Pharmacotherapy for male breast cancer

Review

2002 © Ashley Publications Ltd ISSN 1465-6566 701

Ashley Publicationswww.ashley-pub.com

1. Introduction

2. Therapy

3. Adjuvant therapy

4. General approach to treatment

of metastatic disease

5. Prognosis

6. Conclusions

Acknowledgements

Monthly Focus: Oncologic

Pharmacotherapy for male breast cancerTeresa HayesBaylor College of Medicine, Houston, Texas

Breast cancer in males is uncommon, occurring at ~ 1% of the rate of femalebreast cancer. Male breast carcinomas tend to be highly positive for hormonereceptors, including oestrogen, progesterone and androgen receptors.Owing to this, hormone therapy is recommended as the primary treatmentmodality. Adjuvant therapy is recommended for male breast cancers withlarge size or positive axillary nodes. For metastatic disease, options for ther-apy include tamoxifen, orchiectomy, anti-androgens with or without luteinis-ing hormone releasing hormone analogues or combination chemotherapy.The newer hormonal treatments, such as the selective aromatase inhibitors ornovel antioestrogens, have not yet been well studied in male breast cancerbut have potential for efficacy in this disease.

Keywords: chemotherapy, hormonal therapy, male breast cancer, orchiectomy, tamoxifen

Expert Opin. Pharmacother. (2002) 3(6):701-708

1. Introduction

1.1 Risk factorsCancer of the breast in males is an uncommon malignancy, occurring at ~ 1% of therate of breast cancer in females. In the US this year, ~ 1500 cases of male breast can-cer are expected, with 400 deaths [1]. Male breast cancer is more common in certainparts of the world, notably Egypt, Hungary and sub-Saharan Africa [2-4]. It is morecommon in African-Americans than in Caucasians [5,6].

The aetiology of male breast cancer is incompletely understood. The incidence ofbreast cancer in males is increased in states of hormonal imbalance caused by eithertesticular dysfunction or oestrogen excess. These include undescended testes, testic-ular injury, orchitis, late puberty, infertility, schistosomiasis, liver cirrhosis, iatro-genic oestrogen administration and multiple other conditions [3,7-16]. Klinefeltersyndrome, resulting from the inheritance of an extra X chromosome (XXY pheno-type), is one of the strongest risk factors for developing male breast cancer. Patientswith Klinefelter syndrome carry an ~ 50-fold increased risk of developing breast can-cer compared to the general population [17-19]. Recently, the BRCA2 gene on chro-mosome 13q12-13 has been linked to familial male breast cancer. Members offamilies carrying this gene are also at risk for female breast, ovarian and prostate can-cers. BRCA2 mutations account for 11 – 33% of cases of familial male breast cancer,as well as a significant proportion of sporadic male breast cancer [2,20-25].

1.2 Hormone statusProliferation of breast cancer cells is stimulated by endogenous oestrogen. There aremultiple sources of oestrogen production in the normal male. The adrenal glandproduces very small amounts of oestrogen, as well as androgens such as dihydroepi-androsterone and androstenedione that are converted to oestrogens by aromatase inperipheral tissues, particularly adipose tissue [26-27]. Testosterone produced by thetestes can also be converted to oestrogen in peripheral tissues. The testes are respon-sible for up to 15% of circulating oestrogens [28]. In addition, multiple extragonadal

Pharmacotherapy for male breast cancer

702 Expert Opin. Pharmacother. (2002) 3(6)

sites, such as the mesenchymal cells of the adipose tissue andthe skin, bone, endothelium and brain, are responsible forlocal oestrogen biosynthesis [29].

The normal male breast is sensitive to the effects of oestro-gen, as shown by the development of gynecomastia in menexposed to exogenous oestrogen. In transsexuals given ethyniloestradiol in combination with androgen suppression by cypro-terone acetate, the genetically male breast is able to developacini and lobules [30]. However, the role of oestrogens in malebreast tissue under normal conditions is not understood.

Male breast cancer typically arises in the setting of lowserum oestrogen and high serum androgen concentrations.In situ oestrogen produced by aromatase from breast cancerstromal cells is thought to play an important role in thepathogenesis of hormone receptor-positive male breast cancer,which comprises the majority of cases [31]. Preliminary studiesindicate that aromatase may be present in higher concentra-tion in male than in female breast cancers [31-33].

1.3 Hormone receptorsMale breast cancer has some biological differences from femalebreast cancer. In females, ~ 60% of cases are oestrogen receptor(ER) positive, while 80 – 100% of cases in males are ER-posi-tive [34-49]. The majority of male breast cancers are also positivefor the progesterone receptor and more than a third of themhave detectable androgen receptors [34,37,39-48]. Male breast can-cers differ from female breast cancers in that there is a lowerpercentage of p53-positive and a higher percentage of bcl-2-positive tumours [34,45]. Her2/neu (c-erbB-2) overexpression isdetectable in 21 – 39% of male breast cancer [34,50-52].

It is possible that the apparent differences in hormonereceptor expression in male and female breast cancer is anartefact of the older average age at diagnosis of male breastcancer patients [6]. ER expression is known to increase withage in female breast cancer [53]. There are conflicting reportsas to whether this occurs in male breast cancer [34,45]. How-ever, the level of ER expression is similar in age-matchedmales and females with breast cancer [48,54]. Progesteronereceptor expression, which is less age-dependent in females[53], was higher in age-matched males in one study but equalin males and females in another [48,54]. The apparent discrep-ancies in these reports are likely to be due to the small num-bers of male breast cancer cases available for study.

2. Therapy

2.1 Endocrine therapy2.1.1 Orchiectomy or anti-androgensThe earliest treatments for male breast cancer took advantageof the known presence of hormone receptors in a substantialpercentage of male breast cancers. Orchiectomy was the tradi-tional therapy. Removal of testicular sources of androgen pre-vented the conversion of the hormone to oestrogen in theperipheral tissues, thereby depriving the tumour of a prolifera-tive stimulus. Orchiectomy was very effective in prolonging

survival in patients with recurrent or generalised disease [55].Approximately half of patients responded to orchiectomy,with responses lasting a median of 11 – 20 months [56-59].Responses to testicular removal occur more frequently inpatients with ER-positive tumours [35,36,38,56]. There is littlepublished information on the relationship between androgenreceptor status and response to orchiectomy.

As many male patients found orchiectomy to be undesira-ble, other means of suppressing endogenous androgens weresought. Metastatic male breast cancer has responded to theantiandrogen cyproterone acetate [60] and to the combinationof luteinising hormone releasing hormone (LHRH) analogueand antiandrogen [61-63] or LHRH analogue alone [63,64]. It isnot clear whether the responses to anti-androgens are due tothe antagonism of androgen receptors or simply to theremoval of potential substrates for conversion to oestrogen.The number of androgen receptors does not seem to correlatewell with clinicopathological features or prognosis [47], sug-gesting that the latter mechanism may be more important.

2.1.2 Suppression of adrenal androgensMethods to decrease production of adrenal androgens, includ-ing hypophysectomy, bilateral surgical adrenalectomy, andmedical adrenalectomy using aminoglutethimide or high-doseketoconazole, were successfully used in the past to treat meta-static male breast cancer [58,65-68]. Objective responses toadrenalectomy were reported to be as high as 55% [69]. Adre-nal ablation is generally only effective in patients who havehad previous orchiectomy [67,70], although this has been dis-puted [59]. The disadvantages of these approaches include highrates of surgical morbidity and significant medication toxicity.

2.1.3 Oestrogens and progestational agentsA mainstay of treatment of female breast cancer in the mid-20th century was therapy with oral diethylstilbestrol.Although oestrogens are known to stimulate the proliferationof breast cancer cells, in high concentrations they can some-times suppress their growth. This therapy was effective inmale breast cancer, with a response rate of ~ 38% in meta-static disease [65,71]. Apart from the typical side effects of nau-sea and venous thromboembolic disease, in the male thistreatment had the disadvantage of causing feminisation andgynecomastia. Progestins such as megestrol acetate andmedroxyprogesterone were also reported to induce tumourregression in male breast carcinoma [72,73].

2.1.4 Tamoxifen and antioestrogensWhen it became evident that the majority of male breast can-cer was ER-positive, ablative surgical procedures were quicklyreplaced by medical therapy with the antioestrogen tamoxifen(Nolvadex™, AstraZeneca) [62,74]. Tamoxifen was effective ininducing complete and partial responses in patients with met-astatic breast cancer, including in one patient with brainmetastases [75-82]. When used as adjuvant therapy in patientswith ER-positive tumours, there was a significant prolonga-

Hayes

Expert Opin. Pharmacother. (2002) 3(6) 703

tion of survival compared with historical controls [83]. This issimilar to the effect of tamoxifen in females. Tamoxifen inmen may have a higher rate of adverse effects, such asdecreased libido, hot flashes and mood alterations, than inwomen [84]. As yet, there are no published data on the use ofthe newer ER antagonists, such as fulvestrant, in the treat-ment of male breast cancer.

2.1.5 Aromatase inhibitorsRecently anastrozole, a potent and selective inhibitor of thearomatase system, has been widely used in female metastaticbreast cancer, with good results. The medical literature cur-rently details only one heavily pretreated, male breast cancerpatient in whom anastrozole was used without response [85].However, aromatase inhibitors have been shown to decreaselevels of serum oestrogens in healthy men by ~ 50% [86, 87]. Asmale breast cancer most often occurs in a setting of low circu-lating oestrogen and high levels of ERs on cancer cells, similarto the situation in postmenopausal females, a favourableresponse to anastrozole would be anticipated. Other selectivearomatase inhibitors, such as letrozole and exemestane, havenot yet been well studied in males.

2.1.6 Other endocrine therapiesGlucocorticoids have been used in the treatment of metastaticmale breast cancer with an overall response rate of ~ 43%[58,59]. However, long-term steroid use has many disadvan-tages, including the induction of adrenal suppression, oste-oporosis, Cushing’s syndrome, cataract formation and asepticnecrosis of the hip. Androgens, such as calusterone, hadresponse rates of up to 60% in small numbers of patients[59,88]. Although it seems counterintuitive that both androgensand anti-androgens would be effective in the treatment ofmale breast cancer, this is probably to be due to disruption ofto the complex and delicate balance between the various sexsteroid hormones in the human system.

2.2 ChemotherapyOwing to the high percentage of hormone positivity in malebreast cancer, chemotherapy is generally employed as a pri-mary therapy only for patients who are hormone-receptornegative or who have visceral metastases. It can be used as asecond-line therapy in patients who have failed hormonaltreatment [89].

2.2.1 Single-agent chemotherapyIn some male breast cancer patients, single-agent regimens ofchemotherapy including 5-fluorouracil (5-FU), methotrexate,thiotepa, cyclophosphamide and melphalan were reported tohave an overall response rate of 44% [90]. Recent trials withnewer agents, such as the taxanes, contain small numbers ofmale patients but the results are not stratified by gender [91,92].However, the general impression is that the response ofadvanced male breast cancer to systemic single agent chemo-therapy is similar to that for advanced female breast cancer.

2.2.2 Combination chemotherapyDue to the paucity of available patients there are no ran-domised trials evaluating combination chemotherapy in malebreast cancer. The older literature details a 35% response ratewith the Cooper regimen (cyclophosphamide–methotrexate–5-FU–vincristine–prednisone) and adriamycin-containing reg-imens [93]. Today, commonly used combination regimens formale breast cancer are similar to those used in the treatment ofbreast cancer in females, that is, doxorubicin–cyclophospha-mide; docetaxel–doxorubicin; 5-FU–cyclophosphamide–dox-orubicin; cyclophosphamide–methotrexate–5-FU; 5-FU–epirubicin–cyclophosphamide; and doxorubicin–paclitaxel [94-

98,201]. Overall, the response rate in metastatic disease is ~ 30 –40%, with higher responses in patients with less advanced dis-ease [7,56,89,90,99].

2.3 Other treatment modalitiesSince Her2/neu overexpression is detectable in many cases ofmale breast cancer [34,50-52], it would seem reasonable thatmale breast cancer might respond to treatment with Hercep-tin, a monoclonal antibody against the Her2 oncogene. Thereis a single case report in the medical literature of a male breastcancer patient responding to this therapy [100]. This is a thera-peutic option to be explored in the future.

3. Adjuvant therapy

Adjuvant therapy is given after breast cancer surgery to reducethe recurrence risk. It can consist of hormones, chemotherapyor both. There are no large randomised trials to confirm thebenefits of adjuvant therapy in male breast cancer. However,there is abundant information available about adjuvanttherapy in female breast cancer. A recent meta-analysis ofinformation on 37,000 women in 55 trials of adjuvanttamoxifen done by the Early Breast Cancer Trialists’ Collabo-rative Group showed that in women with ER-positive or ER-unknown breast tumours who took tamoxifen for 5 years,there was a 10-year reduction in recurrence and mortality of47 and 26%, respectively [101]. There are indications that adju-vant hormone therapy may be as beneficial in males withbreast cancer as it is in females. In a series of 39 patients, adju-vant tamoxifen was administered to patients with Stage II oroperable Stage III disease. The actuarial 5-year survival was61% in the treated group versus 44% in historical controls(p = 0.006) and 5-year disease-free survival was 55 versus 28%(p = 0.005) [83].

The Early Breast Cancer Trialists’ Collaborative Groupmeta-analysis also examined the benefits of adjuvant chemo-therapy in female breast cancer. Combination chemotherapyimproved survival by 35% for women < 50 years old(2p < 0.00001) and by 20% for women aged 50 – 69 years(2p < 0.00001) [101]. After standardisation for age and timesince randomisation, 10-year survival improved from 71 to78% for women < 50 years old with node-negative diseaseand from 42 to 53% for those with node-positive disease. For



women aged 50 – 69 years, combination chemotherapyimproved 10-year survival from 67 to 69% for those withwith node-negative disease and from 46 to 49% for thosewith node-positive disease [101,201].

Again, controlled studies are lacking in men but there aresuggestions that the same principles may apply. In a series fromthe National Cancer Institute, 24 male patients with Stage IIdisease were treated with cyclophosphamide–methotrexate–5-FU chemotherapy. The projected 5-year actuarial survival ratewas > 80%, a substantial improvement over historical survivalrates [102]. In a very small series of Stage II or operable Stage IIIcancers in which 10 of 11 patients were treated with adjuvant5-FU–cyclophosphamide–doxorubicin chemotherapy, the dis-ease- free survival and overall survival at 52 months were 64and 91%, respectively [103]. In another study of 50 patients, the35 men who received adjuvant postoperative therapy, includ-ing radiation, hormone therapy and chemotherapy, had amedian survival of 86 months, compared to 33 months for the15 patients receiving surgery alone (p = 0.003) [104]. A reviewof patients treated at the Royal Prince Alfred Hospital in Aus-tralia noted that the majority of patients with distant relapseswere those who had not received adjuvant therapy [105].

There is also the question of whether both chemotherapyand tamoxifen should be given as adjuvant therapy in patientswith hormone-positive tumours. The addition of chemother-apy to tamoxifen in postmenopausal women with ER-positivedisease results in a small but significant survival advantage [201].Like postmenopausal women, men have low levels of endog-enous oestrogens and predominantly hormone-positivetumours and might be expected to have a similar response.However, since men tend to have an older age at diagnosis ofbreast cancer and the risk:benefit ratio of chemotherapybecomes more unfavourable with age, some physicians feel thatthe optimal adjuvant therapy of male breast cancer should belimited to hormonal therapy. A recent study showed thatpatients with ER-positive tumours and involved axillary nodeshad improved survival when treated with various combinationsof chemotherapy and hormonal therapy [49].

In addition to medical adjuvant therapy, radiation therapyis recommended for patients at high risk for local recurrence.The risk estimate is based on the experience in female patientsand includes patients with four or more positive axillarynodes, grossly evident extracapsular nodal extension, large pri-mary tumours and very close or positive deep margins ofresection of the primary tumour [106-108].

4. General approach to treatment of metastatic disease

Because most men with carcinoma of the breast have hor-mone-positive tumours, the first-line of therapy of metastaticsoft tissue disease is generally hormonal treatment. Tamoxifenis an effective and generally well-tolerated choice. Orchiec-tomy is also a reasonable option for men who prefer not totake medications or in whom medication compliance might

be a problem. Second-line therapy in patients progressing aftertamoxifen could include androgen ablation either by LHRHanalogue or anti-androgen or orchiectomy. In women, faslo-dex and anastrozole are effective treatments after tamoxifenfailure and are moving into first-line therapy [109]. Whetherthese agents will be useful for first- or second-line treatment ofmetastatic male breast cancer remains to be determined.

Just as in female breast cancer, the recommendations fortreatment of life-threatening visceral disease include combina-tion chemotherapy regimens, such as doxorubicin–cyclophos-phamide, 5-FU–cyclophosphamide–doxorubicin, 5-FU–epirubicin–cyclophosphamide, cyclophosphamide–meth-otrexate–5-FU or a taxane-based regimen.

5. Prognosis

There has been intense debate in the medical literature aboutthe prognosis of male breast cancer compared to that offemale breast carcinoma. Many authors feel that breast cancerhas a worse prognosis in males than in females [99,110-114].Others feel that if patients are matched for prognostic factors,such as age and TNM stage, the clinical outcome is similar[89,115-125]. Moreover, a recent study indicated that males withbreast carcinoma fared better than females [126]. It is clear thatmale breast cancer is often diagnosed in later age and at amore advanced stage than in females and male patients maybe less likely to receive adjuvant therapy than females [7,49,127].As these factors are associated with poorer survival, they maymake the ultimate outcome appear to be worse [49,128]. Inaddition, mortality from comorbid disease in older men is animportant factor in their poor prognosis [49]. The question ofwhether male breast cancer prognosis is worse than in femaleswill remain unanswered until there are prospective ran-domised trials that address the issue.

6. Conclusions

Male breast cancer is an uncommon disease that has been lesswell-studied than female breast cancer because of its rarity.Most treatment decisions are based on the larger knowledgebase available for female breast cancer. Although there aresome differences in proportions of hormone receptors andcertain genetic alterations in male versus female breast cancer,most evidence would suggest that male breast cancers behavesimilarly to the breast cancers that develop in postmenopausalfemales. Thus, it is appropriate to use similar treatment prin-ciples. Future studies on some of the newer hormonal agentsused in the therapy of female breast cancer will determinetheir utility for treatment of breast cancer in the male.

Acknowledgments

This material is the result of work supported with resourcesand the use of facilities at the Houston Veterans Administra-tion Medical Center.

Hayes


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Website

201. www.cancer.gov/cancer_information/doc_pdq.aspx?version = provider&viewid = 53d97cba-89a2-45d4-b55d-b7b5ad7dc2dd.Breast Cancer (PDQ®): treatment.

AffiliationTeresa Hayes MD PhD1,2

1Acting Chief, Hematology-Oncology Section, Medical Care Line, Department of Veterans Affairs Medical Center, VA 111H, 2002 Holcombe Blvd., Houston, TX 77030, USA2Assistant Professor, Baylor College of Medicine, Houston, Texas, USATel: +1 713 794 7368; Fax: +1 713 794 7733;E-mail: [email protected]

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Pharmacotherapy for male breast cancer