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Male Breast Cancer

Male breast cancer is uncommon, men account for approximately 1% of all breast cancer cases. Incidence in Western populations is under 1 case per 100,000 men, though rates reported in some African countries are much higher. The majority of male breast cancers are of the infiltrating ductal type, this is where the cancer has spread beyond the cells lining ducts in the breast. In many respects male breast cancer is similar to that found in women, though in general men tend to be older than women at diagnosis. Treatment tends to be the same as that for women with breast cancer of the same type and stage.

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  • PubMed search for publications about Male Breast Cancer - Limit search to: [Reviews]

    PubMed Central search for free-access publications about Male Breast Cancer
    MeSH term: Breast Neoplasms, Male
    International US National Library of Medicine
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Humphries MP, Jordan VC, Speirs V
Obesity and male breast cancer: provocative parallels?
BMC Med. 2015; 13:134 [PubMed] Free Access to Full Article Related Publications
While rare compared to female breast cancer the incidence of male breast cancer (MBC) has increased in the last few decades. Without comprehensive epidemiological studies, the explanation for the increased incidence of MBC can only be speculated. Nevertheless, one of the most worrying global public health issues is the exponential rise in the number of overweight and obese people, especially in the developed world. Although obesity is not considered an established risk factor for MBC, studies have shown increased incidence among obese individuals. With this observation in mind, this article highlights the correlation between the increased incidence of MBC and the current trends in obesity as a growing problem in the 21(st) century, including how this may impact treatment. With MBC becoming more prominent we put forward the notion that, not only is obesity a risk factor for MBC, but that increasing obesity trends are a contributing factor to its increased incidence.

Niemiec J, Sas-Korczynska B, Harazin-Lechowska A, et al.
Lymphatic and blood vessels in male breast cancer.
Anticancer Res. 2015; 35(2):1041-8 [PubMed] Related Publications
BACKGROUND: It is assumed that lymphatic vessels are responsible for breast cancer dissemination.
PATIENTS AND METHODS: In 32 male breast carcinomas we evaluated the correlation between: (i) lymphatic vessel density (LVD), distribution of podoplanin-immunostained vessels (DPV), blood vessel density (BVD), infiltration of immune cells and (ii) known clinicopathological parameters.
RESULTS: Lymphatic and blood vessels were found in 77.8% and 100% of breast carcinomas, respectively. Double-negative estrogen and progesterone receptor tumors (ER-/PR-) presented significantly higher LVD than ER/PR positive cases, while high-grade tumors exhibited significantly higher DPV than low-grade carcinomas. We detected significantly higher frequency of vascular invasion in high-grade and double-negative carcinomas than in low-grade and ER/PR-positive ones, respectively.
CONCLUSION: The relationship between high number of lymphatic vessels and high tumor grade or steroid receptor negativity might confirm the hypothesis regarding the influence of lymphangiogenesis on the formation of a more aggressive phenotype in male breast cancer.

Jiang H, Wang T, Jiang Z
Goserelin plus endocrine treatments maintained long-term clinical benefit in a male patient with advanced breast cancer.
World J Surg Oncol. 2014; 12:393 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Goserelin plus aromatase inhibitors (AI) have already been used in male advanced breast cancer, but the cases that fulvestrantin male breast cancer are rare.
CASE PRESENTATION: Here we report a case of long-term (3 years) response to Goserelin plus continuing endocrine treatments given for a male advanced breast cancer. The patient prolongs his life with high life quality, and has more time with his family.
CONCLUSION: Goserelin plus endocrine treatments may benefit male breast cancer.

Deb S, Wong SQ, Li J, et al.
Mutational profiling of familial male breast cancers reveals similarities with luminal A female breast cancer with rare TP53 mutations.
Br J Cancer. 2014; 111(12):2351-60 [PubMed] Article available free on PMC after 09/12/2015 Related Publications
BACKGROUND: Male breast cancer (MBC) is still poorly understood with a large proportion arising in families with a history of breast cancer. Genomic studies have focused on germline determinants of MBC risk, with minimal knowledge of somatic changes in these cancers.
METHODS: Using a TruSeq amplicon cancer panel, this study evaluated 48 familial MBCs (3 BRCA1 germline mutant, 17 BRCA2 germline mutant and 28 BRCAX) for hotspot somatic mutations and copy number changes in 48 common cancer genes.
RESULTS: Twelve missense mutations included nine PIK3CA mutations (seven in BRCAX patients), two TP53 mutations (both in BRCA2 patients) and one PTEN mutation. Common gains were seen in GNAS (34.1%) and losses were seen in GNAQ (36.4%), ABL1 (47.7%) and ATM (34.1%). Gains of HRAS (37.5% vs 3%, P=0.006), STK11 (25.0% vs 0%, P=0.01) and SMARCB1 (18.8% vs 0%, P=0.04) and the loss of RB1 (43.8% vs 13%, P=0.03) were specific to BRCA2 tumours.
CONCLUSIONS: This study is the first to perform high-throughput somatic sequencing on familial MBCs. Overall, PIK3CA mutations are most commonly seen, with fewer TP53 and PTEN mutations, similar to the profile seen in luminal A female breast cancers. Differences in mutation profiles and patterns of gene gains/losses are seen between BRCA2 (associated with TP53/PTEN mutations, loss of RB1 and gain of HRAS, STK11 and SMARCB1) and BRCAX (associated with PIK3CA mutations) tumours, suggesting that BRCA2 and BRCAX MBCs may be distinct and arise from different tumour pathways. This has implications on potential therapies, depending on the BRCA status of MBC patients.

Bezić J, Šamija Projić I, Projić P, et al.
Flow cytometric DNA hypertetraploidy tends to be more frequent in male than in female breast cancers.
Virchows Arch. 2015; 466(2):185-9 [PubMed] Related Publications
The aim of the study was to explore possible differences in DNA flow cytometric characteristics, particularly differences in distribution of DNA indices of aneuploid clones, between male and female breast cancers. We retrospectively analyzed 31 male breast cancers. Clinicopathological and DNA flow cytometric characteristics of male breast cancers (patient age, tumor size, histological type, histological grade, axillary lymph node status, hormone receptor expression, ploidy, and S-phase fraction) were compared with that of the control group of matched female breast cancers. Hormone receptors and HER-2/neu were investigated immunohistochemically with additional chromogenic in situ hybridization (CISH) analysis of HER-2/neu 2+ cases. Ploidy and S-phase fraction were determined by DNA flow cytometry. Comparison with clinicopathological features was made using χ (2) and t test. Aneuploidy was found in 78% of the cases, with the predomination of hypotetraploid clones (39%), followed by tetraploid (23%) and hypertetraploid clones (16%). We found higher frequency of hypertetraploidy in male breast cancers (16 and 6%, respectively) than in the control group of matched female breast cancers. Clinicopathological features of hypertetraploid male breast cancers did not differ from that of non-hypertetraploid cancers. Higher frequency of hypertetraploidy among male breast cancers might indicate different cytogenetical evolutionary pathway between male and female breast cancer.

Bonneau C, Bendifallah S, Reyal F, et al.
Association of the number of sentinel lymph nodes harvested with survival in breast cancer.
Eur J Surg Oncol. 2015; 41(1):52-8 [PubMed] Related Publications
AIMS: In patients with breast cancer, the association between the number of sentinel lymph node (SLN) removed and survival is poorly known. Our objective was to evaluate this association on disease-specific survival (DSS).
METHODS: Data of 144 517 patients with invasive T1-3M0 breast carcinoma and initial treatment with SLN biopsy were extracted from the SEER database. Univariate and multivariate analyses were performed.
RESULTS: The number of SLNs harvested and the completion of axillary lymph node dissection (ALND) were not associated with DSS improvement for patients without metastatic nodes. After adjustment, patients with three SLNs had a better DSS than did other groups (HR of 0.73 CI 95% [0.60-0.88], p = 0.001). This result was mainly driven by the group of patients with one metastatic LN. When patients had two or more metastatic LNs, there was no difference in DSS according to the number of SLNs or to completion of ALND.
CONCLUSIONS: The number of SLN harvested was associated with DSS. According to DSS, the optimal number of SLNs harvested was three in this large series, thereby calling into question the understaging or undertreatment of SLN biopsy in which only one or two SLNs are harvested but also the therapeutic effect of completion ALND.

Karagöz Özen DS, Ozturk MA, Aydin Ö, et al.
Receptor expression discrepancy between primary and metastatic breast cancer lesions.
Oncol Res Treat. 2014; 37(11):622-6 [PubMed] Related Publications
BACKGROUND: Recent studies have shown that the expression status of hormone receptors and human epidermal growth factor receptor 2 (HER2) in breast cancer may change during disease progression. The aim of this study was to determine and compare the estrogen receptor (ER), progesterone receptor (PR), and HER2 expression status in primary breast cancer and metastatic lesions.
METHODS: 58 patients with registered biopsy reports or available samples of the primary tumor and distant metastases were included in the final analysis. Biopsy samples were re-stained using immunohistochemical methods to determine receptor status (if not already recorded in previous reports) and re-examined by 2 independent pathologists.
RESULTS: Discordance rates for receptor expression status of the primary tumor and distant metastases for ER, PR, and HER2 were 17.4, 45.4, and 13.3%, respectively. No statistically significant difference in overall survival due to receptor expression discordance between the primary tumor and metastatic sites (p>0.05) was found, although a tendency toward worse survival time was observed in patients with HER2 expression discrepancies.
CONCLUSION: This study showed receptor discordance rates between primary and metastatic breast cancer sites for ER, PR, and HER2 of 17.8, 45.4, and 13.3%, respectively. Re-biopsy and IHC evaluation of metastatic sites for receptor status may change treatment decisions in patients with relapsed/progressed BC.

Budd GT, Barlow WE, Moore HC, et al.
SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer.
J Clin Oncol. 2015; 33(1):58-64 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
PURPOSE: To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer.
PATIENTS AND METHODS: A 2 × 2 factorial design was used to test two hypotheses: (1) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome.
RESULTS: Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor-negative/human epidermal growth factor receptor 2 (HER2) -negative tumors (P = .067), with no differences seen with hormone receptor-positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40).
CONCLUSION: Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor-negative/HER2-negative tumors.

Danza K, De Summa S, Pilato B, et al.
Combined microRNA and ER expression: a new classifier for familial and sporadic breast cancer patients.
J Transl Med. 2014; 12:319 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BACKGROUND: The role of miRNAs in familial breast cancer (fBC) is poorly investigated as also in the BRCA-like tumors. To identify a specific miRNA expression pattern which could allow a better fBC classification not only based on clinico-pathological and immunophenotypical parameters we analyzed miRNA profile in familial and sporadic samples. Moreover since BRCA1 tumors and sporadic triple negative (TN) breast tumors share similarities regarding clinical outcomes and some histological characteristics, we focused on TN and not TN cases.
METHODS: The sample set included fresh frozen tissue samples, including 39 female fBCs (19 BRCA-related and 20 BRCAX) and 12 male fBC (BRCAX). Moreover, we considered TN and non TN (NTN), 21 BRCA-related and 27 sporadic BCs. MiRNA profiling was performed through GeneChip miRNA v.1.0 Array (Affymetrix). ANOVA, hierarchical and consensus clustering analyses allowed identification of pattern of expression of miRNAs and pathway enrichment analysis, considering validated target genes, was carried out to achieve a deeper biological understanding.
RESULTS: ANOVA test led to the identification of 53 deregulated miRNAs; hierarchical and consensus clustering of female fBCs (fFBCs) and male fBCs (fMBCs) highlighted the presence of 3 sample clusters named FBC1, FBC2 and FBC3. We found a correlation between ER-status and the three sample clusters. The three clusters are distinct by a different expression of two clusters of miRNAs (CLU1 and CLU2), which resulted to be different in targeted pathways. In particular, CLU1 targets cellular pathways and CLU2 is involved in epigenetic activities. Considering TN and NTN BRCA-related and sporadic tumors, a hierarchical clustering identified two clusters of miRNAs, which were not so different from CLU1 and CLU2, both in miRNA content and targeted pathways.
CONCLUSIONS: Our results highlighted the importance of miRNA regulation to better clarify similarities and differences between familial and sporadic BC groups.

Zhou R, Yu L, Zhou S, et al.
Male breast carcinoma: a clinicopathological and immunohistochemical characterization study.
Int J Clin Exp Pathol. 2014; 7(10):6852-61 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Male breast carcinoma is a relatively rare disease. This study retrospectively investigated the clinicopathological features of 73 cases of male breast carcinoma in Chinese population, and classified the molecular subtype based on surrogate immunohistochemical definitions. The expression of GCDFP15, MGB, AR and FOXP1 were evaluated. Invasive carcinoma of no special type was the most common histological type in the study group (71.2%, 52/73). The luminal A and B subtypes were the major types of male breast carcinoma (60.9%, 34.8% respectively). AR and FOXP1 are expressed in 84.2% (48/57) and 71.9% (41/57) of the studied cases. Carcinoma of the luminal A subtype expressed GCDFP15 (73.5%, 25/34) and MGB (58.8%, 20/34) more frequently than cases of the luminal B subtypes (34.8%, 8/23 and 43.5%, 10/23, respectively; P = 0.004, P = 0.255, respectively). In conclusion, invasive carcinoma of no special type was the most common histological type in male breast carcinoma among Chinese population. Our study revealed that the luminal A and B subtypes were the major types of male breast carcinoma. AR and FOXP1 are highly expressed in male breast cancer. The luminal A subtype tends to express GCDFP15 and MGB more frequently than the luminal B subtype.

Coppa A, Buffone A, Capalbo C, et al.
Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14.
Breast Cancer Res Treat. 2014; 148(3):629-35 [PubMed] Related Publications
Hereditary breast and ovarian cancer are mainly linked to mutations in BRCA1 and BRCA2 genes which confer a similar cumulative risk of developing breast cancer. Importantly, while BRCA2 mutation carriers generally have a lower cumulative risk for ovarian cancer, mutations clustered in the central portion of BRCA2 are associated with a higher proportion of ovarian compared with breast cancer cases. The boundaries of this ovarian cancer cluster region (OCCR) have been tentatively defined within a 3.3 kb region of BRCA2 exon 11, and herein, we reassessed these boundaries using our series of Italian breast/ovarian cancer families. We used direct sequencing to investigate BRCA mutations in 367 breast/ovarian cancer families. We also studied the association between the location of the mutations and the ovarian cancer phenotype in our cohort of BRCA2-mutated families. We observed the novel c.7309_7309delA frameshift mutation and the c.7007G>A deleterious mutation in BRCA2 exons 14 and 13, respectively, in five independent Italian families characterized by a high proportion of ovarian cancer cases. Of note, a significantly higher proportion of ovarian versus breast cancer cases was associated not only with mutations in the previously defined OCCR (OR = 5.91; p = 0.004), but also with the exon 13-14 region (OR = 7.37; p = 0.001) in our BRCA2-mutated families. Our data provide initial evidence for a novel putative OCCR in BRCA2 exons 13-14.

Pinto R, De Summa S, Danza K, et al.
MicroRNA expression profiling in male and female familial breast cancer.
Br J Cancer. 2014; 111(12):2361-8 [PubMed] Article available free on PMC after 09/12/2015 Related Publications
BACKGROUND: Gender-associated epigenetic alterations are poorly investigated in male and female familial breast cancer (fBC). MicroRNAs may contribute to the different biology in men and women particularly related to RASSF1A pathways.
METHODS: Microarray technology was used to evaluate miRNA profile in 24 male and 43 female fBC. Key results were validated using RT-qPCR in an external samples set. In vitro studies were carried out to verify microRNA-target gene interaction.
RESULTS: Pathway enrichment analysis with the 287 differentially expressed microRNAs revealed several signalling pathways differently regulated in male and female cases. Because we previously hypothesised a peculiar involvement of RASSF1A in male fBC pathogenesis, we focussed on the MAPK and the Hippo signalling pathways that are regulated by RASSF1A. Male miR-152 and miR-497 upregulation and RASSF1A and NORE1A interacting gene downregulation were observed, confirming a possible indirect interaction between miRNAs and the two genes.
CONCLUSIONS: For the first time, a different microRNA expression pattern in male and female fBC has been shown. Moreover, the importance of RASSF1A pathway in male fBC carcinogenesis has been confirmed, highlighting a possible role for miR-152 and miR-497 in controlling MAPK and Hippo signalling pathways, regulated by RASSF1A.

Ottini L, Rizzolo P, Zanna I, et al.
Association of SULT1A1 Arg²¹³His polymorphism with male breast cancer risk: results from a multicenter study in Italy.
Breast Cancer Res Treat. 2014; 148(3):623-8 [PubMed] Related Publications
Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg(213)His (638G>A) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg(213)His could exert an effect on MBC development. The primary aim of this study was to evaluate the influence of the SULT1A1 Arg(213)His polymorphism on MBC risk. The secondary aim was to investigate possible associations with relevant clinical-pathologic features of MBC. A total of 394 MBC cases and 786 healthy male controls were genotyped for SULT1A1 Arg(213)His polymorphism by PCR-RFLP and high-resolution melting analysis. All MBC cases were characterized for relevant clinical-pathologic features. A significant difference in the distribution of SULT1A1 Arg(213)His genotypes was found between MBC cases and controls (P < 0.0001). The analysis of genotype-specific risk showed a significant increased MBC risk in individuals with G/A (OR 1.97, 95% CI 1.50-2.59; P < 0.0001) and A/A (OR 3.09, 95% CI 1.83-5.23; P < 0.0001) genotypes in comparison to wild-type genotype, under co-dominant model. A significant association between SULT1A1 risk genotypes and HER2 status emerged. Results indicate that SULT1A1 Arg(213)His may act as a low-penetrance risk allele for developing MBC and could be associated with a specific tumor subtype associated with HER2 overexpression.

Ottini L
Male breast cancer: a rare disease that might uncover underlying pathways of breast cancer.
Nat Rev Cancer. 2014; 14(10):643 [PubMed] Related Publications
There are similarities between breast cancers that arise in men and women but there are also differences. What can be learned from male breast cancer to gain insight into breast cancer pathogenesis?

Bratman SV, Horst KC, Carlson RW, Kapp DS
Solid malignancies in individuals with Down syndrome: a case presentation and literature review.
J Natl Compr Canc Netw. 2014; 12(11):1537-45 [PubMed] Related Publications
Individuals with Down syndrome (DS) are at elevated risk for acute leukemia, whereas solid tumors are uncommon, and most types, including breast cancers, have significantly lower-than-expected age-adjusted incidence rates. This article reports on a man with DS and breast cancer, thought to be the first in the literature, and presents the management of his cancer. The literature on malignancies in patients with DS is reviewed and the major epidemiologic studies that have examined the spectrum of cancer risk in individuals with DS are summarized. Potential environmental and genetic determinants of cancer risk are discussed, and the potential role of chromosomal mosaicism in cancer risk among patients with DS is explored. Trisomy of chromosome 21, which causes DS, provides an extra copy of genes with tumor suppressor or repressor functions. Recent studies have leveraged mouse and human genetics to uncover specific candidate genes on chromosome 21 that mediate these effects. In addition, global perturbations in gene expression programs have been observed, with potential effects on proliferation and self-renewal.

Kanatas A, Lowe D, Velikova G, et al.
Issues patients would like to discuss at their review consultation in breast cancer clinics--a cross-sectional survey.
Tumori. 2014 Sep-Oct; 100(5):568-79 [PubMed] Related Publications
AIMS AND BACKGROUND: In breast cancer (BC) there are different therapies available with different side effects affecting the health-related quality of life (HRQOL) of patients. Here we report a novel tool, the BC-specific Patient Concerns Inventory (PCI). This work includes a survey that is part of the validation process to allow a larger cohort and comparisons with clinical characteristics. We report the concerns that BC patients would like to discuss in the outpatient clinic - using the PCI - and also their choice of multidisciplinary team members they would like to see.
METHODS AND STUDY DESIGN: We carried out a cross-sectional survey - using the BC-specific PCI, the EORTC QLQ-C30 and the EORTC BC QLQ-BR23 - of patients who had completed their initial treatment and were attending a review outpatient clinic. 249 patients were recruited from February to July 2012.
RESULTS: Survey responses were obtained from 80% (200/249). The three most frequent items were fear of cancer coming back (62%, 124), breast sensitivity/pain (46%, 92), and fatigue/tiredness and low energy levels overall (46%, 92). The most frequently selected members of the multidisciplinary team that patients wished to see were the breast care nurse (46%, 92), the medical oncologist (28%, 55) and the psychologist (20%, 40).
CONCLUSIONS: The PCI provides the opportunity for multiprofessional engagement across a range of issues specific to BC. It can identify issues relating to physical, psychological, sexual and social functioning, as well as issues relating to body image and lifestyle.

Branca G, Irato E, Barresi V, et al.
A rare case of male breast cavernous-type angioleiomyoma.
Tumori. 2014 Jul-Aug; 100(4):148e-52e [PubMed] Related Publications
Cutaneous leiomyomas of the breast are extremely rare, particularly in men. Leiomyomas are categorized into three groups: angioleiomyomas, pilar leiomyomas and genital leiomyomas. Angioleiomyomas, or vascular leiomyomas, are benign tumors arising from smooth muscle cells of arterial or venous walls. We report the case of a 70-year-old man who was admitted to the surgery unit because of a painful lump in the left periareolar region. Ultrasound investigation showed a well-delimited, hyperechogenic, inhomogeneous nodular lesion. The final diagnosis was made after surgical excision and pathological evaluation of the mass. The histological features and immunohistochemical profile, characterized by positive expression of the spindle-shaped tumor cells for desmin and smooth muscle actin and by positive expression of the endothelial cells of the vascular channels for pan-endothelial markers CD34 and CD31, confirmed the diagnosis of a cavernous-type angioleiomyoma.

Lee HW, Kim TE, Cho SY, et al.
Invasive Paget disease of the breast: 20 years of experience at a single institution.
Hum Pathol. 2014; 45(12):2480-7 [PubMed] Related Publications
Mammary Paget disease with dermal invasion (invMPD) is rare, and its prognosis remains largely unknown. We reviewed MPD cases diagnosed at our institution and analyzed the clinicopathological characteristics of invMPD and non-invMPD to compare their incidences and outcomes. We retrospectively reviewed 205 cases of women diagnosed as having MPD between 1994 and 2013. Sixteen of 205 MPD cases (7.8%) had dermal invasion. Twelve of 16 invMPD cases had separate, underlying invasive breast carcinoma, and 3 invMPD cases had ductal carcinoma in situ. To exclude the influence of underlying disease on prognosis, we compared prognosis of invMPD with matched non-invMPD. The mean depth and extent of Paget cell invasion in invMPD cases were 0.637 and 1.268 mm, respectively. The horizontal extent of MPD was significantly larger in invMPD versus non-invMPD (mean, 14.31 mm versus 7.35 mm; P = .002). Distant metastasis and disease-related death were observed in 12.6% (24/189) and 12.1% (23/189) of non-invMPD patients, respectively, compared with 6.3% (1/16) and 6.3% (1/16) of invMPD patients; this difference was not significant (P = .7 and P = .7). Clinical outcomes of the invMPD patients were also not significantly different from the matched non-invMPD patients. In this study, MPD extent significantly correlated with MPD invasion. However, other clinicopathological parameters were not associated with dermal MPD invasion. Dermal MPD invasion was rare and did not predict regional lymph node metastasis or poor prognosis. The prognosis is usually similar for invMPD and non-invMPD, and MPD must be distinguished from locally advanced breast cancer presenting as satellite skin nodules.

Saura C, Garcia-Saenz JA, Xu B, et al.
Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer.
J Clin Oncol. 2014; 32(32):3626-33 [PubMed] Related Publications
PURPOSE: Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two).
PATIENTS AND METHODS: Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR).
RESULTS: In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m(2) per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively.
CONCLUSION: Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib.

Calligaris D, Caragacianu D, Liu X, et al.
Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis.
Proc Natl Acad Sci U S A. 2014; 111(42):15184-9 [PubMed] Article available free on PMC after 09/12/2015 Related Publications
Distinguishing tumor from normal glandular breast tissue is an important step in breast-conserving surgery. Because this distinction can be challenging in the operative setting, up to 40% of patients require an additional operation when traditional approaches are used. Here, we present a proof-of-concept study to determine the feasibility of using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) for identifying and differentiating tumor from normal breast tissue. We show that tumor margins can be identified using the spatial distributions and varying intensities of different lipids. Several fatty acids, including oleic acid, were more abundant in the cancerous tissue than in normal tissues. The cancer margins delineated by the molecular images from DESI-MSI were consistent with those margins obtained from histological staining. Our findings prove the feasibility of classifying cancerous and normal breast tissues using ambient ionization MSI. The results suggest that an MS-based method could be developed for the rapid intraoperative detection of residual cancer tissue during breast-conserving surgery.

Di Lauro L, Vici P, Barba M, et al.
Antiandrogen therapy in metastatic male breast cancer: results from an updated analysis in an expanded case series.
Breast Cancer Res Treat. 2014; 148(1):73-80 [PubMed] Related Publications
Male breast cancer is a rare disease treated as hormone receptor-positive female breast cancer. The characterization of breast cancer at the molecular level has lately revealed gender-related differences. As the androgen receptor is emerging as a potential oncogenic driver in male breast cancer, we analyzed efficacy data from metastatic patients treated with antiandrogens. We evaluated the activity of cyproterone acetate, either as a monotherapy or combined with a GnRH analog, in 36 metastatic male breast cancer patients. Fourteen patients were treated with cyproterone acetate as monotherapy and 22 patients with complete androgen blockade. We recorded 4 complete responses and 15 partial responses, for an overall response rate of 52.8 % (95 % CI, 36.5-69.4). Stable disease was reported in 11 patients. Median PFS was 8.9 months (95 % CI, 6.1-11.7), and median OS was 24.3 months (95 % CI, 22.5-26.1). Data on androgen receptor expression were available for 7 patients. All the 4 patients with androgen receptor-expressing tumors had a clinical benefit, including a patient with an estrogen receptor-negative disease. Conversely, none of the 3 patients with androgen receptor-negative tumors had a tumor response. Antiandrogen-based therapy showed efficacy in metastatic male breast cancer patients. Our results encourage considering antiandrogens in the therapeutic continuum, especially if supported by androgen receptor expression.

Sharma S, Sambyal V, Guleria K, et al.
TP53 polymorphisms in sporadic North Indian breast cancer patients.
Asian Pac J Cancer Prev. 2014; 15(16):6871-9 [PubMed] Related Publications
BACKGROUND: The purpose of this study was to evaluate the potential association of five (p.P47S, p.R72P, PIN3 Ins16bp, p.R213R and r.13494g>a) polymorphisms of TP53 with the risk of developing breast cancer in North Indian Punjabi population.
METHODS: We screened DNA samples of 200 sporadic breast cancer patients (197 females and 3 males) and 200 unrelated healthy, gender and age matched individuals for the polymorphisms.
RESULTS: For the p.P47S polymorphism, we observed the PP genotype in 99.5% of the patients and PS genotype in only 1 patient. All the controls had the wild type PP genotype. The frequency of RR, RP and PP genotype of p.R72P was 23.5% vs 33.5%, 51.5% vs 45.5% and 25% vs 21% in patients and controls respectively. Heterozygous (RP) genotype was increased in breast cancer patients as compared to controls (51.5 vs 45.5%) and showed 1.61 fold significantly increased risk for breast cancer (OR=1.61, 95% CI, 1.01-2.58, p=0.04). In breast cancer patients the frequencies of A1A1, A1A2 and A2A2 genotypes of PIN3 Ins16bp polymorphism were 67%, 26% and 7% respectively whereas in controls the genotype frequencies were 68.5%, 27.5% and 4% respectively, with no significant difference. For p.R213R (c.639A>G), all individuals had homozygous wild type genotype. The frequencies of GG, GA and AA genotypes of TP53 r.13494g>a polymorphism were 62 vs 67.5%, 33 vs 28% and 5 vs 4.5% in patients and controls respectively, again without significant difference. We observed that RP- A1A1 genotype combination of p.R72P and PIN3 Ins16bp and RP-GG combination of p.R72P and r.13494g>a polymorphism showed significant risk of breast cancer (OR=1.65, 95%CI: 0.98-2.78, p=0.05; OR=1.72, 95%CI: 1.01-2.92, p=0.04).
CONCLUSION: The results of present study indicated that among the five TP53 polymorphisms investigated, the p.R72P polymorphism, and the RP-A1A1 and RP-GG genotype combination contribute to breast cancer susceptibility in North Indians.

Gao YG, Zhang SH, Wang Y
A case of accessory mammary cancer in a male patient and a literature review.
Eur J Gynaecol Oncol. 2014; 35(4):452-5 [PubMed] Related Publications
A 68-year-old Chinese male patient was referred to the present hospital because of a right axillary lump in May 2011. Physical examination showed a rigid movable mass measuring 35 mm in diameter in the right axilla. No mass was palpable in either breast. Mammograms were normal. Physical and imaging examination of the head and neck region, lung, and upper and lower gastrointestinal tract also revealed no evidence of a primary tumor. Ultrasonography and resonance imaging (MRI) revealed no evidence of tumors in the bilateral mammary glands. Fine needle histological biopsy for suspected malignancy was performed, and the patient underwent tumor resection with axillary lymph node dissection on Jun 2011. Moderately differentiated adenocarcinoma in ectopic breast tissue was diagnosed based on the pathologic result, the tumor was immunohistochemically positive for ER, PR, and HER-2.

Maugeri-Saccà M, Barba M, Vici P, et al.
Aromatase inhibitors for metastatic male breast cancer: molecular, endocrine, and clinical considerations.
Breast Cancer Res Treat. 2014; 147(2):227-35 [PubMed] Related Publications
Male breast cancer is a rare condition. Aromatase inhibitors are widely used for treating metastatic male breast cancer patients. In this setting, their use is not substantiated by prospective clinical trials, but is rather driven by similarities supposedly existing with breast cancer in postmenopausal women. This oversimplified approach was questioned by studies addressing the molecular and endocrine roots of the disease. In this manuscript, we discuss relevant aspects of the current use of aromatase inhibitors in metastatic male breast cancer in light of the most updated evidence on the molecular landscape of the disease and the specific changes in the hormonal background occurring with aging. We further point to strategies for blocking multiple hormonal pathway nodes with the goal of improving their therapeutic potential. We searched PubMed from its inception until March 2014 for relevant literature on the use of aromatase inhibitors in metastatic male breast cancer. Selected terms were combined and used both as medical headings and text words. The reference list of the suitable manuscripts was inspected for further publications. Aromatase inhibitors represent the mainstay of treatment in the metastatic setting. Yet, efforts aimed at sharpening the therapeutic potential of aromatase inhibitors still pose a challenge due to the paucity of data. The choice of dual hormonal (or sequential) therapy combining aromatase inhibitors with a GnRH analogue may represent a valid alterative, particularly if informed by cancer- and patient-related features including molecular, endocrine, and clinic characteristics.

Tewes M, Kasimir-Bauer S, Welt A, et al.
Detection of disseminated tumor cells in bone marrow and circulating tumor cells in blood of patients with early-stage male breast cancer.
J Cancer Res Clin Oncol. 2015; 141(1):87-92 [PubMed] Related Publications
BACKGROUND: Male breast cancer (MBC) is a rare malignant disease, accounting for <1% of all breast cancers (BCs). Treatment of men with early-stage BC is based on standards established in female BC. Prognostic or predictive markers to guide therapeutic decisions, in particular in early-stage male BC, are missing. Here, we explored whether disseminated tumor cells (DTC) in bone marrow (BM) and circulating tumor cells (CTC) in blood could be suitable biomarkers in male BC.
PATIENTS AND METHODS: Five male patients (pT2-4, pN0-2, M0) with hormone receptor-positive, HER2-negative, and ductal primary BC (median age 70 years, range 51-73) were enrolled in a prospective study of patients with early-stage breast cancer. Here, we analyze the male subgroup. DTC in BM were analyzed before therapy and identified by immunocytochemistry using the pancytokeratin antibody A45B/B3. Blood samples (10 ml) were analyzed for CTC using the AdnaTest BreastCancer (AdnaGen AG, Langenhagen, Germany).
RESULTS: DTC were found in three out of five male patients (60%) with two DTC detected in one patient and one DTC detected in each of the other two patients. This is compared to a detection rate of 25-40% in pooled analyses of female patients. CTC were only found in one of five patients. After a median follow-up time of 3 years (range 1-10 years), all patients were still alive and free of relapse.
CONCLUSION: The prevalence of DTC and CTC in male BC seems comparable with female BC. No prognostic relevance could be documented in this small population. A prospective study or at least larger cases series will be required to assess the prognostic or predictive value of DTC and CTC in this rare disease.

Wenhui Z, Shuo L, Dabei T, et al.
Androgen receptor expression in male breast cancer predicts inferior outcome and poor response to tamoxifen treatment.
Eur J Endocrinol. 2014; 171(4):527-33 [PubMed] Related Publications
OBJECTIVE: Androgen receptor (AR) plays an important role in male breast cancer (MBC). Additionally, endocrine therapy is the most important treatment in oestrogen receptor (ER)-positive advanced breast cancer. This study was aimed to investigate the role of AR in MBC treatment and prognosis and to analyse the relationship between AR and the effect of tamoxifen treatment in MBC patients.
METHODS: AR protein levels and other tumour characteristics (e.g. expression of ER (ESR1), PR (PGR), AR, HER2 (ERBB2) and Ki-67 (MKI67)) in breast cancer tissue from 102 MBC patients were determined using immunohistochemical analysis. Additionally, the relationship between AR status and clinicopathological features was analysed using the χ(2)-test. Association with survival was initially analysed using the Kaplan-Meier method and the log-rank test, and Cox regression analysis was used to adjust for other prognostic indicators.
RESULTS: High expression of AR was not correlated with T-stage, histological grade, HER2 status and the status of other sex hormone receptors, but was associated with lymph node metastases (P=0.032). AR-positive patients showed significantly shorter 5-year overall survival (OS) rates (P=0.045) and 5-year disease-free survival (DFS) rates (P=0.026) than AR-negative patients. By contrast, for patients who received tamoxifen therapy, AR-negative patients showed a higher clinical benefit rate than AR-positive patients (P=0.025). Additionally, the median TTP and OS were significantly different (P=0.02 for TTP; P=0.029 for OS).
CONCLUSIONS: AR expression correlates strongly with both OS and DFS in patients with MBC. AR-positive patients can predict a poorer clinical outcome than AR-negative patients after adjuvant tamoxifen therapy.

Park YM, Wu Y, Wei W, Yang WT
Primary neuroendocrine carcinoma of the breast: clinical, imaging, and histologic features.
AJR Am J Roentgenol. 2014; 203(2):W221-30 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to evaluate the clinical, imaging, and histopathologic findings of primary neuroendocrine carcinoma of the breast.
MATERIALS AND METHODS: A pathology database was searched for the records of patients with a histopathologic diagnosis of primary neuroendocrine carcinoma of the breast who had undergone mammography, sonography, or MRI between 1984 and 2011. The imaging studies of eligible patients were retrospectively reviewed according to the BI-RADS lexicon, and clinical presentation and histopathologic characteristics were documented. Imaging characteristics were compared with historical controls of invasive mammary carcinoma.
RESULTS: Eighty-seven patients (84 women, three men; mean age, 62.9 years; range, 28-89 years) were included in the study. The mean tumor size was 3.1 cm (range, 0.6-11 cm). Sixty-five of 84 (77.4%) cancers were estrogen and progesterone receptor positive and ERBB2 negative. A palpable mass (55.8%) was a common clinical manifestation. A high-density, round or oval, or lobular mass with nonspiculated margins on mammograms and an irregular (65.4%), hypoechoic (78.4%) mass, with indistinct margins (43.5%), no or enhanced posterior acoustic features (77.9%) on sonograms were common findings. MRI revealed an irregular mass (83.3%), irregular margins (63.6%), and washout kinetics (85.7%). Neuroendocrine carcinoma presented more frequently as masses on mammograms. Calcifications were infrequent compared with their occurrence in invasive mammary cancer.
CONCLUSION: Primary neuroendocrine carcinoma of the breast has mammographic features that differ from those of invasive mammary carcinoma. A round, oval, or lobular mass with nonspiculated margins, positive estrogen and progesterone receptor results, and negative ERBB2 results should raise suspicion of primary neuroendocrine carcinoma.

Groheux D, Hindié E, Marty M, et al.
¹⁸F-FDG-PET/CT in staging, restaging, and treatment response assessment of male breast cancer.
Eur J Radiol. 2014; 83(10):1925-33 [PubMed] Related Publications
PURPOSE: Male breast cancer (BC) is a rare disease, with patterns different from those found in women. Most tumors are detected at more advanced stages than in women. The aim of this study was to analyze the performance of [18F]fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) in staging, restaging, and therapy response assessment.
METHODS: We performed a systematic analysis in the database of Saint-Louis Hospital to identify male patients with BC referred for PET/CT. (18)F-FDG-PET/CT findings considered suspicious for malignancy were compared to biopsy results, further work-up and/or patient follow-up of at least 6 months. Performances of (18)F-FDG-PET/CT were compared to that of conventional imaging (CI) using the McNemar test. The impact of PET/CT on management was evaluated.
RESULTS: During 6 consecutive years, among 12,692 (18)F-FDG-PET/CT oncology studies, 30 were performed in 15 men with BC: 7 examinations for initial staging, 11 for restaging, and 12 for response assessment. Tumors profile was ER+ and one had HER2 overexpression. PET/CT sensitivity, specificity, positive predictive value, negative predictive value and accuracy to detect distant metastases were 100%, 67%, 86%, 100% and 89%, respectively. PET/CT was more informative than CI in 40% of studies (p=0.03; 95% confidence interval: 3.26 - 40%). Findings from (18)F-FDG-PET/CT led to modification in the planned treatment in 13/30 cases (43%).
CONCLUSION: Although all the tumors were ER+, primary lesions and metastases were diagnosed with high sensitivity. (18)F-FDG-PET/CT seems to be a powerful imaging method to perform staging, restaging and treatment response assessment in male patients with BC.

Grenader T, Yerushalmi R, Tokar M, et al.
The 21-gene recurrence score assay (Oncotype DX™) in estrogen receptor-positive male breast cancer: experience in an Israeli cohort.
Oncology. 2014; 87(1):1-6 [PubMed] Related Publications
OBJECTIVE: The 21-gene recurrence score (RS) assay has been widely adopted for use in early estrogen receptor (ER)-positive breast cancer to assess the risk for distant recurrence and the potential benefit of adjuvant chemotherapy. The primary aim of this study was to assess RS distribution in Israeli male breast cancer (MBC) patients.
METHODS: The study population included 65 newly diagnosed Israeli MBC patients. Clinical and pathologic data were collected at the time of referral. Pathologic examinations were conducted at the pathology departments of the referring centers. The RS assay (Oncotype DX™) was performed on paraffin-embedded tumor samples at Genomic Health laboratories.
RESULTS: The mean age of the patients was 65.1 years (range 38-88 years). Low-risk (RS<18), intermediate-risk (RS 18-30) and high-risk (RS≥31) scores were noted in 29 patients (44.6%), 27 patients (41.5%) and 9 patients (13.9%), respectively. The distribution of RS in male patients was similar to the distribution in 2,455 female patients from Israel referred during the same time period.
CONCLUSION: Our data suggest that the distribution of Oncotype DX RS in ER-positive MBC patients is similar to that of female breast cancer patients.

Lu CS, Huang SH, Ho CL, et al.
Primary neuroendocrine carcinoma of the breast.
J BUON. 2014 Apr-Jun; 19(2):419-29 [PubMed] Related Publications
PURPOSE: Primary neuroendocrine carcinoma of the breast (NECB) is a rare distinct type of breast carcinoma. There are only some case reports on this topic published in the past. There is still little known on the optimal treatment outcomes, while a wide variety of treatments is proposed by several authors. In this study we searched the literature on NECB in PubMed to clarify its prognosis and possible optimal therapeutic strategies.
METHODS: Eighty-six cases of primary NEC, included our case, were collected from PubMed between 1980 and 2013. Initial stage, estrogen receptor (ER)/progesterone receptor (PR)/ human epidermal growth factor receptor 2 (HER-2), surgical procedures, adjuvant treatment and overall survive (OS) were analyzed using the Statistical Package for the Social Sciences ( SPSS, v 16.0 ).
RESULTS: All 86 patients enrolled were eligible. Their mean age at diagnosis was 53.9 years (range 25-83) and 1 case was in a male. Overall survival (OS) at 48 months was 83.5%. Patients with enlarged tumor size (10 patients with tumor size >5.0 cm) or advanced stage (stage III 15 patients, stage IV 2 patients) had poor OS (48-month OS: 51.4 vs 97.1% with tumors >5cm vs ≤2cm, respectively and 0.0%, 68.1%, 72.9% and 95.8% in stage IV, III, II and I, respectively). Patients with positive ER, PR or HER-2 had significantly better OS than did those without (ER, p<0.001; PR, p<0.001; HER-2, p=0.082). Besides, all 60 patients with initial primary surgery and without lymph node dissection (LND) showed better OS than those with initial primary surgery without LND, the difference however being not significant (p=0.133).
CONCLUSION: Definite diagnosis and clinical stage are prerequisites in the initial approach in NECB. When detected early the disease may have a good prognosis with combined modality treatment such as chemotherapy, surgery, and radiation therapy. An appropriate therapeutic strategy for this group is also important. Our analysis showed that for patients with early localized disease only primary surgery is recommended and LND is optional. In patients with positive steroid receptors postoperative hormonotherapy is suggested.

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