Principles of Gender-Specific Medicine || The Differences between Male and Female Breast Cancer

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<ul><li><p>Chapter 42</p><p>AnAtomy And development</p><p>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 </p><p>e</p><p>pa YoCopyright 2010, Elsevier Inc. All rights reserved.459Principles of Gender-Specific Medicine 2010</p><p>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 1520 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.</p><p>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 IntroductIon</p><p>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.</p><p>the Dif ferencesFemale Breast C</p><p>Coral omene1, and amy TiersT1New York University Langone Medical Center, De2Associate Professor of Medicine (Oncology), NewOncology, New York, NY, USAMale and female breasts are similar at birth, consisting of a small number of rudimentary branching ducts beneath the nippleareola 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.</p><p>epIdemIology</p><p>between Male and ancer</p><p>n2</p><p>rtment of Medicine, Division of Oncology, New York, NY, USArk University Langone Medical Center, Department of Medicine, Division of </p></li><li><p>seCt ion 7 l Oncology460one 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</p><p>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.</p><p>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</p><p>Year of diagnosis</p><p>1953</p><p>1955</p><p>1956</p><p>1957</p><p>1958</p><p>1959</p><p>1960</p><p>1961</p><p>1962</p><p>1963</p><p>1964</p><p>1966</p><p>1968</p><p>1969</p><p>1970</p><p>1972</p><p>1973</p><p>1974</p><p>1975</p><p>1976</p><p>1977</p><p>1978</p><p>1979</p><p>1980</p><p>1981</p><p>1982</p><p>1983</p><p>1984</p><p>1985</p><p>1986</p><p>1987</p><p>1988</p><p>1989</p><p>1990</p><p>1991</p><p>1992</p><p>1993</p><p>1994</p><p>1995</p><p>1996</p><p>0</p><p>10</p><p>20</p><p>30</p><p>Num</p><p>ber </p><p>of c</p><p>ases</p><p>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 &amp; Sons, Inc.rIsk fActors</p><p>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 womans 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</p><p>reproductive and HormonalIn epidemiologic studies, a womans 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 womans 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</p><p>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. </p></li><li><p>Chapter 42 l the DifOne study of note is the estrogen plus progestin compo-nent of the Womens Health Initiative (WHI), a randomized controlled primary prevention trial, in which 16 608 post-menopausal women aged 5079 years were recruited by 40 US clinical centers in 19938. The study was stopped early due to the estimated hazard ratios for breast cancer of 1.26 (1.001.59) 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</p><p>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 37% 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</p><p>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</p><p>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 ferences between Male and Female Breast Cancer 461</p><p>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 (510 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.2426</p><p>dietary and environmentalThe 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.2732 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 womans risk of subsequent breast cancer.</p><p>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</p><p>Clearly, there are numerous studies examining female breast cancer and potential risk factors for th...</p></li></ul>