Male breast cancer: pink ribbon blues

Male breast cancer: pink ribbon blues The pink ribbon is an internationally recognized symbol of breast cancer awareness. However, it has been argued that the colour pink may reinforce the misconception that breast cancer only affects women, potentially leading to delays in the diagnosis of male breast cancer, due to ignorance regarding the significance of male breast cancer signs and symptoms. The lifetime risk of developing breast cancer for men in the general population is 0.1%, and <1% of all breast cancer diagnoses occur in men [1]. Including a blue spot or a blue section in the pink ribbon has been advocated, to signify and acknowledge breast cancer also occurs in men. Cardoso et al. are to be congratulated on initiating academic research dedicated to male breast cancer, the ‘poor relation’ of predominant female breast cancer [2]. This report has arisen from part I of the International Male Breast Cancer Program, a research collaboration conducted by groups from Europe and North America. It details the analysis of a large retrospective cohort of 1483 men diagnosed with breast cancer, with tumour available for central pathology assessment. The median age at diagnosis of 68 years is 7–10 years older than for female breast cancer. The study confirms that male breast cancers are predominantly ductal luminal HER2-negative grade 2 tumours that are androgen receptor positive. A smaller proportion of HER2-positive (8.7%) and triple negative (0.3%) male breast cancers were found, than observed in female breast cancer. Lobular carcinomas were also much less frequent in these male tumours. In this cohort, for men diagnosed with non-metastatic disease, only 77% received adjuvant endocrine therapy, despite >95% having ER-positive tumours. Moreover, some men received adjuvant aromatase inhibitors, which might not be effective in the absence of concurrent gonadotropin-releasing hormone agonist (GnRHa). With a median follow-up of 7.1 years for overall survival, centrally assessed histologic grade was not significantly correlated with overall survival [3]. This program also recently reported that DCIS was the most commonly observed precursor lesions observed in male breast cancers, with very low rates of LCIS found [4]. Utilizing immunohistochemical (IHC) surrogates and study definitions of Ki67 ≥ 20% and/or Progesterone Receptor (PR) Allred score of <5 to distinguish luminal B-like from luminal A-like tumours, this cohort analysis classified 48.6% of the male breast tumours as luminal B-like/HER2-negative [2]. Given that high Ki67 ≥20% was reported in only one in four cases, it seems surprising that such a high proportion of cases were ‘classified’ as luminal B-like. Perhaps the use of the Allred score of <5 for PR, increased the proportion of tumours classified as luminal B-like, as compared with PR ≤20% cells positive which has been described as having utility [5]. Planned studies using RNA sequencing and the Nanostring platform may help to clarify the relative proportion of luminal B tumours in male breast cancer more accurately. A recent publication on the genomic landscape of 59 male breast cancers has noted less frequent PIK3CA mutations and TP53 mutations than are seen in ER-positive HER2-negative female breast cancers, but more frequent somatic mutations in genes associated with DNA repair pathways [6]. Systemic treatment strategies for male breast cancer have mostly been determined by extrapolation from results of clinical trials conducted in women. Given the differences in the hormonal milieu and the importance of endocrine therapy in the management of luminal breast cancer, this is of concern. Published results in men treated for breast cancer are more limited; pooled analyses of men treated with hormonal therapies fulvestrant and aromatase inhibitors have been reported [7, 8]. Males are often excluded from pivotal phase III breast cancer clinical trials, perhaps without a valid scientific rationale. ASCO has recently introduced an initiative to broaden eligibility criteria to make clinical trials more representative, although male breast cancer is not a focus of their recent statement [9]. The randomized trials testing the addition of oral CDK4/6 inhibitors to endocrine therapy in hormone receptor-positive metastatic breast cancer have collectively enrolled a few thousand women. Some included premenopausal women receiving GnRHa therapy [10], but the trials did not allow men receiving concurrent GnRHa therapy to participate. In contrast numerically, a first case of male breast cancer responding to combined aromatase inhibitor plus palbociclib therapy was reported in 2016 [11]. There have been some opportunities for men with early breast cancer to participate in phase III adjuvant therapy trials in recent years. The APHINITY trial testing adjuvant pertuzumab with trastuzumab in HER2-positive breast cancer allowed men to participate. In total, 11 men were randomized (0.2% of trial population) [12]. The currently enrolling PALLAS trial testing the addition of a CDK4/6 inhibitor palbociclib to adjuvant endocrine therapy in hormone receptor-positive, HER2-negative breast cancer allows men to participate. Of relevance to men with breast cancer, the adjuvant OLYMPIA trial testing the adjuvant PARP inhibitor olaparib in patients with a germline BRCA mutation, allows men to participate. It is estimated that men with a germline BRCA2 mutation have a life-time risk of 7% of developing breast cancer, while those with a BRCA1 mutation have a risk of 1% [13]. While the majority of male breast cancer is sporadic, a significant minority of men with breast cancer will have a BRCA mutation, underscoring the importance of considering genetic counselling and testing in this population. BRCA2 mutations are the most common germline mutation detected in men with breast cancer and this mutation also confers increased risks for prostate cancer. The International Male Breast Cancer Program also includes a prospective study of new male breast cancer diagnoses with tumour collection, as well as prospective clinical studies testing the efficacy of breast cancer treatments in men. In the future such research will hopefully provide greater insights into the pathobiology and prognosis of male breast cancer, and enable evidence-based optimal management. Funding None declared. Disclosure The author received honoraria from AstraZeneca and gave an overseas lecture for Pfizer. References 1 Giordano S, Cohen D, Buzdar A et al.   Breast carcinoma in men: a population-based study. Cancer  2004; 101( 1): 51– 57. Google Scholar CrossRef Search ADS PubMed  2 Cardoso F, Bartlett JMS, Slaets L et al.   Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. Ann Oncol  2018; 29( 2): 405– 417. 3 Vermeulen MA, Slaets L, Cardoso F et al.   Pathological characterisation of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NNABCG International Male Breast Cancer Program. Eur J Cancer  2017; 82: 219– 227. Google Scholar CrossRef Search ADS PubMed  4 Doebar SC, Slaets L, Cardoso F et al.   Male breast cancer precursor lesions: analysis of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. Mod Pathol  2017; 30( 4): 509– 518. Google Scholar CrossRef Search ADS PubMed  5 Prat A, Cheang MC, Martin M et al.   Prognostic significance of progesterone receptor-positive tumour cells within IHC defined luminal A breast cancer. J Clin Oncol  2013; 31: 203– 209. Google Scholar CrossRef Search ADS PubMed  6 Piscuoglio S, Ng CKY, Murray MP et al.   The genomic landscape of male breast cancers. Clin Cancer Res  2016; 22( 16): 15. Google Scholar CrossRef Search ADS   7 Zagouri F, Sergentanis TN, Chrysikos D et al.   Fulvestrant and male breast cancer: a pooled analysis. Breast Cancer Res Treat  2015; 149( 1): 269– 275. Google Scholar CrossRef Search ADS PubMed  8 Zagouri F, Sergentanis TN, Azim HA et al.   Aromatase inhibitors in male breast cancer: a pooled analysis. Breast Cancer Res Treat  2015; 151( 1): 141– 147. Google Scholar CrossRef Search ADS PubMed  9 Kim ES, Bruinooge SS, Roberts S, et al.   Broadening eligibility criteria to make clinical trials more representative: American Society of Clinical Oncology and Friends of Cancer Research joint research statement. J Clin Oncol  2017; 35: 3737– 3744. Google Scholar CrossRef Search ADS PubMed  10 Turner C, Ro J, Andre F et al.   Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med  2015; 373( 3): 209– 219. Google Scholar CrossRef Search ADS PubMed  11 Sorscher S. A first case of male breast cancer responding to combined aromatase inhibitor/palbociclib therapy. Int J Cancer Clin Res  2016; 3( 5): 069. Google Scholar CrossRef Search ADS   12 Von Minckwitz G, Procter M, de Azambuja E et al.   Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med  2017; 377( 2): 122– 131. Google Scholar CrossRef Search ADS PubMed  13 Tai Y, Domchek S, Parmigiani G et al.   Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst  2007; 99: 1811– 1814. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

Male breast cancer: pink ribbon blues

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0923-7534
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1569-8041
D.O.I.
10.1093/annonc/mdx752
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Abstract

The pink ribbon is an internationally recognized symbol of breast cancer awareness. However, it has been argued that the colour pink may reinforce the misconception that breast cancer only affects women, potentially leading to delays in the diagnosis of male breast cancer, due to ignorance regarding the significance of male breast cancer signs and symptoms. The lifetime risk of developing breast cancer for men in the general population is 0.1%, and <1% of all breast cancer diagnoses occur in men [1]. Including a blue spot or a blue section in the pink ribbon has been advocated, to signify and acknowledge breast cancer also occurs in men. Cardoso et al. are to be congratulated on initiating academic research dedicated to male breast cancer, the ‘poor relation’ of predominant female breast cancer [2]. This report has arisen from part I of the International Male Breast Cancer Program, a research collaboration conducted by groups from Europe and North America. It details the analysis of a large retrospective cohort of 1483 men diagnosed with breast cancer, with tumour available for central pathology assessment. The median age at diagnosis of 68 years is 7–10 years older than for female breast cancer. The study confirms that male breast cancers are predominantly ductal luminal HER2-negative grade 2 tumours that are androgen receptor positive. A smaller proportion of HER2-positive (8.7%) and triple negative (0.3%) male breast cancers were found, than observed in female breast cancer. Lobular carcinomas were also much less frequent in these male tumours. In this cohort, for men diagnosed with non-metastatic disease, only 77% received adjuvant endocrine therapy, despite >95% having ER-positive tumours. Moreover, some men received adjuvant aromatase inhibitors, which might not be effective in the absence of concurrent gonadotropin-releasing hormone agonist (GnRHa). With a median follow-up of 7.1 years for overall survival, centrally assessed histologic grade was not significantly correlated with overall survival [3]. This program also recently reported that DCIS was the most commonly observed precursor lesions observed in male breast cancers, with very low rates of LCIS found [4]. Utilizing immunohistochemical (IHC) surrogates and study definitions of Ki67 ≥ 20% and/or Progesterone Receptor (PR) Allred score of <5 to distinguish luminal B-like from luminal A-like tumours, this cohort analysis classified 48.6% of the male breast tumours as luminal B-like/HER2-negative [2]. Given that high Ki67 ≥20% was reported in only one in four cases, it seems surprising that such a high proportion of cases were ‘classified’ as luminal B-like. Perhaps the use of the Allred score of <5 for PR, increased the proportion of tumours classified as luminal B-like, as compared with PR ≤20% cells positive which has been described as having utility [5]. Planned studies using RNA sequencing and the Nanostring platform may help to clarify the relative proportion of luminal B tumours in male breast cancer more accurately. A recent publication on the genomic landscape of 59 male breast cancers has noted less frequent PIK3CA mutations and TP53 mutations than are seen in ER-positive HER2-negative female breast cancers, but more frequent somatic mutations in genes associated with DNA repair pathways [6]. Systemic treatment strategies for male breast cancer have mostly been determined by extrapolation from results of clinical trials conducted in women. Given the differences in the hormonal milieu and the importance of endocrine therapy in the management of luminal breast cancer, this is of concern. Published results in men treated for breast cancer are more limited; pooled analyses of men treated with hormonal therapies fulvestrant and aromatase inhibitors have been reported [7, 8]. Males are often excluded from pivotal phase III breast cancer clinical trials, perhaps without a valid scientific rationale. ASCO has recently introduced an initiative to broaden eligibility criteria to make clinical trials more representative, although male breast cancer is not a focus of their recent statement [9]. The randomized trials testing the addition of oral CDK4/6 inhibitors to endocrine therapy in hormone receptor-positive metastatic breast cancer have collectively enrolled a few thousand women. Some included premenopausal women receiving GnRHa therapy [10], but the trials did not allow men receiving concurrent GnRHa therapy to participate. In contrast numerically, a first case of male breast cancer responding to combined aromatase inhibitor plus palbociclib therapy was reported in 2016 [11]. There have been some opportunities for men with early breast cancer to participate in phase III adjuvant therapy trials in recent years. The APHINITY trial testing adjuvant pertuzumab with trastuzumab in HER2-positive breast cancer allowed men to participate. In total, 11 men were randomized (0.2% of trial population) [12]. The currently enrolling PALLAS trial testing the addition of a CDK4/6 inhibitor palbociclib to adjuvant endocrine therapy in hormone receptor-positive, HER2-negative breast cancer allows men to participate. Of relevance to men with breast cancer, the adjuvant OLYMPIA trial testing the adjuvant PARP inhibitor olaparib in patients with a germline BRCA mutation, allows men to participate. It is estimated that men with a germline BRCA2 mutation have a life-time risk of 7% of developing breast cancer, while those with a BRCA1 mutation have a risk of 1% [13]. While the majority of male breast cancer is sporadic, a significant minority of men with breast cancer will have a BRCA mutation, underscoring the importance of considering genetic counselling and testing in this population. BRCA2 mutations are the most common germline mutation detected in men with breast cancer and this mutation also confers increased risks for prostate cancer. The International Male Breast Cancer Program also includes a prospective study of new male breast cancer diagnoses with tumour collection, as well as prospective clinical studies testing the efficacy of breast cancer treatments in men. In the future such research will hopefully provide greater insights into the pathobiology and prognosis of male breast cancer, and enable evidence-based optimal management. Funding None declared. Disclosure The author received honoraria from AstraZeneca and gave an overseas lecture for Pfizer. References 1 Giordano S, Cohen D, Buzdar A et al.   Breast carcinoma in men: a population-based study. Cancer  2004; 101( 1): 51– 57. Google Scholar CrossRef Search ADS PubMed  2 Cardoso F, Bartlett JMS, Slaets L et al.   Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. Ann Oncol  2018; 29( 2): 405– 417. 3 Vermeulen MA, Slaets L, Cardoso F et al.   Pathological characterisation of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NNABCG International Male Breast Cancer Program. Eur J Cancer  2017; 82: 219– 227. Google Scholar CrossRef Search ADS PubMed  4 Doebar SC, Slaets L, Cardoso F et al.   Male breast cancer precursor lesions: analysis of the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program. Mod Pathol  2017; 30( 4): 509– 518. Google Scholar CrossRef Search ADS PubMed  5 Prat A, Cheang MC, Martin M et al.   Prognostic significance of progesterone receptor-positive tumour cells within IHC defined luminal A breast cancer. J Clin Oncol  2013; 31: 203– 209. Google Scholar CrossRef Search ADS PubMed  6 Piscuoglio S, Ng CKY, Murray MP et al.   The genomic landscape of male breast cancers. Clin Cancer Res  2016; 22( 16): 15. Google Scholar CrossRef Search ADS   7 Zagouri F, Sergentanis TN, Chrysikos D et al.   Fulvestrant and male breast cancer: a pooled analysis. Breast Cancer Res Treat  2015; 149( 1): 269– 275. Google Scholar CrossRef Search ADS PubMed  8 Zagouri F, Sergentanis TN, Azim HA et al.   Aromatase inhibitors in male breast cancer: a pooled analysis. Breast Cancer Res Treat  2015; 151( 1): 141– 147. Google Scholar CrossRef Search ADS PubMed  9 Kim ES, Bruinooge SS, Roberts S, et al.   Broadening eligibility criteria to make clinical trials more representative: American Society of Clinical Oncology and Friends of Cancer Research joint research statement. J Clin Oncol  2017; 35: 3737– 3744. Google Scholar CrossRef Search ADS PubMed  10 Turner C, Ro J, Andre F et al.   Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med  2015; 373( 3): 209– 219. Google Scholar CrossRef Search ADS PubMed  11 Sorscher S. A first case of male breast cancer responding to combined aromatase inhibitor/palbociclib therapy. Int J Cancer Clin Res  2016; 3( 5): 069. Google Scholar CrossRef Search ADS   12 Von Minckwitz G, Procter M, de Azambuja E et al.   Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med  2017; 377( 2): 122– 131. Google Scholar CrossRef Search ADS PubMed  13 Tai Y, Domchek S, Parmigiani G et al.   Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst  2007; 99: 1811– 1814. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Feb 1, 2018

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