Abstract
Purpose. The aim of this study was to review the clinical presentation and to evaluate prognostic factors, treatment modalities, outcome, and second malignancy in male breast cancer patients. A chart review was conducted of all men treated for breast cancer between January 1991 and December 2007. Cox proportional hazards regression model and Kaplan–Meier curve were used to determine prognostic factors and plot survival probabilities. Invasive carcinoma was diagnosed in 22 patients and ductal carcinoma in situ in 7 patients. With mortality as the endpoint, tumor size indicated hazard ratio (HR) of 1.5 for each 1-cm increase in tumor size (p = .03). Overall stage and increased age were associated with increased risk of mortality (HR = 2.1, p = .055; HR = 1.09 for a 1-year increase in age, p = .08, respectively). Adjuvant radiation therapy yielded an HR of 0.1 (p = .058), indicating a favorable association with the survival. Advanced age, higher stage, and increasing tumor size were unfavorable to survival in male breast carcinoma. The benefit of adjuvant radiation therapy should be addressed in future collaborative studies.
Male breast cancer is rare, accounting for only 0.7% of all breast cancer diagnoses. In 2010 in the United States, there were an estimated 1,970 new cases of male breast cancer, and 390 men are predicted to die from the disease annually (American Cancer Society, 2010).
The etiology of male breast cancer remains unclear. Predisposing risk factors may include radiation exposure, estrogen administration, and diseases associated with hyperestrogenism, such as cirrhosis or Klinefelter’s syndrome. Testicular abnormalities such as undescended testes, orchitis, and infertility have also been associated with an elevated risk of breast cancer (Sasco, Lowenfels, & Pasker-de Jong, 1993; Thomas et al., 1992). Benign breast conditions, including gynecomastia, mastitis, and breast trauma have been implicated, although the evidence in these cases is conflicting.
An increased risk of male breast cancer has been reported for patients carrying mutations in the BRCA2 tumor suppressor gene. In two population-based series, between 4% and 16% of men with breast cancer were reported to carry the mutation (Basham et al, 2002; Friedman et al., 1997).
In 90% of males with breast cancer, the histopathological diagnosis is invasive duct carcinoma, with the remaining 10% being noninvasive ductal carcinomas (Stalsberg et al., 1993). Because the rarity of male breast cancer precludes any large clinical trials, treatment protocols have been modified from those arising from large female breast cancer trials. Treatment can be tailored to the stage of the disease, general health, age of the patient, hormone-receptor and HER2 status, and BRCA gene mutation status. In approximately 20% of female breast cancers, there is amplification of the Her2/neu gene or overexpression of its protein products. The overexpression of this receptor in breast cancer is associated with increased recurrence and worse prognosis. However, treatments with Trastuzumab that target Her2 receptor cells are very effective in reducing cancer recurrence. The most common primary treatment is surgery. For invasive carcinoma, modified radical mastectomy (MRM) with removal of the entire breast and most of the axillary lymph nodes is the conventional surgical treatment. Mastectomy is preferred over lumpectomy (in which only the tumor is removed from the breast with suitable margins), which is rarely performed in men because of the typically small amount of breast tissue and the frequent involvement of the skin or chest wall by the lesion. If lumpectomy is performed, adjuvant radiation treatment is usually recommended. Sentinel lymph node (SLN) evaluation of axillary nodes in place of complete axillary dissection is recommended (Albo et al., 2003). For ductal carcinoma in situ (DCIS), a simple mastectomy where the entire breast is removed, including the nipple, areola, and skin but not all the axilla lymph nodes or lumpectomy followed by adjuvant radiation therapy to the breast is recommended. However, a number of studies have suggested that, although radiation therapy reduces the risk of local recurrence, it has no impact on overall survival (Cutuli et al., 1995; Donegan, Redlich, Lang, & Gall, 1998; Izquierdo, Alonso, De Andres, & Ojeda, 1994; Yidrim & Berberoglu, 1998).
Tumor size and lymph node involvement are recognized as clear prognostic factors for male breast cancer. The risk of mortality has been reported to be 50% higher in men with lymph node involvement. Patients with tumors measuring between 2 and 5 cm had a 40% higher mortality risk compared with those with smaller tumors. Mortality has also been reported to be higher in men aged 65 years and older. The 5-year survival rates for each stage are as follows: Stage I, 78%; Stage II, 67%; Stage III, 40%; and Stage IV, 19% (Giordano, Cohen, Buzdar, Perkins, & Hortobagyi, 2004).
Following surgery, adjuvant chemotherapy is recommended in patients who have locally advanced tumors and axillary node involvement with risk for systemic recurrence. In a study by Giordano et al. (2005), 25% of patients received chemotherapy alone, and 37% received chemotherapy and hormonal therapy.
More than 90% of male breast cancers are estrogen-receptor (ER) positive, and Tamoxifen is frequently prescribed as adjuvant hormone therapy, having been reported to decrease breast cancer recurrence and mortality (Fentiman, Fourquet, & Hortobagyi, 2006). Studies have shown that Trastuzumab, a monoclonal antibody used in combination with chemotherapy, can reduce the rate of recurrence in female breast cancer patients who are positive for with Her2neu proto-oncogene (Ross et al., 2009). This adjuvant treatment has been extended to male breast cancer patients with Her2neu positive tumors.
In this study, a chart was survey done of all men treated at our institution for breast carcinoma between 1991 and 2007. The clinical presentation, various prognostic factors, treatment patterns, and outcomes, including data on second malignancy are described.
Materials and Methods
A retrospective chart review of all men with a diagnosis of breast cancer that had been treated at our institution (New York Hospital Medical Center of Queens) between January 1991 and December 2007 was conducted. The hospital institutional review board approved the study. Patients were identified through the Cancer Center Tumor Registry of the hospital. Of the 30 cases that were identified, 29 cases were suitable for analysis, with the remaining case excluded due to insufficient data.
Information was also collected regarding type of surgery, any adjuvant treatment with chemotherapy, hormone therapy, or radiation therapy, as well as BRCA1/2 genetic testing and the incidence and type of second malignancy. The data were then analyzed to evaluate the various prognostic factors.
Statistical Methods
The patient characteristics were summarized using summary statistics (e.g., percentage and frequencies). The Cox proportional hazards regression model was applied to determine the prognostic factors for all-cause mortality and to estimate the corresponding hazard ratios (HRs) along with the confidence intervals and statistical significance. As a result of the small sample size, each prognostic factor was evaluated separately, adjusting for age. Age, stage, and tumor size were treated as continuous variables whereas lymph node positivity, grade, adjuvant radiation, ER, progesterone receptor (PR) status were treated as categorical variables. Statistical analyses were performed using SAS software (Version 9.2, SAS, Cary, NC).
Kaplan–Meier analysis was used to estimate survival probabilities over time. The survival curves for invasive carcinoma and DCIS were compared. Median survival was estimated from the Kaplan–Meier curve, noting that it is validly estimated as long as the curve reached a survival probability of .5. The follow-up time was defined as the interval between the date of cancer diagnosis and the date of death. When a patient died, the follow-up time was considered to be the complete survival time. Otherwise, survival time was censored. Because the cause of death and comorbidities in each case was not definitely known, overall survival was used. The conventional thresholds were not emphasized for significance (i.e., p < .05) in statistical analyses because of the small number of patients in our cohort.
Results
The mean and median age of 29 patients at presentation were 66 and 71 years, respectively (range 41-90 years). Median survival for all patients was 87 months. The majority of patients (77%) presented with a self-detected lump. Of the 7 patients in our study with DCIS, 6 presented with a palpable lump and 1 had bloody nipple discharge. Invasive ductal carcinoma was diagnosed in 76% (22/29) of patients and DCIS in 24% (7/29). The American Joint Commission on Cancer (AJCC) staging system was used (Greene et al., 2002). Of the former group, 17% of patients (5/29) were classified as Stage I, 34.4% (10/29) as Stage II, and 24% (7/29) as Stage III. Lymph nodes with metastases were noted in 68% of the invasive cancer patients (15/22). Lymphatic–vascular invasion was seen in 23% (5/22). Patient characteristics are presented in Table 1.
Patient Characteristics
Note. DCIS = ductal carcinoma in situ; TNM = tumor, node, metastasis.
Of the 22 patients with invasive carcinoma, 21 (95%) underwent MRM while one patient was treated with lumpectomy. SLNs were evaluated in 32% (7/22). Of the 7 patients with DCIS, 4 (57%) underwent lumpectomy, 2 had a simple mastectomy, and 1 had a MRM for possible invasive carcinoma.
Adjuvant chemotherapy was delivered in 54.5% (12/22) of patients and consisted of some combination of adriamycin, cyclophosphamide, 5-flurouracil, methotrexate, or taxol. One patient refused chemotherapy. Adjuvant hormone therapy was given in 61% (17/28) of cases (one was ER negative), with 15 patients receiving tamoxifen and 2 receiving an aromatase inhibitor. One patient whose tumor was receptor-positive refused hormone therapy.
In this study, 34% (10/29) of patients received adjuvant radiation therapy for localized breast cancer. Adjuvant radiation therapy was given to 7 of the 22 (32%) patients in the invasive group following MRM, and to 3 of the 4 patients with DCIS following a lumpectomy. Three patients with DCIS underwent simple mastectomy and did not require adjuvant radiation therapy. In the seven patients with invasive cancer, adjuvant radiation therapy was given for risk factors such as a large tumor or lymph node involvement, cases where axilla node was positive for metastases/presence of perinodal disease and inadequate number of axilla lymph nodes (<6) in the pathology report. There were five postmastectomy, node positive patients who did not receive adjuvant radiation therapy. They received adjuvant chemotherapy. Among them, three patients presented with distant metastases and received palliative radiation therapy.
Adjuvant radiation dose consisted of 5,000 to 5,040 cGy, delivered in 180 to 200 cGy fractions to the chest wall and/or the regional lymph nodes using megavoltage energy via a linear accelerator. There were no local recurrences observed. Adjuvant radiation therapy yielded an HR of 0.1 (p = .058), indicating a favorable effect on the survival in the Cox regression model for mortality as the endpoint. Tumor size had a HR of 1.52 for each 1 cm increase in tumor size (p = .03). Overall higher stage was also associated with increased risk (HR = 2.1 for one level increase in stage, p = .055). An HR of 1.09 was associated with each 1-year increase in age (p = .08). Adjuvant radiation therapy yielded an HR of 0.1 (p = .058), indicating a favorable association with survival (see Table 2).
Prognostic Factors for Mortality and Corresponding Hazard Ratios
Note. Each prognostic factor was analyzed separately, all adjusting for age (years). Age showed a hazard ratio of 1.09 to 1.16 (p = .02 to .10) in these analyses. Observations with missing data were not included. CI = confidence interval: ER = estrogen receptor; PR = progesterone receptor.
Median survival, estimated from the Kaplan–Meier curves, was 87 months for the entire group and 83 months for the invasive cancer patients (see Figure 1). Among the entire group of 29 patients, 11 patients (38%) were deceased, 10 of whom were in the invasive cancer group. Of the 7 patients with DCIS, 6 were alive with no evidence of disease.
Kaplan–Meier curves to estimate survival probabilities over time for patients with invasive carcinoma and ductal carcinoma in situ (DCIS)
Although there were no local recurrences in the patients in our study, four invasive cancer patients were diagnosed with metastases to bone, lung, or brain. Metastases to bone were seen in two patients, to bone and lung in one patient, and to brain in the remaining patient. Each of these patients had been node positive and had received chemotherapy, and three had been estrogen receptor positive and had additionally received adjuvant hormone therapy. One patient whose tumor metastasized to the brain was ER positive. All these patients received palliative radiation therapy for metastases. Three of the deceased patients had documented metastases and had disease progression.
Second, primary contra lateral breast cancer was observed in two patients. The histopathology in both patients was DCIS; in one patient it was of noncomedo type and in the other it was of intermediate grade with solid, cribriform, and comedo patterns. In 7 of 29 patients, a diagnosis of second malignancy was recorded (see Table 3). There was a family history of breast, ovarian, or colon cancer in nine of the male breast cancer patients included in the study. Five patients had a strong family history of breast carcinoma, including a sister with the disease. Two patients had a mother with a history of colon cancer. There was a history of ovarian cancer in the sister of one patient and in the mother and maternal aunts of another. BRCA1/2 analysis was performed in 8 of 29 patients since year 2000 and was negative.
Type of Second Malignancies in Male Breast Cancer Patients
Discussion
Overall 5-year survival rates of between 40% and 65% have been reported for male patients with breast cancer (Goss, Reid, Pintilie, Lim, & Miller, 1999). In this study, a median survival of 87 months was observed among all the enrolled patients; median survival was 83 months for those with invasive disease. The median age at diagnosis for patients with DCIS was 71 years, with a median age of 66 years for invasive cancer patients, which is comparable to the value of 67 described in the population-based comparison study using the SEER registry reported by Anderson, Jatoi, Tse, and Rosenberg (2010). Giordano et al. (2004) reported that men aged 65 years and older with breast cancer have a higher risk of mortality. For the 29 patients in our study, an increase in age corresponded with an increased risk for mortality (HR =1.09 for a 1-year increase in age, p = .08). Overall survival rates tend to be lower for men with breast cancer than for women because of a typically greater age at diagnosis and more advanced disease at presentation (Giordano et al., 2004).
The majority of our male breast cancer patients (20/29) were Caucasian (see Table 1). Published studies have reported a higher incidence of breast cancer in African American compared with Caucasian men (1.8 vs. 1.1 per 100,000, respectively; Anderson, Althuis, Brinton, & Devesa, 2004). African American men also tend to have poorer prognostic indicators and more advanced disease when diagnosed (Korde et al., 2010). Accordingly, in our study 3 of 29 (10%) patients were African American and two of them presented with locally advanced disease with multiple axillary lymph node metastases.
Late stage at diagnosis is more common in men because they may not be aware of the entity of male breast cancer or of subtle changes or symptoms in the breasts that require medical attention. In addition, men, unlike women, are not screened for breast cancer. Because of the rarity of breast cancer in men, mammography is not recommended as a screening tool (Giordano et al., 2004). The majority of the patients in our study presented with self-detected lump and tumors larger than 2 cm in diameter, and 58% had Stage II or III disease. Lymph node metastases were observed in 68%. This finding is similar to previous studies that have suggested that breast cancer in men tends to be diagnosed at a more advanced stage than in women, possibly because of a greater delay in diagnosis (Fentiman et al, 2006; Pant & Dutta, 2008). In accordance with a greater age and more advanced disease at the time of presentation and diagnosis, overall survival rates are lower for male than for female breast cancer patients (Giordano et al., 2004). Similarly, in this study, we observed that the higher stage at diagnosis was associated with an increased risk of mortality (HR = 2.1 with p = .055); an HR of 1.5 was associated with each 1-unit increase in tumor size (p = .03). In contrast, the HR values of 1.79 and 1.5 for lymph node involvement and grade, respectively, were not statistically significant, a probable consequence of the lack of power due to the relatively small sample size of the study.
Male breast cancers have high rates of receptor- positivity for both estrogen and progesterone (Korde et al., 2010). In accordance with these findings, we found that of our 22 male patients with invasive cancer, 91% were ER positive and 73% were PR positive. In our study, HER2 receptor was negative in all 13 patients that were tested. Although the existing literature on HER2 expression in male breast cancer is inconsistent (Korde et al., 2010), our findings are in accordance with those of Bloom, Govil, Gattuso, Reddy, and Francescatti (2001), who reported that only 1 of 58 men studied (1.7%) had cancers with over expression of HER2.
Although treatment of male breast cancer is similar to that in females, the surgical approach tends to be less conservative. The most common procedure, used in approximately 70% of male patients with invasive breast cancer, is MRM with axillary lymph node dissection, followed by radical mastectomy (8% to 30%), total mastectomy (5% to 14%), and lumpectomy with or without radiation (1% to 13%; Cutili, 2007). In our study, 95% of men underwent MRM for invasive carcinoma. Although complete axillary lymph node dissection has been the standard of care, SLN sampling, as commonly performed in female cancer, is considered to constitute a reliable evaluation of the axilla (Flynn, Park, Patil, Cody, & Port, 2007). In our study, sentinel node evaluation was performed in 32% of patients with invasive cancer.
Chemotherapy as adjuvant treatment is recommended in patients who are younger, present with larger tumors, and have axillary nodal involvement. In a study carried out at the M.D Anderson Cancer Center, 25% of patients received chemotherapy alone, and 37% received chemotherapy as well as hormones (Giordano et al., 2005). In our study, in which 58% of patients were Stage II or III and 68% were node-positive, adjuvant chemotherapy was delivered in 54.4%, typically those with larger tumors and/or lymph node involvement. In 33.3% of the patients who received chemotherapy, distant failures were noted, and radiation therapy was given for palliation of symptoms.
In the few studies where male breast cancer patients were treated with postmastectomy radiation, treatment rates ranged between 3% and 100%, and recurrence rates were in the range of 3% to 29% (Chakravarthy & Kim, 2002). Indications for radiation treatment have been extrapolated from protocols developed for female breast cancer, and include larger tumors, involvement of axillary lymph nodes, and higher tumor stage with muscle invasion, each of these factors being a strong predictor for local recurrence (Cutili, 2007). However, one study has reported that, although postoperative radiation therapy is beneficial in reducing local and regional recurrence, it appears to have no effect on survival (Meguerditchian, Falardeau, & Martin, 2002). In a review of 42 cases, Fogh, Hirsch, Goldberg, Powell, and Kachnic (2005) reported a 10-year disease-free and overall survival rate of 100% (p = .2) in 9 patients when adjuvant radiation therapy and tamoxifen were used following surgery (Fogh et al., 2005). Similarly, in a study by Atahan, Yidiz, Selek, and Sari (2006), 142 men with breast cancer who were treated with postoperative radiation, with a median follow-up time of 29 months, showed decreased local recurrence with no survival benefit. These patients received a total median dose of 50 Gy in 25 fractions to the chest wall (Atahan et al., 2006). Schuchardt, Seegenschmiedt, Krischner, Renner, and Sauer (1996) studied 17 patients who received adjuvant radiation therapy to the chest wall and ipsilateral regional lymph nodes at a dose of 50 Gy in 25 fractions. At the end of the 53-month follow-up period, 8 of 9 patients were alive and disease free. The authors concluded that radiation therapy should play an important role in the management of male breast cancer (Schuchardt et al., 1996).
In our study, 34% (10/29) of patients received adjuvant radiation therapy for localized breast cancer. In 32% of patients with invasive cancer, adjuvant radiation therapy was given for risk factors, such as a large tumor or multiple lymph node involvement, and no local recurrences were observed. Adjuvant radiation therapy yielded an HR of 0.1 (p = .058), indicating a favorable effect on the survival. However, the limited number of patients in our study may have precluded the ability to detect a clear survival benefit with sufficient confidence. A multi-institutional study setting with large sample size would be required to more definitively understand this issue.
In the current study, there appeared to be a high risk (24%) of both breast and nonbreast second malignancies. A recent SEER database (1973-2004) review of multiple primary tumors in men with breast cancer reported that 1.9% had a second breast cancer whereas 21% had other, nonbreast, primary malignancies (Wernberg, 2009). In BRCA mutation carriers, the risk of second breast cancers as well as other second malignancies, including melanoma and prostate cancer may be elevated (Auvinen, Curtis, & Ron, 2002). Aside from age, the other known risk factor for breast cancer is genetic predisposition, which can include a family history of the disease and carriage of BRCA2 gene mutations. Men with breast cancer should thus undergo genetic counseling and testing. In our study, the results of BRCA1/2 analysis were negative for mutation in the eight patients on whom it was performed. The National Comprehensive Cancer Network recommends that providers teach and encourage breast self-examination to men with BRCA1/2 mutations, and also that they perform clinical examinations twice a year. Men carrying BRCA1/2 mutations are also advised to follow population-screening guidelines for prostate cancer, and there is an ongoing trial for prospective prostate cancer screening in these patients (Impact, n.d.).
There are some limitations of this study. One is that it was a retrospective data analysis of a relatively small number of patients treated over a span of 16 years. This was unavoidable, as male breast cancer is a rare disease, and it is therefore difficult to collect a large number of patients from a single institution. Treatment recommendations of management for local and regional male breast cancer at our institution have most recently included adjuvant radiation therapy following lumpectomy and sentinel node biopsy. MRM continues to be the recommend treatment for larger or more locally advanced tumors. For tumor diameters in excess of 5 cm, with extension to skin or pectoral muscles, and four or more positive lymph nodes, adjuvant radiation is recommended. Radiation therapy is also indicated if the margins of the mastectomy specimen are found to have included the tumor.
Our current knowledge of male breast carcinoma is derived largely from single-institute retrospective data analyses. A Multidisciplinary Meeting on Male Breast Cancer was held in Bethesda, Maryland on September 4, 2008, (sponsored by the National Institutes of Health and Rare Diseases and the National Cancer Institute Divisions of Cancer Epidemiology and Genetics and Cancer Treatment and Diagnosis). There it was agreed that male breast cancer is a rare, distinct entity, and that large collaborative studies are crucial to advancing our understanding of the biology, epidemiology, and optimum treatment of this disease (Korde et al., 2010).
Conclusions
Male breast cancer is a rare disease, and hence there is paucity of prospective studies. MRM is the established standard of care. For patients with DCIS, lumpectomy followed by breast irradiation is recommended, and for smaller invasive tumors, lumpectomy and sentinel node biopsy followed by adjuvant radiation therapy is an acceptable option. For locally advanced tumors adjuvant loco-regional radiation to the chest wall and regional lymph nodes should be recommended.
In our study, advanced age, higher stage, and increasing tumor size were unfavorable to survival in male breast carcinoma in accordance with published literature (Cutili, 2007; Giordano et al., 2004). The survival benefit with adjuvant radiation therapy should be confirmed in a larger study. The role of adjuvant radiation therapy in conjunction with other factors should be studied in future multi-institutional collaborative studies.
Footnotes
This work was an oral presentation at the Radiological Society of North America (RSNA) Annual Meeting, 2008, Chicago.
The author(s) declared no conflicts of interest with respect to the research, authorship, and/or publication of this article.
The author(s) received no financial support for the research, authorship, and/or publication of this article.