Adjuvant systemic therapy for male breast carcinoma

Authors


  • Presented in abstract form (Abstract 177) at the 26th Annual San Antonio Breast Cancer Symposium, 2003, San Antonio, Texas.

Abstract

BACKGROUND

In the current study, the authors describe the M. D. Anderson experience with adjuvant systemic therapy in male breast carcinoma patients.

METHODS

A total of 156 men with a diagnosis of breast carcinoma registered and were treated at the M. D. Anderson Cancer Center between 1944 and 2001. One hundred thirty-five men had nonmetastatic breast carcinoma at diagnosis and were included in this analysis. Patients' charts were retrospectively reviewed to obtain details of patient characteristics, adjuvant therapy, and outcomes. Analysis was performed with descriptive statistics; the log rank test was used to compare outcomes.

RESULTS

The median patient age was 59 years (range, 25–80 yrs). Median follow-up was 13.8 years (range, 0.6–32.5 yrs). Sixty percent of patients had tumors 2 cm or smaller. Pathologic lymph node involvement was seen in 55% of patients. Tumors were estrogen receptor-positive in 85% of cases and progesterone receptor-positive in 71%. Chemotherapy was administered to 32 men (84% with adjuvant chemotherapy, 6% with neoadjuvant chemotherapy, and 9% with both). Approximately 81% received anthracycline-based regimens; 9% received additional taxanes; and 16% were treated with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). The median number of cycles was 6 (range, 4–14 cycles). Thirty-eight men received adjuvant hormonal therapy (92% received tamoxifen and 8% were treated with other therapy). The 5-year and 10-year overall survival rates were 86% and 75%, respectively, for men with lymph node-negative disease and 70% and 43%, respectively, for men with lymph node-positive disease. For men with lymph node-positive disease, adjuvant chemotherapy was associated with a lower risk of death (hazards ratio [HR] of 0.78), although this difference was not statistically significant. Overall survival was significantly better for men who received adjuvant hormonal therapy (HR of 0.45; P = 0.01).

CONCLUSIONS

This relatively large series of men with breast carcinoma suggests that men benefit from adjuvant systemic therapy for breast carcinoma, with the greatest benefit from adjuvant hormonal therapy. Cancer 2005. © 2005 American Cancer Society.

Breast carcinoma in men is a rare disease, although the incidence has been increasing.1 In 2004, an estimated 1450 new cases will be diagnosed, and 470 men will die as a result of breast carcinoma in the U.S. alone.2 The rarity of the disease has precluded randomized clinical trials and has made prospective studies difficult to conduct.3 Most available information on adjuvant therapies for male breast carcinoma comes from small retrospective series, which have had conflicting findings on the benefit of adjuvant chemotherapy and hormonal therapy in male patients.3–11

Because of this lack of data on men treated with adjuvant chemotherapy and hormonal therapy, the optimal treatment for men with breast carcinoma remains unknown. Most experts recommend similar treatment as that given to women with breast carcinoma, recognizing that there are very little data to substantiate this recommendation. At the M. D. Anderson Cancer Center, we have one of the largest institutional experiences with male breast carcinoma. Therefore, this study was undertaken to describe our experience with adjuvant systemic therapies in men with breast carcinoma.

MATERIALS AND METHODS

A total of 156 male patients who registered and were treated at M. D. Anderson between 1944 and 2001 and who had a diagnosis of breast carcinoma were identified using the Institutional Database. Twenty-one patients were excluded because they presented with metastatic disease at diagnosis. The final study population included 135 men with nonmetastatic breast carcinoma.

Patients' charts were reviewed and data were abstracted into a database. Data were collected on patient age and demographics and presenting tumor characteristics, including pathologic size, lymph node involvement, stage of disease, tumor grade, and estrogen receptor (ER) and progesterone receptor (PR) status. Grade was classified as low, intermediate, and high because specific grading systems changed over the years of this study. Detailed information was collected regarding primary surgical therapy and adjuvant therapies with chemotherapy, radiation, and hormonal therapy. The type of chemotherapy and hormonal therapy was recorded. Dates of disease recurrence and date and cause of death were noted. This study was approved by our Institutional Review Board.

The statistics used to describe these patients consisted of the tabulation of categorical variables and cross-tabulation of the categorical variables by adjuvant therapy status, overall survival, and disease-free survival. Continuous variables were described by their medians. Median follow-up time and median time to recurrence were calculated by the ‘reverse’ Kaplan–Meier method. Kaplan–Meier plots were used to describe differences in both overall survival and disease-free survival, by type of adjuvant therapy. The following comparisons were performed: 1) patients who received any adjuvant systemic therapy (chemotherapy or hormonal therapy) versus those who received no adjuvant systemic therapy; 2) patients who received any adjuvant hormonal therapy versus those who received none; and 3) patients with lymph node involvement who received adjuvant chemotherapy versus those patients with lymph node involvement who received no adjuvant chemotherapy. The adjuvant chemotherapy analysis was restricted to those patients with lymph node involvement to make the overall prognosis of the two groups more comparable. The log rank test was used to compare outcomes, with a two-sided P-value ≤ 0.05 considered statistically significant. Statistical analyses were performed using S-plus® software (version 6.1; Insightful®, Seattle, WA) and Stata software (StataCorp LP, College Station, TX).

RESULTS

A total of 135 male breast carcinoma patients with a median follow-up time of 13.8 years was included in this study. Table 1 shows the characteristics of this patient population. The median age at diagnosis was 59 years (range, 25–80 yrs). The patients were predominantly white (72%), with 15% who were black and 12% who were Hispanic. Approximately one-third of the patients were diagnosed before 1970. Sixty percent of patients had tumors measuring 2 cm or less, and only 7% had tumors larger than 5 cm in total dimension. Despite the small tumors, the majority of patients had pathologic lymph node involvement. The tumors tended to be intermediate or high grade. Among those patients with known estrogen and progesterone status, most had tumors that expressed hormone receptors (85% and 71%, respectively). The median time to disease recurrence was 6.1 years. Five- and 10-year overall survival rates were 86% and 75%, respectively, for men with lymph node-negative disease and 70% and 43%, respectively, for men with lymph node-positive disease.

Table 1. Patient Characteristics of 135 Male Breast Carcinoma Patients, Overall and by Receipt of Adjuvant Systemic Therapies
 All patients No. (%) n = 135Any adjuvant systemic therapy No. (%) n = 51Any hormonal therapy No. (%) n = 38Any chemotherapy No. (%) n = 32
Median age in yrs (range)59 (25-80)60 (38-80)61 (40-80)58 (38-75)
Race (n = 135)    
White97 (72)42 (82)31 (82)27 (84)
Black20 (15)4 (8)2 (5)4 (13)
Hispanic16 (12)5 (10)5 (13)1 (3)
Other2 (1)000
Year of diagnosis (n = 135)    
1940-196942 (31)1 (2)1 (3)0
1970-197922 (16)1 (2)01 (3)
1980-198933 (24)17 (33)13 (34)13 (41)
1990+38 (28)32 (63)24 (63)18 (56)
Pathologic tumor size (n = 102)    
≤ 2 cm61 (60)30 (64)23 (66)20 (69)
2-5 cm34 (33)16 (34)11 (31)8 (28)
> 5 cm7 (7)1 (2)1 (3)1 (3)
No. of positive lymph nodes (n = 104)    
047 (45)16 (33)13 (36)6 (19)
1-334 (33)21 (43)16 (44)15 (48)
≥ 423 (22)12 (24)7 (19)10 (32)
Grade (n = 76)    
Low8 (11)3 (7)1 (3)3 (12)
Intermediate39 (51)24 (57)21 (68)12 (48)
High29 (38)15 (36)9 (29)10 (40)
Estrogen receptor (n = 47)    
Positive40 (85)36 (88)31 (97)20 (83)
Negative7 (15)5 (12)1 (3)4 (17)
Progesterone receptor (n = 41)    
Positive29 (71)27 (73)21 (75)14 (61)
Negative12 (29)10 (27)7 (25)9 (39)

Of all patients, 51 received adjuvant systemic therapy. Thirty-eight men were treated with adjuvant hormonal therapy and 32 men with adjuvant chemotherapy. Nineteen patients received both chemotherapy and hormonal therapy, 19 had only hormonal therapy, and 13 had chemotherapy alone. Patients who received adjuvant therapies were generally similar with regard to age and racial distribution to those patients who did not receive systemic therapies (Table 1). Before 1980, very few patients were treated with adjuvant systemic therapies. One patient underwent an orchiectomy in 1960, and one patient was treated with seven cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in 1979. Otherwise, all patients who received systemic therapy were diagnosed after 1980. Patients with lymph node involvement were more likely to be treated with systemic therapy, and patients with hormone receptor-positive disease were more likely to receive adjuvant hormonal therapy.

Details of treatment are shown in Table 2. Fifty-five percent of patients underwent a modified radical mastectomy, 31% underwent a radical mastectomy, and 14% underwent a mastectomy without axillary lymph node dissection. Adjuvant radiotherapy was administered in nearly 40% of patients. Among those patients treated with chemotherapy, 72% were treated with anthracycline-based regimens, which included 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC); 5-fluorouracil, doxorubicin, cyclophosphamide, methotrexate, and vinblastine (FAC-MV); vincristine, doxorubicin, cyclophosphamide, and prednisone (VACP); 5-fluorouracil, doxorubicin, cyclophosphamide, vincristine, and prednisone (FAC-VP); cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); and doxorubicin and cyclophosphamide (AC). Approximately 9% of patients received both an anthracycline and a taxane, and 16% were given CMF. The median number of cycles of chemotherapy was 6 (range, 4–14 cycles). The majority of patients received chemotherapy in the adjuvant setting, although 15% received at least some portion of their chemotherapy before surgical resection.

Table 2. Treatment Received by Male Breast Carcinoma Patients
TreatmentNo. (%)
  1. CMF: cyclophosphamide, methotrexate, and 5-fluorouracil; LHRH: luteinizing hormone-releasing hormone.

Surgery (n = 135) 
Surgery without lymph node dissection19 (14)
Modified radical mastectomy74 (55)
Radical mastectomy42 (31)
Adjuvant radiotherapy (n = 135) 
Yes51 (38)
No84 (62)
Systemic therapy (n = 51) 
Chemotherapy alone13 (25)
Chemotherapy and hormonal therapy19 (37)
Hormonal therapy alone19 (37)
Chemotherapy regimens (n = 32) 
Anthracycline-based23 (72)
Anthracycline and taxane3 (9)
CMF5 (16)
Chemotherapy scheduling (n = 32) 
Adjuvant27 (84)
Neoadjuvant2 (6)
Both neoadjuvant and adjuvant3 (9)
Hormonal therapy regimens (n = 38) 
Tamoxifen35 (92)
Other (LHRH agonist, megestrol acetate)3 (8)

There was less variety in the types of adjuvant hormonal therapies used. Approximately 92% (35 of 38 patients) of patients who received hormonal therapy received tamoxifen. One patient underwent orchiectomy, one was given megestrol acetate, and one was treated with an luteinizing hormone–releasing hormone agonist. Of the 38 patients who received adjuvant hormonal therapy, 31 had ER-positive tumors, 6 had an unknown ER status, and 1 had ER-negative tumors. Among those patients who had known ER-positive tumors, 31 of 40 were treated with adjuvant hormonal therapy. Of those known to have tumors negative for ER, 1 of 7 received adjuvant hormonal therapy.

Kaplan–Meier curves of time to recurrence and overall survival for patients with and without systemic therapy are shown in Figure 1. Overall, patients who were treated with systemic therapies tended to have longer time to disease recurrence and survival. The hazards ratio (HR) for time to recurrence was 0.70 (95% confidence interval 95% CI], 0.42–1.17) and the HR for overall survival was 0.57 (95% CI, 0.34–0.95) for patients treated with systemic therapy compared with those who did not receive any systemic therapy. Figure 2 shows significantly longer time to recurrence (HR of 0.49; 95% CI, 0.27–0.90) and survival (HR of 0.45; 95% CI, 0.25–0.84) for patients who received adjuvant hormonal therapy. The adjuvant chemotherapy Kaplan–Meier curves were limited to those patients with lymph node involvement so that groups with more similar prognoses would be compared (Fig. 3). Patients who received adjuvant chemotherapy had lower hazards for time to recurrence and overall survival than those patients who did not receive chemotherapy, but these differences were not statistically significant (HR of 0.88; 95% CI, 0.44–1.73, and HR of 0.78; 95% CI, 0.39–1.55, respectively).

Figure 1.

Kaplan–Meier curves of (A) overall survival and (B) time to disease recurrence for male patients with and without adjuvant systemic therapy.

Figure 2.

Kaplan–Meier curves of (A) time to disease recurrence and (B) overall survival for male patients with and without adjuvant hormonal therapy.

Figure 3.

Kaplan–Meier curves of (A) time to disease recurrence and (B) overall survival for male patients with and without adjuvant chemotherapy among the 57 patients with lymph node-positive disease.

DISCUSSION

The current series, which includes 51 male patients who were treated with adjuvant systemic therapy, is to our knowledge one of the largest reports to date of adjuvant systemic therapies in male breast carcinoma patients. Our male patients who received adjuvant systemic therapies had a 43% lower risk of death than those who did not have systemic therapies. In addition, as those patients who received systemic adjuvant therapies had a baseline poorer prognosis (more lymph nodes involved), these numbers could be an underestimate of the true benefit. The effects were greatest for adjuvant hormonal therapy, which was associated with statistically significant improvement in time to disease recurrence and overall survival. Chemotherapy was also associated with lower risks of disease recurrence and death, but this finding was not statistically significant.

To our knowledge, the existing literature on adjuvant therapies for male breast carcinoma is quite limited; only a single prospective study of adjuvant chemotherapy in male breast carcinoma has been reported to date. This study described the survival experience of 24 men with Stage II breast carcinoma who were treated with CMF; the median survival was 98 months.3 Several retrospective reviews have evaluated adjuvant chemotherapy in male breast carcinoma patients,4, 7, 9–11 but to our knowledge only two have suggested a benefit from adjuvant chemotherapy.9, 11 The interpretation of all these studies is limited by the small number of patients, because the largest report included only 38 patients treated with adjuvant chemotherapy.7 Clearly, these studies are inadequately powered to address the question of survival benefit; however, small retrospective series are currently the best available data on adjuvant therapies for male breast carcinoma. Our current series is not only one of the largest, but also provides considerable information on types of chemotherapy regimens, which to our knowledge has not previously been reported in detail. Although chemotherapy was not associated with a statistically significant improvement in survival, our point estimate of a risk reduction of 22% is consistent with the risk reductions seen in women treated with chemotherapy.12

The data are also sparse for men treated with adjuvant hormonal therapy. To our knowledge, there have been no prospectively collected data on adjuvant hormonal therapy in men, but retrospective series have suggested a survival benefit for men treated with adjuvant tamoxifen.4–6 In what to our knowledge was the largest series of male breast carcinoma patients treated with adjuvant hormonal therapy published to date, Goss et al.4 reported a significant improvement in overall survival among the 57 patients who were treated with adjuvant tamoxifen. However, in a similarly sized multi-institutional cohort of patients from Wisconsin, a benefit of adjuvant systemic therapy was not apparent.7 The current series suggests that men do benefit from adjuvant hormonal therapy because men treated with hormonal therapy had a 51% lower risk of recurrence than men who did not receive treatment with a hormonal agent. The findings are also consistent with the 47% reduction in risk of recurrence among women treated with tamoxifen reported in the Early Breast Cancer Trialists Collaborative Group meta-analysis.13

Perhaps because of the lack of data on the efficacy of chemotherapy and hormonal therapy in male patients, practitioners are less likely to prescribe adjuvant systemic therapy for men with breast carcinoma. In a large series of male patients from the National Cancer Data Base, 27% of male patients were treated with adjuvant chemotherapy as compared to 41% of age- and stage-matched female patients.14 It is possible that male breast carcinoma patients are undertreated for a disease which has a similar stage-by-stage prognosis in men and women.1 This series of patients provides additional evidence that men who are at a substantial risk of breast carcinoma recurrence will benefit from adjuvant systemic therapy. In particular, men are likely to benefit from adjuvant hormonal therapy, especially since over 90% of men have hormone receptor-positive disease.1

Our findings are limited by the problems inherent in a retrospective single-institution review. Survival for patients with breast carcinoma has been improving over time, which makes the use of historical controls problematic.15 In addition, the possibility of selection biases in treatment assignments confounds the comparisons of patients who did and did not receive a particular treatment. However, for rare diseases retrospective series covering many years are the only source of data, and despite their limitations are the best available resource for understanding an uncommon disease.

In conclusion, the current series provides suggestive evidence that male patients with breast carcinoma will benefit from adjuvant systemic therapy, and that the magnitude of the benefit is similar to that seen in women. Unfortunately, the question of whether men benefit from adjuvant systemic therapies will never be definitively answered from a retrospective series. Thus, we would strongly encourage the prospective collection of data on male breast carcinoma patients so that we can continue to advance our understanding of this rare disease.

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