Chapter 42

the Dif ferences between Male and Female Breast Cancer

Coral omene1, and amy TiersTen2

1New York University Langone Medical Center, Department of Medicine, Division of Oncology, New York, NY, USA2Associate Professor of Medicine (Oncology), New York University Langone Medical Center, Department of Medicine, Division of Oncology, New York, NY, USA

IntroductIon

Breast cancer is a disease that develops in both men and women. While there are similarities in this disease between the two genders, there are also differences. It is the most com-monly diagnosed malignancy in women, second only to skin cancer, with associated immense socioeconomic ramifica-tions. However, in men, breast cancer is rare. Is this disease biologically different in men and women? Or is it similar between the sexes with the same etiologic, prognostic, and clinical features? The data to date suggest that breast cancer in men is fundamentally identical to breast cancer in women with few exceptions. This chapter explores the classic features of breast cancer in both sexes, highlighting the differences and the similarities between them and what is as yet unknown.

AnAtomy And development

Both men and women have breasts; however, the rate of breast cancer is much higher in women. This is due, in part, to the anatomic differences between them. Breast tissue is well developed only in women. The female breast con-sists of some 15–20 lobules of glandular tissue that form the functional units of the breast. Each lobule is drained by a lactiferous duct, which opens on the nipple. Deep to the areola, each duct enlarges to form a lactiferous sinus in which milk can accumulate. The lobules are connected and supported by various amounts of fibrous connective tissue and adipose tissue. It is these stromal elements that com-prise the majority of the breast volume in the nonlactational state.

45Principles of Gender-Specific Medicine

Male and female breasts are similar at birth, consisting of a small number of rudimentary branching ducts beneath the nipple–areola complex. They diverge at the time of puberty. In males, development ceases. In females there is continued growth and branching of the lactiferous ducts and increased adipose and stromal tissue. As a result, progres-sive enlargement of the breasts occurs. Eventually, the ter-minal ducts give rise to saccular buds from which secretory glands develop during pregnancy. After lactation ceases, there is glandular atrophy and once again the stromal ele-ments are the predominant component of the breast.

epIdemIology

Breast cancer has a significant impact on the health of women. It is the most common cancer among women other than skin cancer and the second leading cause of death in women after lung cancer. It represents 31% of all can-cers diagnosed and 15% of all cancer deaths in women.1 Approximately 184 450 women in the United States were diagnosed with invasive breast cancer in 2008 and 40 930 women died from the disease.2 Through age 85, the lifetime risk of being diagnosed with breast cancer for an American woman is or 1 in 8 and the chance of dying from the disease is 1 in 33.1 This is in contrast to men in whom breast cancer is a rare disease. Male breast cancer accounts for less than 1% (0.7%) of all breast cancer diagnoses,3 and 0.2% of all male cancer deaths.3 Similarly to breast cancer in women, breast cancer in men has been increasing; the incidence has climbed 26% over the past 25 years. However, the overall incidence in the United States remains low: approximately

Copyright 2010, Elsevier Inc. All rights reserved.9 2010

seCt ion 7   l  Oncology460

one case per 100 000 population per year.4 It is dissimilar to female breast cancer, in that the incidence rates are higher among black men than white men and continue rising in men aged 55 years or older, resulting in a late average age at onset.5,6 The mean age at diagnosis for men with breast cancer is 67 years, which is 5 years older than the average age at diagnosis for women.7

According to the SEER database of the National Cancer Institute, the estimated numbers of male breast cancer cases expected in the United States are rising. Since 1987 the annual number of breast cancer cases in males has increased 1.6 times.8,9 In a retrospective review of 217 cases of male breast cancer obtained from tumor regis-tries at 18 institutions between 1953 to 1995, the number of cases registered annually increased progressively.8 Fifty of the cases were diagnosed after 1986 (Figure 42.1). This increase is likely multifactorial, influenced by the prolifera-tion of tumor registries, increased use of urban healthcare facilities, and perhaps by a true rise in the incidence of the disease. In addition, the increased awareness and public education regarding breast cancer and screening directed toward women may play a role in the recognition of this disease by men and their doctors.

Female breast cancer incidence and mortality rates vary between countries and to a lesser extent within different areas of the United States.10 The incidence is highest in the United States and Northern Europe and is lowest in Asia. Muir et al.11 report that the highest incidence for male breast can-cer occurs in Brazil, at a rate of 3.4 cases per 100 000 versus Columbia, Singapore, Hungary, and Japan, where the inci-dence is much lower at 0.1 cases per 100 000. In the United States, the overall age-adjusted breast cancer incidence rate is higher among white than black women, although black women age 35 have a higher incidence rate than white women.10 However, with regards to male breast cancer, black men seem to have a higher incidence of breast cancer than white and Asian-Pacific men in the United States.5,6

Year of diagnosis

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fIgure 42.1 Male breast carcinoma cases by year of diagno-sis. The majority were diagnosed after 1981.Reproduced from Donegan et al., 1998.8 Copyright 1998, American Cancer Society. This material is reproduced with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

rIsk fActors

Breast cancer in females has been extensively studied and this has resulted in a wealth of information of the known factors that may increase a woman’s risk for this disease. However, little is known about the etiology of male breast cancer. This difference is mostly due to the rarity of the disease in men, which greatly limits the application of epi-demiologic methodology to studies in male breast cancer, thus, far fewer data have accumulated. Therefore, risk fac-tors in general remain uncertain. There are some epide-miologic studies that have afforded some insight into this disease. Various hormonal, lifestyle, and genetic factors reported to play a role in the development of breast cancer are described in the following sections. However, most indi-viduals of either gender who develop breast cancer have no apparent risk factor for the disease, and most male patients have no detectable hormonal imbalances.12

reproductive and Hormonal

In epidemiologic studies, a woman’s reproductive history has been consistently shown to contribute to the risk of develop-ing breast cancer, underscoring the role of endogenous related risk factors in normal and abnormal breast development. Early menarche, shorter cycle length, nulliparity or low par-ity, and late menopause are several reproductive variables that increase a woman’s risk for developing breast cancer. After menopause, adipose tissue becomes the major source of estro-gen and obese, postmenopausal women have higher levels of endogenous estrogen and a higher risk of developing cancer.13

Exogenous estrogen use in the form of oral contraceptives use and the risk of subsequent breast cancer is an important concern of women. The Nurses’ Health Study examined more than 3000 cases of breast cancer diagnosed prospec-tively between 1976 to 1992. At the start of the study, 46% of women reported past or current use of oral contraceptive pills. In sum, they found no increased risk of breast cancer associated with the use or duration of use of oral contracep-tives. No conclusions could be drawn, however, for women younger than 40 because there were too few cases of breast cancer in that age group.14 Other studies have suggested a risk for developing breast cancer in women who use oral contraceptives when they are younger than 35 years. In a case-control study of women between the ages of 20 through 44 years, which examined 1648 cases of breast cancer and 1505 controls, the relative risk (RR) for breast cancer devel-opment was 1.3 in oral contraceptive users younger than age 45. The RR increased to 1.7 in users younger than 35 years and up to 2.2 in women using the pill for more than 10 years.15 This slight increase in RR is unlikely to translate into large differences in attributable risk, because the inci-dence of breast cancer is so low in this population. The data regarding postmenopausal hormone replacement therapy have also been examined in many epidemiologic studies.

Chapter 42 l the Differences between Male and Female Breast Cancer 461

One study of note is the estrogen plus progestin compo-nent of the Women’s Health Initiative (WHI), a randomized controlled primary prevention trial, in which 16 608 post-menopausal women aged 50–79 years were recruited by 40 US clinical centers in 1993–8. The study was stopped early due to the estimated hazard ratios for breast cancer of 1.26 (1.00–1.59) with 290 cases. The overall health risks exceeded benefits from use of combined estrogen plus pro-gestin for an average 5.2-year follow-up among healthy postmenopausal US women.16 However, data from the estro-gen-alone component of the WHI study showed that inva-sive breast cancer was diagnosed at a 23% lower rate in the estrogen-alone group compared to placebo and this compari-son narrowly missed statistical significance.17

The hormonal influence on breast cancer risk in men has also been described. Conditions that result in relative estro-gen excess or lack of androgens have been linked to cases of male breast cancer in epidemiologic studies. The strongest risk factor for developing male breast cancer is Klinefelter syndrome, a condition that results from the inheritance of an additional X chromosome. Affected males have atrophic testes resulting in low plasma levels of testosterone. Their circulating levels of gonadotropins (follicle-stimulating hor-mone and luteinizing hormone) remain high, thus exposing them to a high estrogen/testosterone ratio. These men have a 50 times higher rate of developing breast cancer than those with no genetic abnormality and may account for up to 3–7% of male breast cancers.18,19 Other conditions affecting the testes have also been reported to increase risk, including mumps orchitis, undescended testes, or testicular injury.20 This too may suggest a hormonal association; however, it remains unclear if testosterone levels are actually abnormal at the time of breast cancer diagnosis in these men.20

Chronic liver disease leading to cirrhosis may predis-pose males to the development of breast cancer. There have been reports of a four-fold and a nonsignificant three-fold increase in risk associated with liver cirrhosis and male breast cancer.21,22 It is believed that the diseased liver and its altered metabolism lead to a hyperestrogenic state pro-moting the growth of breast tissue and subsequent risk of malignant transformation. Gynecomastia has been reported in association with breast cancer in men. However, the role of gynecomastia as a risk factor in male breast cancer is unclear as it is found in up to 50% of male breast can-cer patients at autopsy and is relatively common in healthy men. It may impart an increased risk for the development of breast cancer or simply serves as a marker for an under-lying hyperestrogenic state.23

Exogenous estrogens have also been implicated in this disease. There have been reports of transsexuals devel-oping breast cancer. Treatment required to induce male-to-female sexual change include surgical and chemical castration and prolonged administration of large doses of female hormones, especially estrogens. Castration may lower androgen levels creating a high estrogen-to-androgen

ratio, thus potentially increasing the risk for breast cancer.24 There have been several documented cases of breast cancer among transsexuals, which are characterized by short latent periods (5–10 years) after exposure to female hormones before the appearance of tumor and at earlier diagnosis.25 Additionally, there have been reports of breast cancer in men receiving treatment for prostate cancer.24–26

dietary and environmental

The causal relationship between dietary fat consumption and breast cancer remains controversial. There have been several prospective cohort studies examining this issue and in those with over 200 incident cases of breast cancer there was no association seen with dietary fat intake.27–32 Hunter et al.33 published a pooled analysis of 4980 cases of breast cancer in 337 819 women and again no association was observed between intake of total, saturated, monounsatu-rated, or polyunsaturated fat and risk of breast cancer. What does appear to play an important but complex role in the causation of breast cancer is energy balance. High-energy intake in relation to expenditure accelerates growth and the onset of menstruation. If this positive balance continues it can lead to weight gain later in life and overall increases a woman’s risk of subsequent breast cancer.

Other dietary factors, including vitamins, fiber, alcohol consumption, and caffeine, and the role they play in the devel-opment of breast cancer, have also been thoroughly explored in women. It appears that alcohol intake is the best-established specific dietary risk factor for breast cancer in women.34 The studies performed to examine this relationship, all of which were controlled for other major breast cancer risk factors, consistently support the existence of a positive association between alcohol consumption and risk of breast cancer in women. In addition, it has been shown that moderate alcohol consumption of approximately two drinks per day has been shown to increase estrogen levels providing a mechanism by which breast cancer risk might be increased.35 In men, two studies of chronic alcoholics noted a two-fold increase in risk in male breast cancer36 and a population-based case-control study observed an approximately six-fold increase in risk in the highest alcohol exposure category compared with light drinkers and non-drinkers.37 While these similarities have been reported, other studies have shown no association.38

Clearly, there are numerous studies examining female breast cancer and potential risk factors for this disease. Through these efforts, an abundance of knowledge has been gained. It remains less clear which of these established or potential risk factors plays a role in the development of male breast cancer. There have been some reported case-control studies in the literature that attempt to further define this issue. For example, Rosenblatt et al. investigated the relationship between food and beverage consumption and the development of breast cancer in men in a report of 220 cases of male breast cancer and 291 controls.38 No trends in

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risk were observed with increasing intakes of specific food, with the exception of citrus fruits. The authors conclude that dietary factors are unlikely to be strong determinants of breast cancer in men.38 Obesity has been implicated in the etiology of male breast cancer due to higher circulating estrogen levels and has fairly consistently been associated with an increased risk of breast cancer in men. For example, Hsing et al. in a case-control study obtained demographic and dietary information from next-of-kin interviews of 178 men who had died of breast cancer and 512 male controls.39 This study reported that obesity was a significant risk fac-tor for male breast cancer whether evaluated by usual adult weight, body mass index or perceived overweight.39

genetics

Several genes that are associated with a high lifetime risk of breast cancer in females have been identified. These genes appear responsible for 5–10% of all breast cancer cases.40 Two such susceptibility genes are BRCA1 located on chro-mosome 17 and BRCA2 on chromosome 13. Mutations in both genes predispose to earlier onset and increase risk of female breast cancer, but the risk profile and risk of can-cers at other sites differs between the two genes.40 Studies by the Breast Cancer Linkage Consortium (BCLC) have shown that both genes increase the risk of female breast cancer to 80–85% by the age of 80.41,42 For ovarian can-cer, BRCA1 confers a 60% lifetime risk and BRCA2 a 27% risk.42 Both genes are also now thought to increase the risk of prostate cancer, and BRCA2 has been associated with a variety of other malignant disorders as well, including male breast cancer.43 In one study that included 237 hereditary breast carcinoma families, 26 families had at least one male member who had been diagnosed with breast cancer and in 77% the disease was linked to mutations in BRCA2.42

Similar to female breast cancer, BRCA2 mutations are thought to be associated with a 6% lifetime risk of male breast cancer representing a 100-fold increased RR over the general population.43 One report by Couch et al.44 ana-lyzed 50 cases of male breast cancer for BRCA2 mutations. The mutation was found in 14% of the cases, but these were men who had a significant family history of breast cancer. The prevalence of BRCA2 mutations in male breast cancer cases unselected for family history has been reported by Friedman et al.45 This study demonstrated a 4% prevalence of BRCA2 mutations. The data remain inconclusive mainly because male breast cancer is an infrequent occurrence and even more difficult to study in the context of an inheritable familial disease. In a recent report examining 94 cases of male breast cancer, there were 9.37 excess cases of breast cancer in female first-degree relatives of which only one was accounted for by BRCA2.46 The authors concluded that BRCA2 accounts for approximately 15% of the excess risk.

The association between male breast cancer and a delete-rious germline mutation in BRCA1 is less clear. Initial data

suggested that inherited male breast cancer was not linked to germline mutations in BRCA1.47 However, a more recent study in a series of 10 000 individuals reported that 21 of 76 men with breast cancer had mutations in either BRCA1 or BRCA2 and that more than one-third of those mutations were in BRCA1.48 In a most recent study, Tai et al.49 reports the estimated cumu-lative risk of breast cancer for male BRAC1 mutation carriers at age 70 years to be 1.2% and for BRCA2 mutation carriers to be 6.8%. The relative risks of developing male breast cancer were highest for men in their 30s and 40s and decreased with increasing age. This trend was most pronounced in BRCA2 mutation carriers, where the relative risk at age 30 years was 22.3 times that at age 70 years.

The possibility of additional male breast cancer suscep-tibility genes is suggested and remains an area of active investigation. Families have been identified with muta-tions of the androgen receptor gene, PTEN (Cowden’s syn-drome)50,51 and mismatch repair gene genes (hMLH1) in male patients with breast cancer.52 However, none of these genes has been demonstrated to have a causal association with male breast cancer. Further studies are needed to elu-cidate their role.

clInIcAl fActors And dIAgnosIs

Breast cancer in males generally occurs a decade later than breast cancer in females with a mean age of presen-tation ranging from 60 to 65.12 The presenting symptom in most patients is a nontender, palpable mass that is cen-trally located 70–90% of the time.12 Nipple involvement is a fairly early event, with retraction seen in 9%, discharge in 6%, and ulceration in 6% of male breast cancer patients. Paget’s disease is rare, being the presenting feature in only 1%, with a mean age of 60 years, similar to that of other men with breast cancer.53,54 Serosanguineous or bloody dis-charge from the male breast is associated with malignancy in 75% of the cases and should always be investigated by biopsy.12,55 When bloody discharge occurs from the female breast it is most commonly due to a benign papillary ade-noma. Axillary adenopathy suspicious for metastatic dis-ease is clinically detected in 40–55% of male patients at diagnosis. Bilateral breast cancer occurs much less freque-ntly in males than in females and is reported to be in the range of 1.4–1.9%.55 This is likely due to the lack of lobu-lar differentiation in men because it is frequently the lobular forms of cancer that present with multicentric and bilateral disease. As in women, there is a slight preponderance of left-sided versus right-sided disease.56

Both male and female breast cancers are staged accord-ing to the American Joint Committee Clinical Staging System (AJCC), which is based on tumor size, axillary lymph node involvement, and evidence of distant metas-tases. In general, breast cancer in men presents at a later

Chapter 42 l the Differences between Male and Female Breast Cancer 463

stage than the disease in women.23,57,58 This has been attrib-uted to a delay in diagnosis. The rarity of male breast can-cer and therefore the low index of suspicion of both patients and doctors have been largely responsible for the delay in diagnosis. The older series reported a mean duration of symptoms anywhere between 14 and 21 months, suggest-ing a lack of recognition of this uncommon entity by men and their physicians.12

One of the largest retrospective series included 215 cases of male breast cancer from 1953 to 1995.8 In this study the aver-age duration of symptoms was 10.2 months. Over time, this appeared to improve as reflected by a decrease in the mean tumor size from 2.87 cm to 2.42 cm during two time periods analyzed (1953–1985 and 1986–1995).8 AJCC TMN staging was available for 155 of these cases (72%). Stage I represented 19%, stage II was 46%, and stages III and IV accounted for 13% and 14% of the cases, respectively.8 Another series of 104 men with breast cancer reported by Borgen et al. com-pared the stage at presentation of the male patients to a female cohort treated at the same time.23 They found a preponderance of stage III tumors in the male group. Between 1975 to 1990, there were 95 male breast cancer cases: 17% of these were stage 0, 27% stage I, 33% stage II, and 22% stage III. In a female cohort of 932 patients who presented to a single insti-tution in 1989 there were 18% with stage 0 disease, 32% with stage I disease, 39% with stage II disease, and only 6% with stage III disease.23

In the evaluation of suspected female breast disease, mammography plays a pivotal and well-accepted role. Most women are diagnosed in an asymptomatic state due largely to mammography. In addition, when used as a screening tool in asymptomatic, older women it has been shown to reduce mortality from breast cancer by 30%.59 Results from seven population-based community screening programs in the United States on 463 372 screening mammograms in women revealed an overall sensitivity of 75% and specifi-city of 92.3%.60 The role of mammography in male breast disease is much less defined. Ideally it would serve to dis-tinguish benign from malignant processes; however, there is no consensus to date on its utility in this capacity. Evans et al.61 attempted to define the diagnostic accuracy of mam-mography in evaluation of male breast disease. Using 104 mammograms categorized into malignant, benign, gyneco-mastia, or normal and comparing them to definitive tissue diagnoses they determined a sensitivity of 92%, specificity of 90%, positive predictive value of 55%, and a negative predictive value of 99% for mammography in diagnosis of malignant disease. In this series, 11 of 12 breast cancers in men were detected by mammography; 6 of the cases had concurrent gynecomastia. Clinical, radiographic, and patho-logic records of 165 symptomatic men presenting to breast imaging over a 4 year period were restrospectively reviewed. Twelve with benign mammographic findings had benign biopsies. All men with benign mammography not undergo-ing biopsy were cancer free. Sensitivity for cancer detection

(mammography) was 100% and specificity was 90%. Positive predictive value (mammography) was 32% (6 of 19) and the negative predictive value was 100%. Thus, it was concluded that mammography had excellent sensitiv-ity and specificity for breast cancer detection and should be included as the initial imaging examination of men with clinical breast symptoms. The negative predictive value of 100% for mammography suggests that mammograms read as normal or negative need no further examination if the clinical findings are not suspicious.62

Although this study addresses the accuracy of mammog-raphy, other factors such as history and physical examina-tion (PE) clearly play a role in making the diagnosis and cannot be replaced by a single test. Many investigators argue that the algorithm in diagnosing male breast disease should involve PE followed by biopsy when needed with mammography reserved for excluding contralateral malig-nant disease.23,63 In addition, because of the rare nature of male breast cancer, screening mammography is not advo-cated for the general male population. Vetto et al.63 stud-ied the combination of PE and fine needle aspiration (FNA) with or without mammography as an alternative approach to surgical biopsy in the diagnosis of breast masses in men. They looked at 51 consecutive men with unilateral breast masses and using these tools scored them as benign or malignant. All tests were benign in 38 cases and no cancers subsequently developed. In six cases, the tests were suspi-cious and open biopsy confirmed malignancy. There were seven cases in which PE and FNA were not in agreement, so open biopsy was performed leading to a diagnosis of benign disease. Mammography, which was performed in 13 of the cases, added no further information. They concluded that the combination of an adequate FNA and PE is diag-nostically accurate and when used appropriately can avoid unnecessary biopsies for benign disease.63

Breast magnetic resonance imaging (MRI) plays an increasing role in the management of selected breast cancer patients. MRI is recognized as the most sensitive modality for the detection of invasive breast cancer and several valu-able clinical applications of MRI have emerged for breast cancer detection and diagnosis from clinical investiga-tions. Annual MRI plus mammography is now the standard of care for screening women aged 30 years or older who are known or likely to have inherited a strong predisposi-tion to breast cancer such as breast cancer gene carriers and patients treated with chest radiation. Breast MRI is helpful for women diagnosed with breast cancer who contemplate breast-conserving surgery; it provides valuable informa-tion on the extent of the disease and it can also help assess for residual invasive cancer in patients who have under-gone lumpectomy with positive margins at pathology.64 Furthermore, MRI is also reliable in finding breast cancer in women with axillary nodal metastases and unknown pri-mary tumour and can help to monitor the response to chem-otherapy.64 However, in general, MRI should not be used in

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place of a well-formed mammogram or ultrasound.64 While MRI is used in women, it has not been studied regarding sensitivity in diagnosis in men, but since lesions are always palpable and can be biopsied easily under palpation, there is no clear role for MRI in male breast cancer.

pAtHologIc feAtures

Since male breast tissue is rudimentary, it usually does not differentiate and undergo lobule formation unless exposed to increased concentrations of endogenous or exogenous estrogen. Thus, similarly to its female counterpart, the most common histology of male breast cancer is invasive ductal carcinoma, which accounts for more than 90% of all male breast tumors. Because of the lack of lobules in the male breast, lobular carcinoma is very uncommon (1%) but has been reported in the literature.65 In situ ductal carcinoma is seen in 20–25% of female breast cancer cases. In men, the percentage is much less, ranging from 0% to 17% .66 There are many pathologic subtypes used to describe female breast cancer-medullary, mucinous, squamous, papillary, and adenocystic-and in general all of these different sub-types have also been reported in men.

Estrogen receptor (ER) and progesterone receptor (PR) status is routine in the pathologic evaluation of female breast cancer. One, or both, is positive in 60–70% of the cases.67 From the literature there seems to be a consen-sus that cancers of the male breast are significantly more likely than cancers of the female breast to express hormone receptors, even after adjustment for tumor stage, grade and patient age.67 There have now been several published series that reported an ER and/or PR positivity rate in male breast tumors of greater than 90%.68 In other published reports the rate is slightly lower ranging between 70% and 90%.53As in female breast cancer, the rates of hormone-receptor positiv-ity increase with increasing patient age.7

The study of molecular markers including protoonco-genes, cell cycle regulatory proteins, and markers of apop-tosis have led to new insights into the biology of female breast cancer. The HER2-neu protein is a transmembrane receptor protein with tyrosine kinase activity involved in normal cell growth and division. HER2 overexpression, usually secondary to gene amplification, is seen in 20–30% of invasive female breast cancers and is associated with a poorer outcome and shortened survival.69 The two methods used to assess HER2-neu status include immunohistochem-istry and fluorescence in situ hybridization (FISH); these are routinely used in the evaluation of female breast tumors. Much less is known about the presence and prognostic sig-nificance of these molecular markers in males with breast cancer although data are emerging.67,70 Table 42.1 high-lights rates of HER2-neu overexpression in various series of male breast cancer reported in the literature. These early

reports have suggested equivalent rates of HER2-neu over-expression between male and female breast cancers, how-ever it is thought that these results were an overestimation likely attributable to periods before improved standardiza-tion of methodology. In support of this, there have been studies that show that HER2-neu proto-oncogene is less likely to be overexpressed in male breast cancer. In one study of a series of 75 patients, only 5% of male breast can-cers overexpressed HER2-neu.74 Similarly, Bloom et al. found that only one of 58 male breast cancers overexpressed HER2-neu and that zero of 58 had gene amplification, com-pared with 26% of female breast cancer tumors showing overexpression and 27% manifesting amplification.75

In a series of 111 male breast cancer patients from the Mayo Clinic, tumor samples were analyzed for the pres-ence of various markers. Androgen receptor was almost uniformly present, positive in 95% of the cases. HER2 was positive in 29% and p53 in 21% of the cases. The cell cycle regulatory protein cyclin Dl, which is expressed in approxi-mately 50% of female breast tumors, was also present in 58% of male cases. Shpitz et al.72 in a report of 26 male breast cancer patients found that p53 and HER2-neu were expressed in 46% and 39%, respectively. They found no correlation between the presence of these biomarkers and adverse clinical features or survival. This is in contrary to a report by Pich et al.74 They retrospectively reviewed 50 male patients with breast cancer and found that HER2-2 and p53 protein overexpression significantly correlated with a worse prognosis. The rate of HER2 positivity was 56% in their series.

prognostIc fActors

Prognostic factors are those measurements available at the time of diagnosis that are associated with disease-free or overall survival and can often be used to predict the natural history of the tumor. Optimizing treatment based on prog-nostic factors plays an important role in the management of female breast cancer. The standard prognostic factors cur-rently applied in new cases of breast cancer include axillary lymph node status, histologic subtype, tumor size, nuclear

tAble 42.1 rates of her2-neu positivity in male breast cancer reported in the literature

study no. of cases Her2- neu

Wick et al.67 10 30%Rayson et al.68 76 29%Joshe et al.58 17 41%Andre et al.71 82 12%Shpitz et al.72 26 39%Pich et al.73 50 56%

Chapter 42 l the Differences between Male and Female Breast Cancer 465

tAble 42.2 survival rates based on axillary lymph node status in males with breast cancer

study no. nodal 5-year survival 5-year dss 10-year survival 10-year dss

Cutuli et al.78 308 Positive 63% 67% 28% 39%Negative 82% 93% 58% 77%

Guinee et al.79 224 Positive NR 65–73% NR 14–44%*

Negative NR 90% NR 84%Borgen et al.23 104 Positive 60% NR NR NR

Negative 100% NR NR NRHerman et al.76 45 Positive 59.6% NR 58.3% NR

Negative 87.4% NR 28.6% NRMcLachlan et al.77 66 Positive 55% NR NR NR

Negative 81% NR NR NR

NR, not reported.*Ranges depending on number of involved nodes (1–3 or 4).

grade, hormone receptor status, measures of proliferation, and molecular markers such as HER2 overexpression. Of these, the presence or absence of metastatic carcinoma in the axillary lymph nodes is the most powerful prognostic factor for patients with primary breast cancer. In male breast cancer, tumor size, and lymph node involvement are two clear prognostic factors for male patients with breast cancer.7 Men with tumors measuring 2–5 cm have a 40% higher risk of death than men with tumors 2 cm in maxi-mum diameter.7 Similarly, men with lymph node involve-ment have a 50% higher risk of death than those without lymph node involvement.7 There are a number of reports in male breast cancer that also correlate outcome with nodal involvement (Table 42.2).76,77 Guinee et al.,79 after review-ing 335 cases of male breast cancer over a 20-year period, found 10-year survival to be 84% for patients with histolog-ically negative nodes, 44% if one to three nodes were posi-tive, and 14% in those patients with more than four positive nodes. Five-year survival in male breast cancer declines with increasing stage of disease (Table 42.3). This is similar to what is seen in females (Table 42.4).

Of the other prognostic factors frequently considered in female breast cancer, controversy exists over their useful-ness in male breast cancer cases. There are numerous series in the literature addressing these issues, but, because of the rarity of male breast cancer, none of them is large enough or designed appropriately to evaluate potential molecular or pathologic markers as prognostic indicators.

tAble 42.3 Five-year survival in men based on stage reported in the literature

study

no. of cases

stage I

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stage III

stage Iv

Borgen et al.23 104 83% 70% 74% NRDonegan et al.8 155 85% 60% 30% 10%Joshe et al.58 46 100% 83% 60% 25%

NR, not reported.

treAtment

surgical management

The mainstay of managing early stage breast cancer is sur-gical removal of the tumor. In women, both modified radical mastectomy and lumpectomy with radiation are equivalent approaches.80 This differs in men. Compared with mastec-tomy, lumpectomy was associated with significantly worse control rate in a Canadian series of 229 patients treated over 40 years where 8.7% of whom where treated with lumpec-tomy.81 Because of the lack of breast tissue and central location of most tumors, breast conservation is not a viable option. Historically, radical mastectomy was often per-formed, but retrospective studies indicate that the outcome for men is equally good when treated with less invasive sur-gery.82 The transition to the modified radical mastectomy in men was also based on the equivalent outcomes to radical mastectomy seen with this approach in women.11

Whether or not the lymph nodes are involved is one of the major prognostic factors in breast cancer, and knowing the status of the axillary lymph nodes is critical in guiding further management of the patient. Sentinel lymph node biopsy (SLNB) is a widely implemented technique for eval-uating the axillary status in clinically node-negative cases in

tAble 42.4 ten-year relative survival rates in women undergoing local and adjuvant treatment

stage of disease 10-year survival

0 95%I 88%II 66%III 36%IV 7%

Source: Fremgen, AM, Bland KI, McGinnis LS Jr et al. Clinical highlights from the National Cancer Data Base, 1999. CA Cancer J Clin 1999;49:145-58

seCt ion 7   l  Oncology466

women. Several case series have established the feasibility of sentinel node biopsy in male breast cancer. Among a total of 56 male patients combined from these reports, the sentinel node was successfully identified in all but one patient.83–86 A combined total of 11 patients with a negative sentinel node biopsy underwent confirmatory axillary dissection and none had any additional nodes.83–86 This procedure is now being increasingly used in male patients who are clinically node-negative. So, similarly to women, most men are treated with modified radical mastectomy with axillary lymph node dissection or sentinel lymph node biopsy.56

Adjuvant systemic therapy

Unfortunately, despite adequate removal of the tumor and regional lymphatics, recent surgical series still produce a 10-year disease-free survival rate of 50%. Thirty percent of node-negative and 75% of node-positive patients eventually have recurrences and die of their disease when surgery is the only therapeutic modality.87 Adjuvant systemic therapy, which is given after the primary surgery to kill or inhibit clinically occult micrometastases, has been extensively studied in women. Physicians can draw on data consisting of many randomized clinical trials with extensive follow-up to assist in counseling and treating their female patients with breast cancer. It has been well established that the use of cytotoxic chemotherapy and/or endocrine therapy in the adjuvant setting improves long-term survival of women with breast cancer.87

EndocrinE ThErapy

In men, the low incidence of breast cancer precludes the development and completion of clinical trials to assess the efficacy of adjuvant therapy. Therefore, the standard treat-ment of male breast cancer has generally been extrapolated from the treatment used in women. As male breast cancers are predominately ER- and/or PR-positive tumors; the use of adjuvant endocrine therapy is recommended. The most commonly used endocrine agent in male breast cancer is tamoxifen. In a report by Ribeiro et al.88 39 male patients who received tamoxifen were compared with a historical control group. Overall survival and disease-free survival at 5 years were higher in the group that received tamoxifen (61% vs. 44% and 56% vs. 28%). The most common side-effects of tamoxifen include decreased libido, weight gain, hot flashes, and mood alterations. More men have been shown to discontinue the drug as compared with females because of side-effects.89 Giordano et al.90 reported data on 38 men who received adjuvant hormonal therapy (including 35 who received tamoxifen) which showed that the recur-rence rate (HR of 0.49) and overall survival (HR 0.45) was significantly better for men who received adjuvant hormo-nal therapy compared with no adjuvant therapy. As adju-vant hormonal therapy for 5 years, the aromatase inhibitor,

anastrozole has recently been shown to impart significantly prolonged disease-free survival and time to recurrence com-pared to tamoxifen in a large multicenter trial in 9366 post-menopausal women with localized breast cancer.90 However use of aromatase inhibitors alone in the absence of orchiec-tomy is biologically doubtful in men given the 20% of cir-culating estrogens produced by the testes and independent of the aromase enzyme. No data exist currently regarding the use of gonadal ablation by gonadotropin-releasing hor-mone (GnRH) analogue with aromatase inhibitors.

chEmoThErapy

Similarly to women with breast cancer, adjuvant chemother-apy is used to treat male patients who have a substantial risk of recurrence and death from breast cancer. Whereas the data supporting adjuvant chemotherapy in women is strong, there is little information on the effectiveness of adjuvant chemo-therapy in men. The limited data that have been published, however, support a similar benefit in male and female patients. One prospective study with a series of 24 male patients with stage II breast cancer treated with adjuvant cyclophospha-mide, methotrexate, and 5-fluorouracil (CMF) chemotherapy projected a 5 year overall survival rate of 80%, which was significantly higher than a similar cohort of untreated histori-cal controls.91 In another study of 11 patients with stage II or III disease treated with 5-fluoro-adriamycin-cyclosphos-phamide (FAC), 63% disease-free survival rate and a 91% survival rate at 52 months was reported.92 A recent 20-year follow-up study of adjuvant CMF in males reports an overall survival probability at 10 years of 64.5%, 15 years of 51.6%, and at 20 years of 42.4%.93

Given the established benefit of chemotherapy in women and suggestive evidence in men, most clinicians use similar guidelines for adjuvant chemotherapy in male and female patients. For instance, at the University of Texas M.D. Anderson Cancer Center chemotherapy is offered to those male patients with breast tumors 1 cm or with lymph node involvement; anthracycline-based chemotherapy is offered to patients without lymph node involvement, while both anthracyclines and taxanes are used for patients with lymph node involvement.

targeted therapy

Finally, although there are no proven clinical trials, male breast cancer patients with HER2 overexpression may benefit from humanized anti-HER2 monoclonal antibody, trastuzumab, especially in light of its proven efficacy in women.68 Future promising agents include PARP-1 inhibi-tors; PARP-1 is a 113 kDa nuclear enzyme that plays a critical role in the repair of DNA single-stranded breaks via the base excision pathway.94 The first clinical evidence that BRCA-mutated cancers may be sensitive to PARP inhibi-tion was presented at the 2007 American Society of Clinical

Chapter 42 l the Differences between Male and Female Breast Cancer 467

Oncology (ASCO), where in a phase I trial of oral PARP inhibitor, AZD2281 in a population of BRCA mutation car-riers, there were partial responses either radiologically or by reduction in tumor markers in 4 out of 10 ovarian cancer patients. Data for breast cancer-associated BRCA mutations were immature and so not presented.95

radiation therapy

Radiation therapy was initially used in the treatment of chest wall recurrences or advanced disease, but, currently, it plays an integral role in managing women after lumpec-tomy and in postmastectomy patients who are at high risk for local recurrence. There are no clinical trials available in male breast cancer patients to evaluate the role of post-operative radiotherapy. However, in several series radiation appeared to reduce postmastectomy recurrence in men but had no obvious impact on survival.96 In a recent review of 42 male breast cancers, superior 10-year disease-free and overall survival rates were seen when both tamoxifen and radiation were used as adjuvant therapy in male breast cancer.97 Given that the data in women do show a survival advantage, it seems prudent to extrapolate this to the male patient with breast cancer,98,99 and in general, similar guide-lines are recommended in men as in women.

treatment of metastatic disease

Despite continued advances in the surgical and adjuvant management of breast cancer, 20–30% of patients will relapse. In addition, 5–10% will present initially with meta-static disease.100 Stage IV breast cancer treatment varies little between the sexes. Both women and men can be treated with hormonal manipulation, cytotoxic chemother-apy, or both with similar responses.

EndocrinE ThErapy

Because the goal of treatment in metastatic disease is pallia-tion of symptoms while maintaining quality of life, most clini-cians tailor therapy to obtain responses with the least toxicity. For hormone receptor-positive patients, endocrine therapy plays an important role. Traditionally, tamoxifen is usually the agent of first choice. Second-line and even third-line endo-crine therapies include estrogen-deprivation therapy in pre-menopausal women, either by oophorectomy or a luteinizing hormone-releasing hormone agonist, aromatase inhibitors (AIs), and progestational agents such as megestrol acetate. Published studies have now shown that AIs are superior to tamoxifen in hormone receptor-positive postmenopausal women as first-line therapy.101,102 Given that the vast majority of men have estrogen-receptor-positive tumors, hormonal the-rapy is often the first approach and response rates as high as 81% have been reported to tamoxifen103 and this is conside-red the preferred first-line approach. There are individual case reports of the efficacy of aromatase inhibitors, anastrozole

and letrozole, in metastatic male breast cancer.103,104 In fema-les with advanced breast cancer, fulvestrant (Faslodex), a pure antiestrogen, has been shown to be at least as efficacious as tamoxifen105 and anastrozole.106 A recent report on two males with metastatic breast cancer showed an objective response, stable disease in one patient and a partial response in the other, to fulvestrant when given as a first-line primary endo-crine therapy.107

chEmoThErapy

Breast cancer is considered one of the most chemosensitive solid tumors. Previously untreated patients receiving chem-otherapy for metastatic disease have a significant chance of responding and therefore benefiting. This benefit comes at the expense of greater toxicity that must be considered with each patient before embarking on a new therapy. The most commonly used agents include: the anthracyclines, particularly doxorubicin; cyclophosphamide; methotrex-ate; 5-fluorouracil and its oral derivatives; taxanes; and the vinca alkaloids among others. The use of these chemother-apeutic agents in metastatic disease has been well studied in women, but less so for men. However, systemic chem-otherapy is another option for men with metastatic breast cancer, but is usually reserved for second-line or third-line therapy since most men will respond favorably to hormonal manipulation. There have been reports of response in hor-mone refractory breast cancer in males of 13% for single agent 5-fluorouracil to as high as 67% for 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC).108

targeted therapy

Targeted therapy has become one of the fastest-growing approaches to managing breast cancer. Trastuzumab is a recombinant monoclonal antibody against HER2, which, as previously discussed, is overexpressed in 20–30% of breast cancer and portends a worse prognosis. Trastuzumab when used alone in HER2-overexpressing metastatic breast cancer is well tolerated and produces durable objective responses.109 A randomized controlled study was conducted in women with metastatic HER2-overexpressing breast cancer com-paring trastuzumab plus chemotherapy with chemotherapy alone. The addition of trastuzumab to chemotherapy was associated with an improved disease-free and overall sur-vival.69 It has become an important addition to the manage-ment of female metastatic breast carcinoma. HER-2 status has also been evaluated in male breast cancer.110 The rates of overexpression are variable in the published series, and tras-tuzumab as a treatment modality has not been investigated.

Lapatinib is an oral dual tyrosine kinase inhibitor against members of the human epidermal growth factor receptor HER family, and is used in female patients whose breast cancer has become resistant to therapy including anthracy-cline, taxanes, and trastuzumab.111 Phase II clinical trials

seCt ion 7   l  Oncology468

have reported an overall response rate of 22% and 14% for lapatinib.111 Ixabepilone, a new agent recently approved for metastatic breast cancer, is an antimicrotubule agent and is used in female patients whose breast cancer has become resistant to therapy including anthracycline, taxanes, and trastuzumab. Phase III clinical data have shown an objective response rate increase from 14% to 35% for ixabepilone compared to another agent, capecitabine.112 Bevacizumab (Avastin), a monoclonal antibody that targets vascular endothelial growth factor (VEGF), providing direct inhibi-tion of angiogenesis was also recently approved by the FDA for use in the first line treatment of patients with locally recurrent or metastatic breast cancer.113 This was based on a Phase III clinical trial data that showed bevacizumab plus paclitaxel resulted in a progression-free survival (PFS) of 11.8 months vs. 5.9 months when compared with paclitaxel alone.113 No data yet exist for these drugs in male breast cancer, but based on prior therapeutic agents, these may be promising agents in the future for male breast cancer.

The rarity of male breast cancer poses a significant impediment to the prospective study of treatment options in this disease. In general, recommendations have primarily been based on successes seen in clinical trials of females with breast cancer.

prognosIs And survIvAl

Male breast cancer is classically described as having a poorer prognosis than female breast cancer, suggesting that, in males, it is a more aggressive disease. However, evidence is accumulating that suggests the disease is biologically similar in both sexes. Despite this, a poorer survival in men is a con-sistent finding.8 This has been attributed to a delay in diagno-sis, later stage at presentation, anatomic factors, and an older age at diagnosis with an increase in non-breast cancer related deaths that is seen in most series of male breast cancer.8,58,114 Because of the older age at diagnosis, many of these patients have co-morbidities and deaths unrelated to breast cancer. Guinee et al.77 reported on 335 male patients: 83 (47%) of the 178 deaths were due to causes other than breast cancer. In another paper, comprising 397 cases of male breast can-cer, 39.5% of the deaths were unrelated to breast cancer.78

The prognosis for male breast cancer has been described as worse or similar to that of age- and stage-matched women.56,57,58,78,79,115,116 In a comparative study using data from the National Cancer Data Base of 4755 men and 624 174 women, 3627 pairs of men and women with breast cancer were matched for age, stage, and demographics. Age-corrected relative survival was equivalent for men and women with stage 0, I, and II disease. The survival curves diverge for stage III and IV disease; men showed worse 5-year survival rates than women, although this did not reach statistical significance.56 In a study by Borgen et al. the

survival of 58 men with breast cancer was compared to that of 174 women who were matched for stage and age at diag-nosis.116 All patients had stage I or II disease and were treated with mastectomy and axillary dissection. He found breast cancer survival at 10 years to be similar between the sexes (Figure 42.2). After stratification by nodal status, survival differences between men and women were more pronounced in the positive-node patients (Figure 42.3) but did not reach statistical significance.116 Another matched study was per-formed in the United Kingdom by Willsher et al.117 Forty-one male patients and 123 female patients with invasive cancer were matched for age, pathologic size and grade of the primary tumor, and pathologic lymph node status. The authors also found no statistical difference in disease-free or overall survival between the groups. When these patients were compared with more than 3000 unmatched women with breast cancer treated at the same time, both the male and female matched groups had a worse outcome (Figure 42.4).

Months

00.4

0.5

0.6

0.7

0.8

0.9

1

12 24 36 48 60 72 84 96 108 120

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cent

sur

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58 Male cases

174 Female cases

fIgure 42.2 Breast cancer survival of 58 male and 174 female breast cancer patients.Reproduced with kind permission from Springer Science Business Media: Borgen et al., 1997 (Fig. 1).116 Copyright 1997

00.4

0.5

0.6

0.7

0.8

0.9

1

12 24 36 48 60

Months

Per

cent

sur

vivi

ng

72 84 96 108 120

33 Male neg

96 Female neg

25 Male neg

78 Female neg

fIgure 42.3 Breast cancer survival of 58 male and 174 female breast cancer patients according to nodal status at diagnosis.Reproduced with kind permission from Springer Science Business Media: Borgen et al., 1997 (Fig. 2).116 Copyright 1997

Chapter 42 l the Differences between Male and Female Breast Cancer 469

The authors suggested that this difference, and the worse outcome in general with male breast cancer patients, is due to a difference in the distribution of prognostic factors. In this case, there was a preponderance of grade 3 tumors, which were seen in 73% of the cases.117

While multi-modality treatment with chemotherapy, radiation, and hormonal therapy have resulted in an increase in survival for women, this may not be true for men with breast cancer currently (Table 42.5). In a retrospective study by Shaub et al.118 of male breast cancer patients at a single institution from 1972 to 1991 (Cohort A) and 1992 to 2005 (Cohort B), more patients received multimodality treatment in Cohort B, although not statistically significant, but the recurrence rates were similar at 50% for Cohort A and B and the 5-year survival was similar at 43% and 51% respec-tively, which was not statistically significant (Figure 42.5). The failure to improve 5-year survival was attributed to an overall decrease in the use of multi-modality therapy com-pared with female patients. Interestingly, male breast can-cer survivors have an increased risk of developing second primary cancers. Published reports from the SEER cancer registry have shown that men with a history of breast can-cer have a relative risk 30-fold greater of developing con-tralateral breast cancer compared with a two- to four-fold risk among women with breast cancer.119

conclusIon

In summary, it appears that breast cancer is a similar disease in men and women. Despite the clear disparity in the incide-nce of breast cancer between the sexes, once it occurs in either a man or a woman its clinical presentation, pathologic appearance, response to treatment, and overall prognosis

Survival (months)

0.40 12 24 36 48 60 72

0.5

0.6

0.7

0.8

0.9

1S

urvi

ving

frac

tion

MaleMatched femaleUnmatched female

fIgure 42.4 Survival curves for male and matched female patients with breast cancer showing no significant difference (p 0.27). Compared with an unmatched female series, both the male patients (p 0.0003) and matched female patients (p 0.0006) have a worse outcome.Reproduced from Willsher et al. 1997.117 Copyright (1997) with permis-sion from Elsevier

are not that different. Given that breast cancer in women is a prevalent disease and the second leading cause of cancer-related death, there is a great socioeconomic burden. This has led to extensive research into this disease. The risk fac-tors, prognostic factors, and treatment algorithm have all been thoroughly explored, and clinicians have resources to draw on when treating their female patients. This is the major difference between the sexes. Breast cancer is a rar-ity in males; therefore, it is much less studied. Although there have been some emerging data in male breast cancer, most knowledge and treatment approaches for this disease in males come from the extrapolation of information about female patients with breast cancer.

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tAble 42.5 treatment and recurrence rates, overall for male breast cancer patients: Cohort a (1972–1991) and

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