMMENTS Male breast cancer represents less than 1% of all breast

cancer, and it is therefore not surprising that this series is retrospective in nature (in common with the previously reported series of male breast cancer).““4*5 In contrast to female patients with breast cancer, there are no reports where male breast cancer patients have been observed prospec- tively in a randomized trial, and it is unlikely that any such trials will be performed.‘a6 If any advances in the management of breast cancer identified in females are to be applied to males with breast cancer, it is important that similarities or differences in clinical outcome between male and female breast cancer are identified.

Clinical Features and Initial Management The mean age of presentation for males with breast cancer

is approximately 10 years older than for females.‘,’ The majority of male patients with breast cancer present with palpable lump, as would be expected in view of the small size of the male breast. In this series only 2 patients did not have a clinically detectable breast mass, and these patients hoth had a serosanguineous nipple discharge as their only clinical feature. Other series have reported nipple discharge as a presenting symptom of breast. cancer in men and suggest

that it should always be investigated by biopsy.‘,’ With respect to the management of male breast cancer,

review of the literature reveals a gradual shift away from radical mastectomy, which appears to parallel a recognition in female breast cancer that more radical local surgery does not influence survival.” There has heen no clinical trial in male breast cancer to prove this, hut retrospective reports show no survival advantage for radical mastectomy.2’4,h In our series, no patient had a radical mastectomy, and the majority were treated with simple mastectomy, with or

1 Surviving Fraction

0.9 /~ 'I1 I ,

0.5

1 o.401---;2---1--- 36-. I

24 &5 72

Months From Diagnosis

without node excision. It is of interest that the 4 patients who had lumpectomy (2 with r&c~therapy) have not developed local recurrence (Table II). While breast conser- vation surgery with radiotherapy has become standard therapy for female breast cancer, at present no conclusive data regarding this approach in male breast cancer is available.

The 23% local recurrence rate in our series falls in the upper range of that reported in female breast cancer.” It should be noteJ that 73% of tumors were histological grade 3 and that, as in female breast cancer, this series found that patients with higher grade tumors were more likely to de- velop local recurrence. Postoperative radiotherapy did im- prove local control in our series (Table II), and this has been reported by others.4 In view of the known benefits of radiotherapy in female breast cancer, ir would seem prudent to provide postoperative radiotherapy- for all T3 tumors and for T1/2 tumors with a high risk of local recurrence. Tumor grade, axillary node status, and lymph-vascular invasion are predictive of local recurrence in female breast cancer.’ While these factors are not statistically significant in this small series, this finding would suggest that male patients with such risk factor should he considered for local adjuvant radiotherapy.

The regional axillary node recurrence rate of 40% (Table III) reflects the conservative manqement of the axilla in this series of patients. Almost half of the patients did not have any initial treatment to the axilla wtth either surgery or radiotherapy. In those who did have axillary surgery, this was largely confined to node sampling. The 10 patients with pathologically involved nodes did not have a full axillary clearance, and only 2 received adjuvant radiotherapy. It should be remembered that some patients in this series were treated up to 20 years ago, and it was notable that earlier patients had excision of palpable axillary nodes only. Latter patients tended to have a four-node axillary sample taken, followed by radiotherapy if node positive. Overall, radiotherapy resulted in a reduction of the regional recurrence rate from 47% to 20% (Table III). This difference was not statistically significant, which may he related to the small size of this series. However, this outcome suggests that the axilla in male breast cancer should he managed as in female breast cancer.

The role of systemic adjuvant therapy in male breast cancer is less well established than in female breast cancer.’ This is confirmed in our series where only 6 patients received adjuvant tamoxifen. This meant that 7 of the 10 patients known to be axillary node positive did not receive any adjuvant systemic therapy. The infrequency of male breast cancer means that no prospective trial of systemic adjuvant therapy has been performed, so that the benefits have not been proven. Bagley et al” and Pate1 et al” have compared a total of 35 patients given adjutant chemotherapy for male breast cancer, with retrospective controls to show an improved outcome. Riberio et al” obtained a 61% 5-year survival in 35 patients given adjuvant tamoxifen for operable breast cancer, compared w~rh 44% survival in his- torical controls. The authors of these reports admit that their series are small and that the USC of retrospective controls does place limitations on their conclusion. However, these reports suggest that a survival henefit similar to female breast cancer could be obtained hy the use of systemic adjuvant therapy in male breast cancer. Several authors now

THE AMERICAN JOURNAL OF SURGERY” VOLUME 173 MARCH 1997 187

IALE AND FEMALE BREAST CANCER OUTCOMENVILLSHER ET AL

recommend the use of adjuvant treatment in node positive patients.‘,‘“,” Since the benefits are unproved, the role of this therapy in node negative patients is not clear. The majority of male breast cancers are estrogen-receptor positive,” and the reported side effects of tamoxifen are few in males. It has been recommended that tamoxifen be the adjuvant therapy of choice in male patients.“” While tamoxifen is the most studied endocrine therapy even in male patients, there are alternative endocrine therapies that may be appropriate in the future. The role of adjuvant chemotherapy is less clear.”

Comparison of Outcome with Female Patients It has previously been stated that male breast cancer has

a poorer outlook than female breast cancer.‘.‘m5.” More re- cent reports have suggested that this may be a misconcep- tion.‘.‘,14 Our comparison between matched male and feemale breast cancer patients allowed for the major prognostic features of breast cancer (tumor size, histological grade and lymph node status). Further, we also attempted to allow for any potential impact on outcome resulting from changes in treatment over the 20 years of this series, by matching patients for the time of diagnosis (eg, adjuvant therapy has only been in use in our unit since 1989). We have confirmed that when the groups are matched in this fashion, that there is a very similar outcome in terms of disease free interval (Figure 1) and survival (Figure 2). Our finding of a worse outcome for both the male and matched female groups compared with the entire female series suggests that the worse outcome for male breast cancer is due to a difference in the distribution of prognostic factors. It is possible that the of preponderance of grade 3 tumors (73%) is the most important factor.

CONCLUSIONS This study shows that breast cancer in males shows simi-

larities to that in females in terms of the clinical outcome, in that inadequate primary treatment results in high local and regional recurrence rates. The comparison of disease- free interval and survival between male and feemale breast cancer patients has shown a similar outcome when they are matched for the known prognostic factors. This finding would suggest that pathological features should be taken into account when determining management for male breast cancer just as they are in female breast cancer. For example, tumor size and histological grade could be used to

select node-negative patients appropriate for adjuvant therapy. In general, it would appear that if the identified differences are taken into account, then both the philosoph- ical and practical management approach should largely be the same for males and females with breast cancer.

ACKNOWLEDGMENT The authors thank Mr. Matthew Mitchell for assistance

with statistical analyses.

This retrospective study matches u sample of mule and female breast cancer patients of simihr qe and histological findings. Interestingly, the prognosis is similar when factors such as tumor size, pde, and axillury lymph node involvement ure considered.

REFERENCES 1. Borgen P, Wang GY, Vlamis V, et al. Current management of male breast cancer. Ann Surg. 1992;215:451-458. 2. Riberlo G. Male breast carcinoma. A review of 301 abes frrom the Christie Hospital and Molt Radium Institute, Manchester. Br J CUTUX~. 1985;51:115-119. 3. Vercoutre A, O’Connell T. Carcmoma of the male breast. Arch Surg. 1984;119:1301-1304, 4. Spence R, MacKenzie G, Anderson J, et al. Long-term survival following cancer of the male breast 111 Northern Ireland. Cancer. 1985;55:648-652. 5. Our&l K, lotze M, Hinshaw J. Prognostic fxtars of carcinoma of the male breast. Sur,q Gy C)bat. 1984;159:373-376. 6. Jaiyesmi I, Buzdar A, Sahin A, et al. Crrcmoma of the male hreast. Ann fntrrn Med. 1992;117(9):77 l-777. 7. Treveh N. Rohbins G, Amoroso W. Serous and serosangumeous discharge from the male nipple. Arch Surg. 1956;73:3 19-329. 8. O’Rourke S, Galea MH, Morgan L). et al. Local recurrence after simple mastectomy. Br ] Surg. 1994;81:386- 389. 9. Bagley CS, Wesley MN, Young RC, Lippman ME. Adjuvant chemotherapy in males with cancer of the breast. Am J Clin On&. 1987;10:55-60. 10. Pate1 H, Buzdar A, Hortohagyi CT. Role uf adjutant chemo- thempy in malt breast cancer. Cancw 1989;64:1585-1589. 11. Riherio G, Swindell R. Ad’ J uvdnt t,mwxlfen for male hreast cancer (MBC). Brl Cancer. 1992;65:252-254. 12. Fox S, Rogers S, Dav C, et al. Oestrogen receptor and epidermal growth factor receptor &pressl~,n m male hrrast carcinoma. J Pa- th&by. 1992;166:13~18. 13. Gattuso P, Reddy L, Green M, et al. “New” prognostic factors *n invasive breast cancer in men. , !40dcm Pathol. 1992;5(l):Abstt~t No. 69,13A. 14. Guinee VF, C&son H, Mollcr T, ct al. The prognosis of breast cancer in males. A report of 335 case>. Cancer. 1993;71:154-161.

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