Susan Onamia, Melanie Ozakia, Joanne E. Mortimerb, Sumanta Kumar Pala
a Division of Genitourinary Malignancies, Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, United States b Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, United States.
S.K. Pal Tel.: +1 626 256 4673; fax: +1 626 301 8233.; E-mail: spal@coh.org.
Abstract
Significant advances have been made in the diagnosis and treatment of female breast cancer, resulting in a decline in incidence and a global improvement in clinical outcome. The statistics for male breast cancer (MBC) stand in sharp contrast-over the past several decades, there has been a steady rise in the incidence of this disease, and clinical outcome has improved at a much slower pace. In the current review, the clinicopathologic features of MBC are described in detail. An emphasis is placed on molecular profiling of MBC, which may identify candidate biomarkers and putative targets for pharmacologic intervention. The current role of cytotoxic chemotherapy and endocrine therapy (including tamoxifen, aromatase inhibitors and GnRH analogues) is defined in the context of currently available studies. Furthermore, the potential role of targeted agents, including HER2-directed therapies, PARP inhibitors, and angiogenesis inhibitors, is delineated.
Keywords: Male breast cancer BRCA, PARP inhibitors, Olaparib, HER2, Estrogen receptor Progesterone receptor Trastuzumab Trastuzumab-DM1.
Introduction
In recent years, much attention has been garnered by data suggesting a drop in the incidence of breast cancer [1]. This trend has been attributed to a decline in use of hormone replacement therapy amongst post-menopausal females according to data reported from the Women’s Health Initiative [1,2]. In contrast, the incidence of male breast cancer (MBC) appears to be rising. Review of Surveillance, Epidemiology and End Result (SEER) data indicate a rise in the incidence of MBC, from 1.0 per 100,000 men in the late 1970s to 1.2 per 100,000 men from 2000 to 2004 [3]. A similar analysis of the United Kingdom Association of Cancer Registries (UKACR) database identified a parallel trend, with the incidence of MBC rising steadily between 1985 and 2004 (Fig. 1) [4]. Furthermore, while it is widely cited that MBC accounts for less than 1% of all cases of breast malignancy, these figures are highly discrepant amongst series, possibly varying due to differences in geography and race [5-8]. For instance, separate single institution studies in India and Pakistan suggest that MBC represents up to 2.5% and 5.9% of breast cancer in both genders, respectively [9,10]. With respect to race, SEER data indicates that African American males have a significantly higher likelihood of developing breast cancer as compared to whites or Asian Americans/Pacific Islanders [11].
Figure 1. A steady rise in the incidence of MBC has been documented in SEER registry analyses (a) and an evaluation of the UKACR (b). (Figures adapted from [3,4]).
Thus, with the incidence of MBC on the rise and the prevalence potentially underestimated, there is a need to better understand the clinicopathologic features of this disease. Furthermore, it appears that males have derived lesser benefit from the substantial advances in breast cancer therapy made over the past several decades. A recent analysis of SEER data investigating trends in survival amongst patients diagnosed between 1996 and 2005 suggested a 42% decrease in breast cancer-related death amongst women, but only a 28% decrease amongst men [12]. In the current review, emerging data related to MBC diagnosis and treatment is presented. The role of molecular profiling is emphasized, given a burgeoning pipeline of targeted agents that have already changed the landscape of breast cancer therapy.
2. Risk factors
A number of studies have assessed risk factors for MBC. A total of 121 males who ultimately developed breast cancer were identified from the prospective National Institute of Health (NIH)-AARP Diet and Health Study [13]. In this analysis, report of a first-degree relative with male breast cancer (relative risk, RR, 1.92; 95%CI 1.24-3.91) and elevated body mass index (>30 versus <25; RR 1.79, 95%CI 1.10-2.91) were associated with development of MBC, while physical activity was inversely related. A separate analysis of the US Veterans Affairs database identified 642 MBC patients [14]. In this analysis, risk factors identified included diabetes (RR 1.30, 95%CI 1.05-1.60), orchitis/epididymitis (RR 1.84, 95%CI 1.10-3.08), Klinefelter’s syndrome (RR 29.64, 95%CI 12.26-71.68) and gynecomastia (RR 5.86, 95%CI 3.74-9.17). Interestingly, amongst African American MBC patients, cholelithiasis was a significant risk factor (RR 3.45, 95%CI 1.59-7.47). The strong association of Klinefelter’s syndrome with MBC observed in the Veterans study is echoed by several other reports; for instance, a Swedish registry study suggested a 50-fold increase in the risk of MBC amongst patients with Klinefelter’s syndrome [15]. Moreover, the rate of Klinefelter’s syndrome in affected patients was suggested to be as high as 7.5% in this experience. Several other risk factors for MBC identified by other studies include previous breast pathology, previous testicular pathology and a history of liver disease [16].
Interestingly, MBC may serve as a risk factor for other malignant processes. A review of 69 patients with MBC identified 12 patients (17%) with concomitant diagnoses of prostate cancer [17]. A theoretical link between these diseases does exist—for example, aromatase inhibitors used to treat MBC may increase serum levels of testosterone, thereby driving growth and proliferation of prostate cancer clones [18]. Although further prospective testing is needed to validate this association, the practitioner may choose to weigh this data in the risk: benefit decision to initiate prostate cancer screening in patients with MBC. Outside of prostate cancer, there is some suggestion that MBC may be associated with leukemia and cancers of the small intestine, rectum, and pancreas [19-21]. Other links between MBC and distinct malignancies may result from the presence of a BRCA-deficiency; these are addressed elsewhere in this manuscript. Finally, the association between breast cancer and meningioma in females does not appear to exist in males [22].
3. Diagnosis
The majority of patients with MBC present with a painless, subareolar mass, often associated with nipple retraction, ulceration, bleeding or discharge [5]. In the absence of other findings, it has been suggested that the presence of nipple discharge may be an indicator of non-invasive disease—hence, early recognition of this symptom is critical [23]. Bilateral involvement is rare, and is estimated to constitute less than 2% of cases [24]. Axillary node metastases appear to be more common in males as opposed to females, and cases of occult breast cancer have been reported in the literature [25,26].
Techniques used for diagnosis of female breast cancer may be relevant to MBC. A series of 517 fine-needle aspirations (FNAs) of the breast performed in males with abnormal clinical findings yielded 70 cases of carcinoma (13.8%), 29 inconclusive cases (5.7%), and 295 negative cases (58%) [27]. With histopathology available in 97 cases, it was suggested that the sensitivity and specificity for FNA approached 100%. In a more recent series of 217 patients evaluated for a breast mass with FNA, pathologic analysis suggested carcinoma in 12 cases (5.5%), suspicious findings in 5 cases (2.3%) and no malignancy in 181 cases (83.4%) [28]. In 26 of these cases (12%), matching biopsies were available. Similar to the previous study, the sensitivity and specificity for detecting malignancy with FNA was 100% [28].
The technique of sentinel lymph node (SLN) biopsy has also been explored in MBC. Amongst 7,315 SLN procedures performed at the Memorial Sloan-Kettering Cancer Center (MSKCC) over a 10-year period, 78 (1%) were in males [25]. Clinical follow-up was available in 76 of these patients. A negative SLN was detected in 39 patients (51%)—of these, a positive non-SLN was detected in 2 patients (8%) by intra-operative palpation. Amongst 37 patients with positive SLNs (49%), the majority had nodal positivity determined intraoperatively and proceeded immediately to axillary lymph-node dissection. With a median follow-up of 28 months, no axillary recurrences were observed, suggesting the utility of this procedure in male patients.
ТЕКСТ
4. Pathologic features
Several studies have characterized the frequency of histologic subtypes in MBC. Using data extracted from ten US registries, a cohort of 282 cases was identified with associated tissue specimens [29]. Roughly 90% of these specimens demonstrated invasive disease, and all of the remaining non-invasive cases were of the ductal subtype (given lack of terminal lobules in the male breast, lobular histologies are exceedingly rare) [5]. Amongst invasive histologies, a larger proportion of ductal and papillary subtypes were recorded as compared to what would be expected in females. Case reports document co-existence of these subtypes, and there are additionally published anecdotes of papillary variants [30,31]. Within the past several years, multiple reports of intracystic papillary carcinoma have been published [32-37]. This non-invasive subtype comprises less than 0.5% of all female breast cancer, but may constitute a more frequent entity in the setting of MBC.
Several series have identified a higher frequency of estrogen receptor (ER) and progesterone receptor (PR) positivity in MBC as compared to female breast cancer, suggesting the role of endocrine therapy in this population [38,39]. These data are summarized in Table 1. In more limited series, it appears that overexpression of human epidermal growth factor receptor-2 (HER2), occurring in 25% of female breast cancer cases, may be higher amongst male cases (30-56%) [40-43]. HER2, a transmembrane receptor, is the target of multiple novel agents, including trastuzumab, lapatinib and trastuzumab-DMl [44-46]. Strategies using both endocrine therapy and HER2-directed agents in combination are currently being explored in the setting of female breast cancer, and may ultimately be applicable in MBC, as well [47,48].
Table 1. Receptor status of male breast cancer as defined in recent series.
5. Molecular profiling
The role of the prolactin receptor in breast cancer pathogenesis is controversial; however, data from prospective efforts do demonstrate a modest association between prolactin level and breast cancer risk [56,57]. In one series, tissue from 30 patients with male gynecomastia and 30 patients with MBC were assessed [58]. Prolactin receptor expression was significantly higher in MBC patients as compared to patients with gynecomastia (60% versus 20%, P = 0.003). In contrast, ER and PR expression (also assessed in this series) did not appear to differ widely between these cohorts. Compounds antagonizing the prolactin receptor have been shown to augment the activity of doxorubicin and paclitaxel in cellular models; this approach may prove clinically useful in the setting of MBC [59].
A step lacking in most biomarker studies of MBC is correlation with clinical outcome. In a series of 39 patients with MBC and available tissue, survivin and COX-2 expression were determined [60]. Survivin is a member of the inhibitor of apoptosis (IAP) family of proteins, and overexpression of survivin may represent a mechanism of resistance to HER2-directed therapies [61]. COX-2 is a mechanistically distinct moiety, and metabolites of COX-2 (such as prostaglandin E2, PGE2) are thought to enhance tumor angiogenesis and suppress anti-tumor immunity [62]. Expression of both survivin and COX-2 were seen in a substantial number of patients (69% and 36%, respectively). Neither biomarker served to predict overall survival (OS), albeit in a relatively small sample. Despite the negative result, study designs such as this are useful in identifying the link between relevant biomarkers and prognosis.
While biomarker discovery in MBC is often driven by observations in female breast cancer, other strategies do exist. Matrix assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry is a novel method of determining differential protein expression in cancer tissue, and may ultimately define unique candidate biomarkers [63]. In a series of patients with MBC, tropomyosin-1 (a tumor suppressor) was shown to be underexpressed. Alterations in cathepsin D and galectin-1, mediators of cellular invasion and metastasis, were also observed. Outside of MALDI-TOF, methods such as comparative genomic hybridization (CGH) may identify broader genetic alterations that occur in MBC [64]. In a series of 39 MBC specimens assessed by CGH, gains were most frequently observed at 1q, 8q and 16p, and losses were most frequently observed at 8p, 16q, and 13q. More detailed exploration of these loci could yield moieties relevant to MBC pathogenesis.
6. BRCA-deficient MBC
Overall, it appears that BRCA2 mutations occur more frequently than BRCA1 mutations in MBC. A review of over 9000 breast cancerrelated referrals to the Regional Genetics service in Manchester, UK, identified 64 families with affected males [65]. Blood lymphocyte DNA testing from affected patients yielded 17 pathogenic BRCA2 mutations and 4 pathogenic BRCA1 mutations. Overall, the rate of BRCA1/2 mutation in MBC families was 34%. This rate is substantially higher than in population-based studies; for example, another UK-based registry analysis identified 94 cases of MBC and identified mutations in only 15% of patients [66]. Similarly, a population- based series comprised of 54 MBC cases from Southern California identified BRCA2 mutations in only 4% of patients. In this series, no BRCA1 mutations were found, and only 13% of patients had a family history of breast and/or ovarian cancer.
A new class of agents has shown promising activity in breast cancer patients with DNA-repair defects. The enzyme poly(ADP- ribosyl)ation polymerase (PARP) complements BRCA-related repair processes; drugs targeting PARP may therefore be particularly active in BRCA-deficient patients (a concept termed ‘synthetic lethality’) [67].The oral PARP inhibitor olaparib has been examined in a cohort of 54 patients with BRGAÎ/2-deficient, metastatic breast cancer who had been previously exposed to a median of 3 lines of chemotherapy [68]. In this heavily refractory population, an overall response rate (ORR) of 38% was observed in 27 assessable patients. Toxicities related to the agent were relatively mild, with fatigue, nausea and vomiting representing the most frequently reported adverse events. Outside of targeted therapies, there is emerging evidence suggesting that DNA-damaging cytotoxic agents (such as cisplatin) may be particularly effective in BRCA-deficient breast cancer [69]. The association observed between MBC and BRCA- deficient disease suggests the potential applicability of olaparib, cisplatin and related agents in this disease process, although this clearly requires further clinical validation.
7. Treatment
7.1. Systemic therapy
The increased incidence of ER- and PR-positivity in MBC suggests the potential utility of endocrine therapy in this disease. As a result of the low incidence of MBC, there are no randomized trials to guide treatment [70]. Nonetheless, a prospective study of tamoxifen therapy for stage II and III operable MBC has been performed. Survival in this cohort of 39 patients was 61% at 5 years, which was significantly greater than the 44% 5-year survival observed in historical controls (P = 0.006). Disease-free survival (DFS) at 5 years was also superior as compared to historical controls (56% versus 28%; P = 0.005). With respect to toxicity data, no serious adverse events were recorded. On the basis of these data, it has been suggested that patients with operable MBC be treated with 5 years of adjuvant tamoxifen therapy ifhormone-receptor positive (Fig. 2).
Figure 2. A proposed schema forevaluation and management of MBC. (Adapted from [5]).
Akin to adjuvant endocrine therapy, use of adjuvant chemotherapy in MBC is guided by a relatively small dataset. In a prospective analysis, 24 patients with operable MBC were treated with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) after mastectomy [71]. At a median follow-up of 46 months, only 4 patients had recurred (2 had died of metastatic disease). In this study, 5-year survival was projected at greater than 80%. Importantly, all patients in this series had nodal involvement. Thus, for patients with high risk, operable MBC, consideration may be given to adjuvant chemotherapy. Limited data is available to guide whether more recently validated taxane- or anthracycline-based adjuvant regimens can be substituted for CMF.
In the setting of metastatic, hormone-receptor positive disease, orchiectomy was the first effective approach documented in the medical literature [72]. Modern endocrine therapies have also been effective; tamoxifen has demonstrated response rates of 49% in the setting of metastatic MBC [73]. Importantly, it appears that the benefit of endocrine therapy lies exclusively in the hormone-receptor positive population—in 43 patients with metastatic MBC treated with tamoxifen, a response rate of 69% was observed amongst 35 men with ER-positive disease, but no responses were observed amongst 8 men with ER-negative disease [73]. More recent data points to the utility of aromatase inhibitors in MBC, which have demonstrated superior activity to other endocrine therapies in metastatic female breast cancer [74]. Review of a French registry identified 15 patients treated with either exemestane, letrozole or anastrazole (n = 5 for each) [75]. Two patients (13%) had a complete response to therapy, while 4 patients (27%) had a partial response. Stable disease was observed in a further 2 patients (13%), yielding an overall clinical benefit rate of 53%. Retrospective correlative studies in 6 assessable patients suggested that all had estradiol levels below the threshold of detection while on aromatase inhibitor therapy. Several subsequent reports have suggested that the activity of aromatase inhibitors can be augmented in MBC by combination with gonadotropin-releasing hormone (GnRH) analogues, such as leuprolide [76,77]. A lesser explored endocrine therapy in MBC is fulvestrant; this inhibitor of ER dimerization has been shown to have activity comparable to aromatase inhibitors in the setting of first-line therapy for metastatic female breast cancer, and demonstrates activity in the same group of patients after failure of tamoxifen [78,79]. Anecdotal reports suggest the efficacy of fulvestrant in metastatic MBC [80].
The role of chemotherapy in metastatic MBC is less clear. Retrospective studies directly comparing chemotherapy and endocrine therapy in this setting suggest greater efficacy from the latter, though it is recognized that chemotherapy may still have a palliative effect (for example, single agent cyclophosphamide offers response rates of up to 53%) [5]. The activity of novel cytotoxic agents has been documented only in small case series; for instance, one report suggested activity with the combination of gemcitabine and nab-paclitaxel in 2 patients with metastatic MBC [81]. The role of HER2-directed therapies is even more vague; though trastuzumab has now been in clinical use for nearly a decade, there are limited reports of its activity in MBC in the published literature [82].
7.2. Surgery and radiation
Despite a general adherence to female breast cancer guidelines, surgical management of MBC more frequently involves either radical or modified radical mastectomy [83]. In a review of 50 years of surgical experience at the Mayo Clinic, 124 patients with MBC were identified [84]. Of these patients, 92% were treated with mastectomy. Roughly equal proportions received radical and modified radical procedures (41% and 39%, respectively), while 12% received simple mastectomy alone. With two large studies in operable female breast cancer reporting the equivalence of mastectomy and breast-conserving approaches at 20-year follow-up, there has been keen interest in determining whether the latter approach is feasible in MBC [85,86]. In one series, 7 men with localized MBC were treated with breast conservation [87]. At a median follow-up of 67 months, no local recurrences were observed, suggesting the feasibility of this approach.
Despite conflicting datasets on the topic, current guidelines from the National Comprehensive Cancer Network advocate use of post-mastectomy radiation therapy (PMRT) in women with 4 or more axillary lymph nodes [88]. Further, strong consideration of the modality is recommended in the setting of 1-3 positive axillary nodes. For patients with MBC, limited data is available to support use of PMRT [5]. In a series of 42 MBC patients who received mas-tectomy, PMRT and either adjuvant or neoadjuvant chemotherapy, 5-year OS was 77%, and DFS at this interval was 45%. In a separate series of 39 patients, 61.8% of patients received a combination of chemotherapy, endocrine therapy and radiation after surgery, while 7.7% of patients received only hormonal therapy and radiation [89]. In this experience, receipt of radiation therapy was not associated with a benefit in DFS or OS.
8. Conclusions
Given the documented rise in MBC incidence in two large registry analyses, developing a more thorough understanding of this disease is of critical importance [3,11]. The receptor profile of MBC (with increased ER, PR and HER2 expression) makes it an attractive candidate for endocrine and HER2-directed therapies [40]. Furthermore, ongoing studies to define the molecular and genetic profile of MBC may yield other relevant biomarkers and therapeutic targets. A challenge that lies ahead in the research community is uniting efforts for the development of prospective trials to address this population. Without a concerted effort, the literature pertaining to MBC will remain a collection of retrospective series and pilot studies. Efforts to develop randomized, prospective studies within cooperative groups and other clinical trial consortia are essential.
Acknowledgements
Dr. Pal’s efforts are supported by CBCRP 151B-0140 (California Breast Cancer Research Program Junior IDEA Award) and N1H K12 2K12CA001727-16A1.
References
Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N EnglJ Med 2007;356:1670-4.
Writing Group fortheWomen’s Health Initiative Investigators: Risks and Benefits ofEstrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results FromtheWomen’s HealthInitiative Randomized ControlledTrial.JAMA 2002 288:321-33.
Stang A, Thomssen C. Decline in breast cancer incidence in the United States: what about male breast cancer? Breast CancerRes Treatment 2008;112:595-6.
Speirs V, Shaaban A. The rising incidence of male breast cancer. Breast Cancer Res Treatment 2009;115:429-30.
Giordano SH, Buzdar AU, Hortobagyi GN. Breast cancer in men. Ann 1nter Med 2002;137:678-87.
Ewertz M, Holmberg L, Karjalainen S, et al. Incidence of male breast cancer in Scandinavia, 1943-1982. IntJ Cancer 1989;43:27-31.
Fentiman 1S, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet 2006;367:595-604.
Thalib L, Hall P. Survival of male breast cancer patients: population-based cohort study. Cancer Sci 2009;100:292-5.
Mitra D, Manna A, Sikdar SK, et al. Clinicopathological study and its prognostic implication in male breast carcinoma.J Indian Med Assoc 2007;105:681-3,686.
Jamal S, Mamoon N, Mushtaq S, et al. Carcinoma ofthe male breast: a study of 141 cases from northern Pakistan. Asian PacJ Cancer Prev 2006;7:119-21.
O’MalleyC, Shema S, White E, et al. Incidence of male breast cancer in California, 1988-2000: racial/ethnic variation in 1759 men. Breast Cancer Res Treatment 2005;93:145-50.
AndersonWF,Jatoi I, TseJ, et al. Male Breast Cancer: A Population-Based Comparison With Female Breast Cancer.J Clin Oncol:JCO.2009.23.8162, 2009.
Brinton LA, Richesson DA,GierachGL, et al. Prospective evaluation of risk factors for male breast cancer.J Natl CancerInst 2008;100:1477-81.
Brinton L, CarreonJ, Gierach G, et al. Etiologic factors for male breast cancer in the U.S. Veterans Affairs medical care system database. Breast Cancer Research and Treatment 119:185-92.
Hultborn R, Hanson C, KopfI, et al. Prevalence ofKlinefelter’s syndrome in male breast cancer patients. Anticancer Res 1997;17:4293-7.
SascoAJ, LowenfelsAB, Pasker-deJong P. Reviewarticle: epidemiologyof male breast cancer. A meta-analysis of published case-control studies and discussion ofselected aetiological factors. IntJCancer 1993;53:538-49.
Lee UJ, Jones JS. Incidence of prostate cancer in male breast cancer patients: a risk factor for prostate cancer screening. Prostate Cancer Prostatic Dis 2008;12:52-6.
Terris MK, McCallum SW. Aromatase inhibitors for male infertility. J Urol 2002;168:1509.
GrenaderT, Goldberg A, Shavit L. Second cancers in patients with male breast cancer: a literature review.J CancerSurvivorship 2008;2:73-8.
Lowe T, Luu T, Shen J, et al. Male breast cancer 15 years after allogeneic hematopoietic cell transplantation including total body irradiation for recurrent acute lymphoblastic leukemia. Onkologie 2008;31:266-9.
Unek IT, Alacacioglu A, Tarhan O, et al. Synchronous appearance of male breast cancer and pancreatic cancer 15 years after the diagnosis of testicular cancer-report ofacase.J BUON 2008;13:421-4.
Rao G, Giordano SH, Liu J, et al. The Association of Breast Cancer and Meningioma in Men and Women. Neurosurgery 65:483-9 10.1227/01.NEU.0000350876.91495.E0, 2009.
Morrogh M, King TA. The significance of nipple discharge of the male breast. Breast J 2009;15:632-8.
dos Santos VM, Cintra Osterne EM, de Castro RA, et al. Bilateral male breast cancer: too many concerns? Asian PacJ Cancer Prev 2007;8:640-1.
Flynn LW, Park J, Patil SM, et al. Sentinel lymph node biopsy is successful and accurate in male breast carcinoma. J Am College Surgeons 2008;206:616-21.
Gu GL, Wang SL, WeiXM, et al. Axillary metastasis asthe first manifestation of male breast cancer: a case report. Cases J 2008;1:285.
Joshi A, Kapila K, Verma K. Fine needle aspiration cytology in the management ofmalebreast masses. Nineteenyearsofexperience.ActaCytol 1999;43:334-8.
Rosen DG, Laucirica R, Verstovsek G. Fine needle aspiration of male breast lesions. Acta Cytol 2009;53:369-74.
Stalsberg H, Thomas DB, Rosenblatt KA, et al. Histologic types and hormone receptors in breast cancer in men: a population-based study in 282 United States men. Cancer Causes Contr 1993;4:143-51.
Bhatia A, Uma Nahar Saikia, Kumar Y. Rare coexistence of invasive papillary carcinoma with infiltrating ductal carcinoma in male breast: report of a case. Int J Surg Pathol 2008;16:311-3.
Farkas A, Istok R, Szekely E, et al. Pigmented papillary carcinoma: a rare tumor ofthe male breast. Pathol Oncol Res 2008;14:341-3.
Brahmi SA, El M’rabet FZ, Akesbi Y, et al. Intracystic papillary carcinoma associated with ductal carcinoma in situ in a male breast: a case report. Cases J 2009;2:7260.
Dragoumis DM,TsiftsoglouAP. Intracystic papillarycarcinomaassociatedwith ductal carcinoma in situ in a male breast. J Postgrad Med 2008;54:39-40.
Hussain A, Sweeney K, Salman R, et al. Intracystic papillary carcinoma of the male breast: a case report and review ofthe literature. Irish J Med Sci.
Olu-Eddo AN, Ohanaka CE. Intracystic papillary carcinoma of the breast in a Nigerian male: case report. Niger Postgrad MedJ 2008;15:270-1.
Romics Jr L, O’Brien ME, Relihan N, et al. Intracystic papillary carcinoma in a male as a rare presentation ofbreast cancer: a case report and literature review. J Med Case Reports 2009;3:13.
Yoshida M, Mouri Y, Yamamoto S, et al. Intracystic invasive papillary carcinoma of the male breast with analyses of loss of heterozygosity on chromosome 16q. Breast Cancer.
Giordano SH, Cohen DS, Buzdar AU, et al. Breast carcinoma in men. Cancer 2004;101:51-7.
Nahleh ZA, Srikantiah R, Safa M, et al. Male breast cancer in the veterans affairs population. Cancer2007;109:1471-7.
Avisar E, McParland E, Dicostanzo D, et al. Prognostic factors in node-negative male breast cancer. Clin Breast Cancer 2006;7:331-5.
Shah P, Robbani I, Shah O. Clinicopathological study of male breast carcinoma: 24 years of experience. Ann Saudi Med 2009;29:288-93.
Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-82.
Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu protooncogene in human breast and ovarian cancer. Science 1989;244:707-12.
Slamon D, Leyland-Jones B, Shak S: Addition of Herceptin (humanized anti- HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer(HER21/MBC) markedly increases anticanceractivity:Arandom- ized multinational controlled phase III trial. ProcAm Soc Clin Oncol 17:(abstr 377), 1998.
Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2- positive advanced breast cancer. N Engl J Med 2006;355:2733-43.
Beeram M, Krop I, Modi S, et al. A phase I study of trastuzumab-MCC-DM1 (T- DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (BC). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 1042.
Clemens M, Kaufman B, Mackey JR, et al. Trastuzumab plus anastrozole may prolong overall survival in postmenopausal women with HER2-positive, hormone-dependent metastatic breast cancer: Results of a post-hoc analysis from the TAnDEM study. ASCO Breast CancerSymposium 2007 (abstr 231).
Chu Q, Goldstein L, Murray N, et al. A phase I, open-label study ofthe safety, tolerability and pharmacokinetics of lapatinib (GW572016) in combination with letrozole in cancer patients. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 3001.
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. 2004 116:281-97.
Fassan M, Baffa R, PalazzoJ, et al. MicroRNA expression profiling of male breast cancer. Breast CancerRes 2009;11:R58.
Burstein HJ, Elias AD, Rugo HS, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2008;26:1810-6.
MillerK, Wang M, GralowJ, et al. Paclitaxel plus Bevacizumab versus Paclitaxel Alone forMetastatic Breast Cancer. N EnglJ Med 2007;357:2666-76.
Bianchi G, Loibl S, Zamagni C, et al. Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anti-Cancer Drugs 2009;20:616-24, doi:10.1097/CAD.0b013e32832b2ea0.
Miles D, ChanA, Romieu G, et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO.J ClinOncol (MeetingAbstracts) 2008;26. LBA1011-.
Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastaticbreast cancer(MBC).JClinOncol(MeetingAbstracts)2009;27,1005.
Clevenger CV, Furth PA, Hankinson SE, et al. The role of prolactin in mammary carcinoma. EndocrRev 2003;24:1-27.
TworogerSS, Sluss P, Hankinson SE. Association between plasma prolactin con-centrations and risk of breast cancer among predominately premenopausal women. Cancer Res 2006;66:2476-82.
Ferreira M, Mesquita M, Quaresma M, et al. Prolactin receptor expression in gynaecomastia and male breast carcinoma. Histopathology 2008;53:56-61.
Howell S, Anderson E, Hunter T, et al. Prolactin receptor antagonism reduces the clonogenic capacityofbreast cancercells and potentiates doxorubicin and paclitaxel cytotoxicity. Breast Cancer Res 2008;10:R68.
Tallal Y, Kelly Dakin H, Daniel R, et al. Survivin and COX-2 expression in male breast carcinoma. Breast (Edinburgh, Scotland): Churchill Livingstone; 2009. p. 228-32.
Foster F, Owens T, Tanianis-Hughes J, et al. Targeting inhibitor of apoptosis proteins in combination with ErbB antagonists in breast cancer. Breast Cancer Res 2009;11:R41.
Krysan K, Reckamp KL, Sharma S, et al. The potential and rationale for COX-2 inhibitors in lung cancer. AnticancerAgents Med Chem 2006;6:209-20.
Gomez-Pozo A, Sanchez-Navarro I, Nistal M, et al. MALDI profiling of human lung cancersubtypes. PLoS ONE 2009;4:e7731.
Rudlowski C, Schulten H-J, Golas MM, et al. Comparative genomic hybridization analysis on male breast cancer. Int J Cancer2006;118:2455-60.
Evans D, Bulman M, Young K, et al. BRCA1/2 mutation analysis in male breast cancer families from North West England. Familial Cancer 2008;7:113-7.
Basham V, Lipscombe J, Ward J, et al. BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res 2002;4:R2.
Pal SK, Mortimer J. Triple-negative breast cancer: novel therapies and new directions. Maturitas 2009;63:269-74.
TuttA, Robson M, GarberJE, et al. Phase IItrial ofthe oral PARP inhibitorolaparib in BRCA-deficient advanced breast cancer. J Clin Oncol (Meeting Abstracts) 2009;27. CRA501-.
Byrski T, Foszczynska-Kloda M, Huzarski T, et al. Cisplatin chemotherapy in the treatment of BRCA1-positive metastatic breast cancer (MBC). J Clin Oncol (Meeting Abstracts) 2009;27,1099.
Ribeiro G, Swindell R. Adjuvant tamoxifen for male breast cancer (MBC). Br J
Cancer 1992;65:252-4.
Bagley CS, Wesley MN, Young RC, et al. Adjuvant chemotherapy in males with cancerofthe breast.AmJClinOncol 1987;10:55-60.
FarrowJH,AdairFE. Effect of orchidectomyon skeletal metastases from cancer ofthe male breast. Science 1942;95:654.
Jaiyesimi IA, Buzdar AU, Sahin AA, et al. Carcinoma of the male breast. Ann Intern Med 1992;117:771-7.
Gibson L, Lawrence D, Dawson C, et al. Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev:CD003370, 2009.
DoyenJ, Italiano A, Largillier R, et al. Aromatase inhibition in male breast cancer patients: biological and clinical implications. Ann Oncol:mdp450, 2009.
Giordano SH, Hortobagyi GN. Leuprolide acetate plus aromatase inhibition for male breast cancer.J Clin Oncol 2006;24:e42-43.
Soon Wong N, Seong Ooi W, Pritchard KI. Role ofgonadotropin-releasing hormone analog inthe management of male metastatic breast cancer is uncertain. J Clin Oncol 2007;25,3787.
RobertsonJFR, Llombart-Cussac A, RolskiJ, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST Study.J Clin Oncol 2009;27:4530-5.
Howell A, Robertson JFR, Quaresma Albano J, et al. Fulvestrant, Formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 2002;20:3396-403.
de la Haba RodriguezJR, Porras Quintela I, Pulido Cortijo G, et al. Fulvestrant in advanced male breast cancer. Ann Oncol 2009;20:1896-7.
Montero AJ,Talebi TN, Zhu Y, et al. Successful use ofbiweekly gemcitabine plus nab-paclitaxel in two male patients with stage iv breast cancer: case reports and review ofthe literature. AmJTher 2009.
Carmona-Bayonas A. Potential benefit of maintenance trastuzumab and anastrozole therapy in male advanced breast cancer. Breast (Edinburgh, Scotland) 2007;16:323-5.
Jim W, James K, Claire M, et al. Are males with early breast cancer treated differently from femaleswith earlybreast cancer inAustralia and New Zealand? Breast (Edinburgh, Scotland) 2009;18:378-81.
Gough DB, Donohue JH, Evans MM, et al. A 50-year experience of male breast cancer: is outcome changing? Surg Oncol 1993;2:325- 33.
Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347: 1233-41.
Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N EnglJ Med 2002;347:1227-32.
Golshan M, Rusby J, Dominguez F, et al. Breast conservation for male breast carcinoma. Breast (Edinburgh, Scotland) 2007;16:653-6.
National Comprehensive Cancer Network Guidelines: Breast Cancer (Available on-line at http://www.nccn.org; last accessedJanuary 8, 2009).
Yoney A, Kucuk A, Unsal M. Male breast cancer: a retrospective analysis. Can- cer/Radiothérapie 2009;13:103-7.