Kartikeya Pant • Udayan Dutta
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
K. Pant (El)Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; E-mail: kpant@mit.edu.
Abstract
Breast cancer is a rare disease in men representing nearly 1% of the total breast cancer cases worldwide. While treatments developed for women with breast cancer are often applied to treat men with breast cancer, however, lack of awareness of this disease leads to its detection at a later stage in men. This review discusses male breast cancer and draws comparisons with female breast cancer and dis-cusses current treatments available to treat this disease. It is believed that this review shall provide concise and relevant information increasing the awareness of issues revolving around male breast cancer (MBC).
Keywords Male breast cancer
Introduction
Breast cancer in men (male breast cancer, MBC) is an uncommon disease [1, 2]. Nearly 2,030 new cases of male breast cancer will be diagnosed in the year 2007 out of a total of 180,510 breast cancer cases (American Cancer Society statistics). While this number represents only 1.12% of all breast cancer cases, it is, however, important to note that the number of cases of MBC have gone up from 1,400 (out of 181,600 cases of breast cancer diagnosed) in 1997 to 2,030 in 2007. This represents a nearly 45% increase in the number of cases of MBC. Table 1 shows the relative numbers of male and female breast cancer cases and deaths over the past decades.
Table 1. Number of Female breast cancer (FBC) and Male breast cancer (MBC) cases and deaths in the last decade.
Due to great advances made in the detection and treat-ments of female breast cancer (FBC), there exist several therapies and detection methods that have been applied to study, detect and treat MBC [3, 4]. However, there exists a severe lack of awareness even among the educated mem-bers of society about MBC. Breast cancer is often wrongly considered a woman’s disease and with a dramatic increase in the number of cases of MBC it is essential that this disease be studied in greater detail. While most treatments of FBC are often extrapolated to MBC, it is however important to realize the inherent differences between these two diseases. Further, only a few studies exist that distin-guish between male and female breast cancers at a molecular and cellular level [2, 5]. The situation is further complicated by the lack of any commercially available cell lines to study MBC.
In this article we discuss the similarities and differences between breast cancer in men and women, the etiology of the disease, the respective treatments and the psychological impact on the patients.
Key differences in male and female breast cancers
Table 2 summarizes some of the important differences between male and female breast cancers. They both exhibit similar range of morphological diversity and histological classification. The majority of MBC’s are classified on histological grounds as infiltrating ductal carcinoma [6]. However, due to the absence of lobules and acini in men, around 1% of all MBC’s are lobular in nature as compared to over 10% in females [7, 8]. The average age of men diagnosed with breast cancer is about 5-10 years greater than women diagnosed with breast cancer. Also, men are more likely to have estrogen and progesterone receptor positive breast cancers. Men with BRCA2 mutations are more likely to possess a higher risk of developing breast cancer as are men with Klinefelter’s syndrome [7-11]. Studies so far performed have not shown any clear trends in relative expression of oncogenes such as Her2, bcl2, and p53 [12]. However, statistics collected over the time clearly shows that MBC patients are more likely to be diagnosed at an advanced stage of the disease having metastasized to the lymph nodes and tumor size larger than 1 cm in diameter [7, 8].
Table 2. Key similarities and differences between male and female breast cancer [7].
Sources of estrogen in men and women
A much greater percentage of breast cancers in men compared to women are likely to be estrogen receptor positive, therefore it is necessary to summarize the sources of estrogen and related hormones in men and women and how these differences are likely to affect men with breast cancer. In pre-menopausal women, the primary sources of estrogen are ovaries (0.37 nmol/l of estradiol in serum) [13]. However, in postmenopausal women there is a dramatic reduction in estrogen production and the amounts of circulating estrogen in the plasma is lower than the amount in men (0.04 nmol/l of estradiol in postmenopausal women compared to 0.1 nmol/l in men) [14]. Further, the amount of testosterone in men is at least 20 times more than that in postmenopausal women (0.6 nmol/l in women compared to 12 nmol/l in men). These increased hormonal levels have been known to contribute towards a greater proliferation of breast cancer [14].
The importance of the role played by locally produced estrogen in MBC, has increasingly been realized in recent years. There are several extragonadal sites of estrogen production, such as mesenchymal cells of the adipose tis-sue or skin, osteoblasts in the bone, vascular endothelial and aortic smooth muscle cells, medial preoptic/anterior/ basal hypothalamus, and the amygdala. In addition to these, in men the leydig cells and other cells of the testes including germ cells produce estrogen [15-20]. The testes are thought to account for 15% of circulating estrogen in men. An important difference in the estrogen production between ovaries and the extragonadal sites is that the ex-tragonadal sites are dependent on the circulating precursor C19 steroids for estrogen biosynthesis unlike the ovaries which can also synthesize the C19 precursors [21-23]. The conversion of steroidal androgens (testosterone and androstenedione) to estrogens (estradiol and estrone) is carried out by a Cytochrome P450 type enzyme called aromatase which is encoded by the CYP19 gene. This gene is regulated differently in various tissues. In ovaries the CYP19 is regulated by the follicle stimulating hormone, in the placenta it is regulated by the distal promoter I.1 and in the bones and tissue the distal promoter I.4 drives CYP19 expression [18, 20].
Studies in cases of female breast cancer have shown the role of estrogen in promoting breast cancer, with women treated with hormone replacement therapy (HRT) likely to have a 1.35-fold higher chance of developing breast cancer (Collaborative Group on Hormonal Factors in Breast Cancer 1997)[15]. Further, the concentration of estradiol in breast cancer patients has been observed to be 20-fold greater in breast tumors compared to that present in plasma. The evidence that aromatase inhibitor treatment results in a decline in estrogen concentration and aromatase activity suggests that the surrounding breast adipose tissue is responsible for the high concentrations of estrogen [15, 24]. Further, the ability of the bone osteoblasts to produce estrogen also make them a target for the metastasis of breast cancer [14, 15]. Therefore, the role of estrogen in promoting the growth and proliferation in women is well documented. In men, due to much lower mass of adipose tissue in the breast, the local estrogen production is much lower, probably leading to lower incidence of breast cancer in men. However, the primary constituents necessary for their conversion to estrogen, such as precursors for estrogen production (testosterone and androstenedione) are present in higher concentrations. It is only the lack of adipose tissue related aromatase that prevents the conversion of these C19 steroids into estrogen [14]. However, the increasing obesity rates across the globe are likely to increase the amount of aromatase thereby significantly raising levels of estrogen. While no studies are available linking obesity and estrogen production or breast cancer in men, there is a very real possibility that changing lifestyles might lead to greater incidence of breast cancer in men.
Treatments for male breast cancer
All treatments for male breast cancer are extrapolated from experience in cases of female breast cancer. There are no treatments that target breast cancer in men, specifically. Although most treatments are similar, we discuss the dif-ferences in hormonal therapies in greater detail due to differences in the levels of hormones between males and females.
Surgery
Radical, simple, and modified mastectomy have been used to treat MBC. Radical mastectomy has been used against larger tumors and it almost always involves the skin and muscle. In invasive MBC cases, axillary dissection is performed. Since axillary dissection has side effects such as shoulder pain, arm pain, loss of sensitivity and arm oedema, there have been cases where sentinel node biopsy has been used. The European Institute of Oncology at Milan has proposed the use of this technique in patients with tumor size less than 2.5 cm and without clinical evi-dence of axillary node involvement (ANI) [25-28].
Radiotherapy
Many studies have asserted the need for adjuvant loco regional irradiation (RT or radiotherapy) in MBC [26, 29, 30]. The European Institute of Oncology has proposed RT in case of tumors that are greater than 1 cm in diameter or with more than one metastatic lymph node [26]. It is strongly recommended after radical or modified mastec-tomy and axillary dissection analogous to similar treatments in postmenopausal women. In a recent France Cancer Center study, out of 690 patients evaluated, 490 underwent postoperative RT. The Chest wall and supraclavicular fossa were treated in 85 and 75% of the patients, respectively. Intermammary chain and axillary were treated in 77 and 51% of the cases, respectively. Local recurrence occurred in 9.5% of the cases (among 7.3 and 13.0% of the patients with and without RT) [26].
Adjuvant hormonal treatment
Since, an overwhelming number of cases of MBC (approximately 90%) are ER-positive, Tamoxifen is used as the standard adjuvant therapy. No large-scale randomized clinical trials have been performed to study the effects of adjuvant tamoxifen treatment on the disease free survival (DFS) or overall survival (OS) rates in MBC although many smaller studies have been performed. In a study published in 1999 by Goss et al. [25] the results of treatments for 229 MBC patients over 40 years were described. Notably, 57 patients were subjected to adjuvant hormonal therapy and this was shown to improve DFS and OS. Another analysis of 301 cases treated in the Christie Hospital and Holt Radium Institute at Manchester showed an increased survival (55%) among patients who were administered adjuvant Tamoxifen for a year following surgery and radiotherapy compared to those who were not administered to adjuvant Tamoxifen (28%) [31].
In a separate study by Giordano et al. [7] at the M.D. Anderson Cancer Center at Houston, data reviewed from 135 men diagnosed with non-metastatic breast cancer between 1994 and 2001 was published. Out of these, 38 men received adjuvant hormonal therapies (19 adjuvant hormonal therapy only and 19 adjuvant hormonal + adju-vant chemotherapy, 35 of them on tamoxifen). The Kaplan-Meier curves of time to recurrence and overall survival of patients plotted clearly revealed better survival for patients exposed to adjuvant hormonal therapy with hazards ratio of for time to recurrence being 0.49 and 0.45 for survival (both at 95% confidence interval) respectively, compared with those who did not receive hormonal ther-apy. Side effects observed in adjuvant tamoxifen treatments have been hot flushes, weight gain, depression, impotence, and thromboembolic accidents.
Aromatase inhibitors (Al’s) have not been used exten-sively to treat MBC and trials performed so far, have been on a very small number of patients with no clear results [32, 33]. It has been proposed that use of Al’s increases the amount of testosterone in men which only increases the androgen available for conversion to estrogen at a later stage or lead to other side effects [30, 34]. On the other hand, it has been proposed that combining Al’s with drugs to suppress testicular estrogen as well as suppress production of androgens (leuprolide acetate, goserelin) is likely to have a better response. A combination of different drugs would ideally be most suited to create an effective drug regimen where adjuvant hormonal therapy is effective in MBC [30]. However due to a much lesser number of patients and availability of a few scattered studies, an elaborate and clear drug regimen is difficult to develop against MBC. Currently the Southwest Oncology group of the National Cancer Institutes in the USA is recruiting 56 patients for a phase II study to evaluate the efficacy of anastrazole in combination with goserelin acetate in ER positive MBC (www.cancer.gov/ clinicaltrials/SWOG-SO511).
Adjuvant chemotherapy
The benefits of adjuvant chemotherapy are not well estab-lished. Further, since over 30% of the cases of MBC are in patients over 70 years of age, problems related to toxicity are high in these cases [35]. Chemotherapy regimes include cyclophosphamide-methotrexate-5-fluoracil (CMF) or anthracycline-based regimens (primarily 5-fluoracil- adriamycin-cyclophosphamide (FAC)), although taxanes have been used in adjuvant setting [36]. In a study on 24 patients with stage II disease treated with CMF, the projected 5 year survival rate was 80% (95% confidence interval 74-100%) while a study on 11 patients with stage II or III disease who were treated with FAC, there was a 63% disease free survival rate and a 91% survival rate in 4.25 years [30, 37-39]. The Early Breast Cancer Trialist Collaborative Group (EBCTCG) recommends adjuvant chemotherapy on patients less than 70 years of age, axillary node involvement and estrogen receptor negative cancer [40].
Support for men with breast cancer
The popular perception of breast cancer as being a woman’s disease leaves many men perplexed and surprised when diagnosed with breast cancer. A recent study on the psychological effects of breast cancer on men suffering from MBC concluded that most men were surprised on being diagnosed by what they had thought was a woman’s disease and often wished it was called something else. The men further felt that there was not enough information oriented for men as most handouts and leaflets dealt with the problems from a women’s perspective and there were no support groups for men to discuss their problems. The lack of awareness on breast cancer causes further distress when patients diagnosed with it try to talk about it with friends and peers, where the reaction is one of disbelief, and sadly often one of amusement [5, 41-43].
Conclusions
Raising awareness about MBC could save many lives. Once men realize that they too could get breast cancer they are more likely to talk to their doctors about it when they observe a lump or related symptoms. As Table 2 shows, the disease is diagnosed in men at a later stage than women. One reason is ignorance about the disease. Further it is likely that men suffering from this disease shall feel free to mention it and discuss it with friends and peers if the awareness of this disease is high.
Another problem is the small number of patients scat-tered round the world hinders any effective and large scale clinical trials. The only possibility of large-scale clinical trials being conducted is through organizing international collaborations involving countries not only in Europe and North America, but also in Asia and Africa. Only by such an international cooperation can useful epidemiological data be gathered and effective clinical trials performed to effectively develop a drug regimen to treat male breast cancer.
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