Accepted Manuscript Hormone therapy for Male Breast Cancer M.H. Khan, R. Allerton, L. Pettit PII:
S1526-8209(15)00025-7
DOI:
10.1016/j.clbc.2015.01.007
Reference:
CLBC 361
To appear in:
Clinical Breast Cancer
Received Date: 18 August 2014 Revised Date:
26 January 2015
Accepted Date: 31 January 2015
Please cite this article as: Khan M, Allerton R, Pettit L, Hormone therapy for Male Breast Cancer, Clinical Breast Cancer (2015), doi: 10.1016/j.clbc.2015.01.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Hormone therapy for Male Breast Cancer.
1
RI PT
Khan MH1, Allerton R1, Pettit L1
Deanesly Centre, The Royal Wolverhampton Hospital, WV10 0QP
Author for correspondence:
AC C
EP
TE D
Dr L. Pettit email: [email protected]
M AN U
SC
.
1
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
COI: Nil
2
ACCEPTED MANUSCRIPT
Hormone therapy for Male Breast Cancer Abstract
RI PT
Male breast cancer is rare but incidence is increasing in keeping with the ageing population. The majority of male breast cancers are oestrogen receptor positive. There is a paucity of
clinical trials to inform practice and much has been extrapolated from female breast cancer. Hormone therapy represents the mainstay of adjuvant and palliative therapy but may have
SC
contra-indications or poor tolerability. This paper reviews the evidence for choice of hormone
AC C
EP
TE D
M AN U
therapy in both the adjuvant and palliative setting in male breast cancer.
3
ACCEPTED MANUSCRIPT
Introduction
Male breast cancer (MBC) is rare with a reported frequency of less than 1% in the population
RI PT
overall, but with an increase in incidence in the seventh decade of life. 1 As with all solid tumours the incidence of male breast cancer is increasing, in keeping with the ageing
population. Historically the disease often presented at a later stage than female breast cancer 2,3
However, the majority of
SC
delays in diagnosis were thought to be due to lack of awareness.
stage III and only 9% stage IV.4,5 ,6,7,8.
M AN U
male breast cancers are now stage I or II at presentation (37% and 21% respectively), 33% at
Factors associated with the development of MBC include: Genetic (BRCA29,10,11, BRCA 112, Klinefelter’s syndrome,13,14 Cowden syndrome15, p53 mutation16), lifestyle17 (obesity18, alcohol excess 19,20, , oestrogen intake or hormonal manipulations21), work22 (high ambient
TE D
temperatures, exhaust emissions23) and other diseases (pituitary adenoma24,25, testicular damage26, orchiditis, 20, 27 liver diseases causing hyperoestrogenism28, radiation exposure to the chest29). A link with gynaecomastia has also been established in the Male Breast Cancer
EP
Pooling Project; a consortium of 11 case–control and 10 cohort investigations involving 2405 case patients reported statistically significant correlation (OR = 9.78; 95% CI = 7.52 to
AC C
12.7)30. There have also been reports of MBC in patients treated with hormonal manipulation for prostate cancer21and in trans-sexual patients.19 21 See table 1 for summary.
Up to 90% of MBC are oestrogen receptor positive, hormonal therapy therefore plays a major role in both the adjuvant and palliative setting. Due to the rarity of MBC there is a paucity of clinical trials to inform practice, the main principals of management have been extrapolated from the wealth of literature available in female breast cancer. It has been reported that the
4
ACCEPTED MANUSCRIPT
female and male breast cancers are biologically similar.31 Given the increasing incidence this
AC C
EP
TE D
M AN U
SC
RI PT
paper aims to collate and review the published data on the use of hormonal therapy in MBC.
5
ACCEPTED MANUSCRIPT
Biology As the majority of MBC are oestrogen receptor positive32 hormonal therapy provides the mainstay of both adjuvant and palliative management32. Ductal carcinoma is the most
RI PT
common subtype33,34, with lobular carcinoma reported less frequently35. Less common
subtypes including inflammatory, medullary, papillary and trabecular duct have also been
SC
reported36.
Luminal A subtype has been reported to be the most common subtype in MBC (83%),
M AN U
followed by luminal B subtype (17%). Fifteen per cent of male breast cancers are HER2 positive – similar to female breast cancer (15 – 20%)37. The incidence of basal-type has not yet been reported. The cumulative risk of breast cancer in male BRCA 2carriers is estimated
Endocrine therapy
TE D
to be 6.3% (95% CI 1.4%-25.6%) by 70 years.
In a similar manner to post-menopausal women, a significant proportion of male oestrogen is
EP
generated by the conversion of circulating androgens via the aromatase enzyme. Estradiol (E2) levels are significantly higher in older males than in post-menopausal females38 and an
AC C
age-associated increase in aromatase activity is well documented in males39. Approximately 20% of circulating oestrogen in men is directly secreted by the testicles40 while the rest is from peripheral conversion, thus providing a direct source of oncogenic stimuli.
The oestrogen receptor belongs to a family of hormone-activated transcription factors that can initiate or enhance the transcription of genes containing specific hormone response elements. The oestrogen (ER) protein consists of 595 amino acids with a molecular weight of
6
ACCEPTED MANUSCRIPT
66kDa 41 chromosome 6q sub band 25.142. In late 1970’s the triphenylethylene compound, now known as tamoxifen became an established option for the treatment of all stages of breast cancer 43, 44. Tamoxifen is an anti-oestrogen in the breast but has oestrogen-like
RI PT
properties in other target tissues such as bone (and endometrium). Tamoxifen is a prodrug which is metabolized in the liver into its active metabolites - 4-hydroxytamoxifen
(afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen)45. Tamoxifen acts as a
SC
selective oestrogen receptor modulator with its active metabolite, hydroxytamoxifen which binds to oestrogen receptors competitively in tissues producing a nuclear complex that
M AN U
reduces DNA formation and inhibits oestrogen effects. It causes cells to remain in G0 and G1 phases of cell cycle. Tamoxifen has also been used in infertility46, gynacomastia, bipolar disorder47 and also has been reported to have antiangiogenic properties.48
Aromatase inhibitors (AI’s) suppress the main source of oestrogen in males by inhibiting the
TE D
aromatase enzyme; they do not affect testicular production of oestrogen. AI’s create a feedback loop with significant decrease in Estradiol (E2) levels, coupled with increasing levels of follicle-stimulating hormone (FSH), luteinising hormone, and testosterone which
EP
provide increased substrate for aromatization. Gonadotrophin-releasing hormone analogues (GNRH) are thought to be able to overcome the increase in substrate issue and therefore
AC C
increase the biological efficacy of AI’s.
7
ACCEPTED MANUSCRIPT
Methods A literature search of pub med, Embase, Cochrane, Library, Web of Science and Google
RI PT
scholar was performed using the terms ‘male’ and ‘breast cancer’. Trials or case reports were included if they were published in English and included details of hormone therapy
administered to male patients diagnosed with breast cancer in either the adjuvant or palliative
AC C
EP
TE D
M AN U
SC
setting.
8
ACCEPTED MANUSCRIPT
Adjuvant Hormonal treatment
Surgical hormonal ablative techniques
RI PT
The first reported hormone manipulation in MBC was orchidectomy in 194249. Adrenalectomy and pituitary surgery have been quoted to provide response rates of 45% but these invasive techniques are seldom used compared to medical options. The adrenal gland
SC
secretes less than 1% of circulating sex steroids and these precursors undergo peripheral conversion which results in
S1526-8209(15)00025-7
DOI:
10.1016/j.clbc.2015.01.007
Reference:
CLBC 361
To appear in:
Clinical Breast Cancer
Received Date: 18 August 2014 Revised Date:
26 January 2015
Accepted Date: 31 January 2015
Please cite this article as: Khan M, Allerton R, Pettit L, Hormone therapy for Male Breast Cancer, Clinical Breast Cancer (2015), doi: 10.1016/j.clbc.2015.01.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Hormone therapy for Male Breast Cancer.
1
RI PT
Khan MH1, Allerton R1, Pettit L1
Deanesly Centre, The Royal Wolverhampton Hospital, WV10 0QP
Author for correspondence:
AC C
EP
TE D
Dr L. Pettit email: [email protected]
M AN U
SC
.
1
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
COI: Nil
2
ACCEPTED MANUSCRIPT
Hormone therapy for Male Breast Cancer Abstract
RI PT
Male breast cancer is rare but incidence is increasing in keeping with the ageing population. The majority of male breast cancers are oestrogen receptor positive. There is a paucity of
clinical trials to inform practice and much has been extrapolated from female breast cancer. Hormone therapy represents the mainstay of adjuvant and palliative therapy but may have
SC
contra-indications or poor tolerability. This paper reviews the evidence for choice of hormone
AC C
EP
TE D
M AN U
therapy in both the adjuvant and palliative setting in male breast cancer.
3
ACCEPTED MANUSCRIPT
Introduction
Male breast cancer (MBC) is rare with a reported frequency of less than 1% in the population
RI PT
overall, but with an increase in incidence in the seventh decade of life. 1 As with all solid tumours the incidence of male breast cancer is increasing, in keeping with the ageing
population. Historically the disease often presented at a later stage than female breast cancer 2,3
However, the majority of
SC
delays in diagnosis were thought to be due to lack of awareness.
stage III and only 9% stage IV.4,5 ,6,7,8.
M AN U
male breast cancers are now stage I or II at presentation (37% and 21% respectively), 33% at
Factors associated with the development of MBC include: Genetic (BRCA29,10,11, BRCA 112, Klinefelter’s syndrome,13,14 Cowden syndrome15, p53 mutation16), lifestyle17 (obesity18, alcohol excess 19,20, , oestrogen intake or hormonal manipulations21), work22 (high ambient
TE D
temperatures, exhaust emissions23) and other diseases (pituitary adenoma24,25, testicular damage26, orchiditis, 20, 27 liver diseases causing hyperoestrogenism28, radiation exposure to the chest29). A link with gynaecomastia has also been established in the Male Breast Cancer
EP
Pooling Project; a consortium of 11 case–control and 10 cohort investigations involving 2405 case patients reported statistically significant correlation (OR = 9.78; 95% CI = 7.52 to
AC C
12.7)30. There have also been reports of MBC in patients treated with hormonal manipulation for prostate cancer21and in trans-sexual patients.19 21 See table 1 for summary.
Up to 90% of MBC are oestrogen receptor positive, hormonal therapy therefore plays a major role in both the adjuvant and palliative setting. Due to the rarity of MBC there is a paucity of clinical trials to inform practice, the main principals of management have been extrapolated from the wealth of literature available in female breast cancer. It has been reported that the
4
ACCEPTED MANUSCRIPT
female and male breast cancers are biologically similar.31 Given the increasing incidence this
AC C
EP
TE D
M AN U
SC
RI PT
paper aims to collate and review the published data on the use of hormonal therapy in MBC.
5
ACCEPTED MANUSCRIPT
Biology As the majority of MBC are oestrogen receptor positive32 hormonal therapy provides the mainstay of both adjuvant and palliative management32. Ductal carcinoma is the most
RI PT
common subtype33,34, with lobular carcinoma reported less frequently35. Less common
subtypes including inflammatory, medullary, papillary and trabecular duct have also been
SC
reported36.
Luminal A subtype has been reported to be the most common subtype in MBC (83%),
M AN U
followed by luminal B subtype (17%). Fifteen per cent of male breast cancers are HER2 positive – similar to female breast cancer (15 – 20%)37. The incidence of basal-type has not yet been reported. The cumulative risk of breast cancer in male BRCA 2carriers is estimated
Endocrine therapy
TE D
to be 6.3% (95% CI 1.4%-25.6%) by 70 years.
In a similar manner to post-menopausal women, a significant proportion of male oestrogen is
EP
generated by the conversion of circulating androgens via the aromatase enzyme. Estradiol (E2) levels are significantly higher in older males than in post-menopausal females38 and an
AC C
age-associated increase in aromatase activity is well documented in males39. Approximately 20% of circulating oestrogen in men is directly secreted by the testicles40 while the rest is from peripheral conversion, thus providing a direct source of oncogenic stimuli.
The oestrogen receptor belongs to a family of hormone-activated transcription factors that can initiate or enhance the transcription of genes containing specific hormone response elements. The oestrogen (ER) protein consists of 595 amino acids with a molecular weight of
6
ACCEPTED MANUSCRIPT
66kDa 41 chromosome 6q sub band 25.142. In late 1970’s the triphenylethylene compound, now known as tamoxifen became an established option for the treatment of all stages of breast cancer 43, 44. Tamoxifen is an anti-oestrogen in the breast but has oestrogen-like
RI PT
properties in other target tissues such as bone (and endometrium). Tamoxifen is a prodrug which is metabolized in the liver into its active metabolites - 4-hydroxytamoxifen
(afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen)45. Tamoxifen acts as a
SC
selective oestrogen receptor modulator with its active metabolite, hydroxytamoxifen which binds to oestrogen receptors competitively in tissues producing a nuclear complex that
M AN U
reduces DNA formation and inhibits oestrogen effects. It causes cells to remain in G0 and G1 phases of cell cycle. Tamoxifen has also been used in infertility46, gynacomastia, bipolar disorder47 and also has been reported to have antiangiogenic properties.48
Aromatase inhibitors (AI’s) suppress the main source of oestrogen in males by inhibiting the
TE D
aromatase enzyme; they do not affect testicular production of oestrogen. AI’s create a feedback loop with significant decrease in Estradiol (E2) levels, coupled with increasing levels of follicle-stimulating hormone (FSH), luteinising hormone, and testosterone which
EP
provide increased substrate for aromatization. Gonadotrophin-releasing hormone analogues (GNRH) are thought to be able to overcome the increase in substrate issue and therefore
AC C
increase the biological efficacy of AI’s.
7
ACCEPTED MANUSCRIPT
Methods A literature search of pub med, Embase, Cochrane, Library, Web of Science and Google
RI PT
scholar was performed using the terms ‘male’ and ‘breast cancer’. Trials or case reports were included if they were published in English and included details of hormone therapy
administered to male patients diagnosed with breast cancer in either the adjuvant or palliative
AC C
EP
TE D
M AN U
SC
setting.
8
ACCEPTED MANUSCRIPT
Adjuvant Hormonal treatment
Surgical hormonal ablative techniques
RI PT
The first reported hormone manipulation in MBC was orchidectomy in 194249. Adrenalectomy and pituitary surgery have been quoted to provide response rates of 45% but these invasive techniques are seldom used compared to medical options. The adrenal gland
SC
secretes less than 1% of circulating sex steroids and these precursors undergo peripheral conversion which results in
![[Hormone therapy of breast carcinoma in men].](/assets/img/hold.png)
