Male breast cancer

Male breast cancer (MBC) is a rare disease representing less than 1% of all breast cancers (BC) and less than 1% of cancers in men. Age at presentation is mostly in the late 60s. MBC is recognized as an estrogen-driven disease, specifically related to hyperestrogenism. About 20% of MBC patients have family history for BC. Mutations in BRCA1 and, predominantly, BRCA2, account for approximately 10% of MBC cases. Because of its rarity, MBC is often compared with female BC (FBC). Based on age-frequency distribution, age-specific incidence rate patterns and prognostic factors profiles, MBC is considered similar to late-onset, postmenopausal estrogen/progesterone receptor positive (ER+/PR+) FBC. However, clinical and pathological characteristics of MBC do not exactly overlap FBC. Compared with FBC, MBC has been reported to occur later in life, present at a higher stage, and display lower histologic grade, with a higher proportion of ER+ and PR+ tumors. Although rare, MBC remains a substantial cause for morbidity and mortality in men, probably because of its occurrence in advanced age and delayed diagnosis. Diagnosis and treatment of MBC generally is similar to that of FBC. Men tend to be treated with mastectomy rather than breast-conserving surgery. The backbone of adjuvant therapy or palliative treatment for advanced disease is endocrine, mostly tamoxifen. Use of FBC-based therapy led to the observation that treatment outcomes for MBC are worse and that survival rates for MBC do not improve like FBC. These different outcomes may suggest a non-appropriate utilization of treatments and that different underlying pathogenetic mechanisms may exist between male and female BC

Invasive carcinomas of the male breast: a morphologic study of the distribution of histologic subtypes and metastatic patterns in 778 cases

The current investigation was conducted to evaluate the proportional distribution of the various histologic subtypes (including newly recognized variants) of male breast carcinomas, to determine whether any histologic subtypes occur with a frequency that is markedly discordant with the expected frequencies from published data on parallel female breast tumors. We also aimed to document the distribution of malignancies metastatic to the breast. Seven hundred fifty-nine archived cases of primary invasive carcinoma involving the male breast were retrieved and subcategorized into histologic subtypes according to contemporary criteria. Six hundred forty-three (84.7%) tumors were pure infiltrating ductal carcinoma (IDC) not otherwise specified. The most common of the remainder included papillary carcinoma with invasion in the form of IDC (n = 34), mixed IDC and mucinous carcinoma (n = 26), and pure mucinous carcinoma (n = 21). In 19 cases, metastases from other sites involved the breast, most commonly (58%) cutaneous melanoma. Invasive carcinoma of the male breast appears to display a morphologic spectrum and distribution of histologic subtypes that is comparable to those of the female breast, with some expected variation. Compared with published experience on their female counterparts, there is a two-fold increase in the frequency of invasive papillary carcinoma in the male breast. Finally, the most common tumor metastatic to the male breast in this series was cutaneous melanoma

Clinical significance of the nuclear receptor co-regulator DC-SCRIPT in breast cancer: an independent retrospective validation study

Contains fulltext : 88921.pdf (publisher's version ) (Open Access

Matched-pair analysis of patients with female and male breast cancer: a comparative analysis

<p>Abstract</p> <p>Background</p> <p>Male breast cancer (MBC) is a rare disease accounting for approximately 1% of all breast carcinomas. Presently treatment recommendations are derived from the standards for female breast cancer. However, those approaches might be inadequate because of distinct gender specific differences in tumor biology of breast cancer. This study was planned in order to contrast potential differences between female and male breast cancer in both tumor biological behavior and clinical management.</p> <p>Methods</p> <p>MBC diagnosed between 1995-2007 (region Chemnitz/Zwickau, Saxony, Germany) was retrospectively analyzed. Tumor characteristics, treatment and follow-up of the patients were documented. In order to highlight potential differences each MBC was matched with a female counterpart (FBC) that showed accordance in at least eight tumor characteristics (year of diagnosis, age, tumor stage, nodal status, grade, estrogen- and progesterone receptors, HER2 status).</p> <p>Results</p> <p>108 male/female matched-pairs were available for survival analyses. In our study men and women with breast cancer had similar disease-free (DFS) and overall (OS) survival. The 5-years DFS was 53.4% (95% CI, range 54.1-66.3) in men respectively 62.6% (95% CI, 63.5-75.3) in women (p > 0.05). The 5-years OS was 71.4% (95% CI, 62.1-72.7%) and 70.3% (95% CI, 32.6-49.6) in women (p > 0.05). In males DFS analyses revealed progesterone receptor expression as the only prognostic relevant factor (p = 0.006). In multivariate analyses for OS both advanced tumor size (p = 0.01) and a lack of progesterone receptor expression were correlated (p = 0.01) with poor patients outcome in MBC.</p> <p>Conclusion</p> <p>Our comparative study revealed no survival differences between male and female breast cancer patients and gives evidence that gender is no predictor for survival in breast cancer. This was shown despite of significant gender specific differences in terms of frequency and intensity of systemic therapy in favor to female breast cancer.</p

Phenotypic features and genetic characterization of male breast cancer families: identification of two recurrent BRCA2 mutations in north-east of Italy

BACKGROUND: Breast cancer in men is an infrequent occurrence, accounting for ~1% of all breast tumors with an incidence of about 1:100,000. The relative rarity of male breast cancer (MBC) limits our understanding of the epidemiologic, genetic and clinical features of this tumor. METHODS: From 1997 to 2003, 10 MBC patients were referred to our Institute for genetic counselling and BRCA1/2 testing. Here we report on the genetic and phenotypic characterization of 10 families with MBC from the North East of Italy. In particular, we wished to assess the occurrence of specific cancer types in relatives of MBC probands in families with and without BRCA2 predisposing mutations. Moreover, families with recurrent BRCA2 mutations were also characterized by haplotype analysis using 5 BRCA2-linked dinucleotide repeat markers and 8 intragenic BRCA2 polymorphisms. RESULTS: Two pathogenic mutations in the BRCA2 gene were observed: the 9106C>T (Q2960X) and the IVS16-2A>G (splicing) mutations, each in 2 cases. A BRCA1 mutation of uncertain significance 4590C>G (P1491A) was also observed. In families with BRCA2 mutations, female breast cancer was more frequent in the first and second-degree relatives compared to the families with wild type BRCA1/2 (31.9% vs. 8.0% p = 0.001). Reconstruction of the chromosome phasing in three families and the analysis of three isolated cases with the IVS16-2A>G BRCA2 mutation identified the same haplotype associated with MBC, supporting the possibility that this founder mutation previously detected in Slovenian families is also present in the North East of our Country. Moreover, analysis of one family with the 9106C>T BRCA2 mutation allowed the identification of common haplotypes for both microsatellite and intragenic polymorphisms segregating with the mutation. Three isolated cases with the same mutation shared the same intragenic polymorphisms and three 5' microsatellite markers, but showed a different haplotype for 3' markers, which were common to all three cases. CONCLUSION: The 9106C>T and the IVS16-2A>G mutations constitute recurrent BRCA2 mutations in MBC cases from the North-East of Italy and may be associated with a founder effect. Knowledge of these two recurrent BRCA2 mutations predisposing to MBC may facilitate the analyses aimed at the identification of mutation carriers in our geographic area

Identification of uPAR-positive Chemoresistant Cells in Small Cell Lung Cancer

BACKGROUND: The urokinase plasminogen activator (uPA) and its receptor (uPAR/CD87) are major regulators of extracellular matrix degradation and are involved in cell migration and invasion under physiological and pathological conditions. The uPA/uPAR system has been of great interest in cancer research because it is involved in the development of most invasive cancer phenotypes and is a strong predictor of poor patient survival. However, little is known about the role of uPA/uPAR in small cell lung cancer (SCLC), the most aggressive type of lung cancer. We therefore determined whether uPA and uPAR are involved in generation of drug resistant SCLC cell phenotype. METHODS AND FINDINGS: We screened six human SCLC cell lines for surface markers for putative stem and cancer cells. We used fluorescence-activated cell sorting (FACS), fluorescence microscopy and clonogenic assays to demonstrate uPAR expression in a subpopulation of cells derived from primary and metastatic SCLC cell lines. Cytotoxic assays were used to determine the sensitivity of uPAR-positive and uPAR-negative cells to chemotherapeutic agents. The uPAR-positive cells in all SCLC lines demonstrated multi-drug resistance, high clonogenic activity and co-expression of CD44 and MDR1, putative cancer stem cell markers. CONCLUSIONS: These data suggest that uPAR-positive cells may define a functionally important population of cancer cells in SCLC, which are resistant to traditional chemotherapies, and could serve as critical targets for more effective therapeutic interventions in SCLC

Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer

BACKGROUND: Signaling pathways that converge on two different transcription factor complexes, NFκB and AP-1, have been identified in estrogen receptor (ER)-positive breast cancers resistant to the antiestrogen, tamoxifen. METHODS: Two cell line models of tamoxifen-resistant ER-positive breast cancer, MCF7/HER2 and BT474, showing increased AP-1 and NFκB DNA-binding and transcriptional activities, were studied to compare tamoxifen effects on NFκB and AP-1 regulated reporter genes relative to tamoxifen-sensitive MCF7 cells. The model cell lines were treated with the IKK inhibitor parthenolide (PA) or the proteasome inhibitor bortezomib (PS341), alone and in combination with tamoxifen. Expression microarray data available from 54 UCSF node-negative ER-positive breast cancer cases with known clinical outcome were used to search for potential genes signifying upregulated NFκB and AP-1 transcriptional activity in association with tamoxifen resistance. The association of these genes with patient outcome was further evaluated using node-negative ER-positive breast cancer cases identified from three other published data sets (Rotterdam, n = 209; Amsterdam, n = 68; Basel, n = 108), each having different patient age and adjuvant tamoxifen treatment characteristics. RESULTS: Doses of parthenolide and bortezomib capable of sensitizing the two endocrine resistant breast cancer models to tamoxifen were capable of suppressing NFκB and AP-1 regulated gene expression in combination with tamoxifen and also increased ER recruitment of the transcriptional co-repressor, NCoR. Transcript profiles from the UCSF breast cancer cases revealed three NFκB and AP-1 upregulated genes – cyclin D1, uPA and VEGF – capable of dichotomizing node-negative ER-positive cases into early and late relapsing subsets despite adjuvant tamoxfien therapy and most prognostic for younger age cases. Across the four independent sets of node-negative ER-positive breast cancer cases (UCSF, Rotterdam, Amsterdam, Basel), high expression of all three NFκB and AP-1 upregulated genes was associated with earliest metastatic relapse. CONCLUSION: Altogether, these findings implicate increased NFκB and AP-1 transcriptional responses with tamoxifen resistant breast cancer and early metastatic relapse, especially in younger patients. These findings also suggest that agents capable of preventing NFκB and AP-1 gene activation may prove useful in restoring the endocrine responsiveness of such high-risk ER-positive breast cancers

Urokinase-type plasminogen activator system in breast cancer: association with tamoxifen therapy in recurrent disease.

The prognostic value of components of the urokinase-type plasminogen activator (uPA) system, its receptor uPAR (CD87), and plasminogen activator inhibitors PAI-1 and PAI-2 is well established. We studied the predictive value of these proteolytic factors by evaluating the association of their tumor expression level and the efficacy of tamoxifen therapy in patients with recurrent breast cancer. The antigen levels of the four factors were determined by ELISA in cytosols prepared from estrogen receptor-positive primary breast tumors of 691 hormone-naive breast cancer patients with recurrent disease and treated with tamoxifen as first-line systemic therapy. High tumor levels of uPA (P < 0.001), uPAR (P < 0.01), and PAI-1 (P = 0.01) were associated with a lower efficacy of tamoxifen therapy. In the multivariable analysis, uPA (P < 0.001) provided additional information independent of the traditional predictive factors to predict benefit from tamoxifen therapy. High levels of uPA, uPAR, and PAI-1 predicted a shorter progression-free survival (PFS) on tamoxifen in an analysis of the first 9 months of therapy. However in the analysis during the total follow-up period, high PAI-2 levels (P = 0.01) showed a longer response to tamoxifen. In conclusion, uPA, uPAR, and PAI-1, components of the urokinase system, are predictive for the efficacy of tamoxifen therapy in patients treated for recurrent breast cancer. Knowledge of their tumor expression levels might be helpful for future individualized therapy protocols, including possible new-targeted therapies based on the interference in the urokinase system

Tumor tissue levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) and survival following adjuvant chemotherapy in pre-menopausal lymph node-positive breast cancer patients (N=525).

Abstract Abstract #6054 Predictive markers are needed to guide planning of adjuvant therapy for breast cancer patients. We have recently shown that high tumor tissue levels of TIMP-1 are associated with decreased response to chemotherapy in metastatic breast cancer (Schrohl et al, Clin Cancer Res, 2006) suggesting that TIMP-1 may be a predictive marker in breast cancer patients.&amp;#x2028; Purpose: This study investigates the association of tumor tissue TIMP-1 levels with response to adjuvant chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil) or an anthracycline-based regimen.&amp;#x2028; Patients and Methods: 525 pre-menopausal lymph node-positive patients were included; 324 patients received adjuvant CMF, 99 received an adjuvant anthracycline-containing regimen and 102 had no adjuvant chemotherapy. Total TIMP-1 levels were measured using ELISA in cytosolic extracts of frozen primary tumors. Using the untreated patient group as a reference group we analyzed the benefit of adjuvant CMF and anthracyclines in TIMP-1 high and low patients, respectively. The median TIMP-1 concentration was used to dichotomize patients into high and low TIMP-1 groups. End points were disease-free and overall survival (DFS, OS).&amp;#x2028; Results: The median TIMP-1 level in the total patient group was 12,54 ng/mg of total protein (range, 0 – 112,9 ng/mg). TIMP-1 levels in subgroups according to adjuvant therapy were not significantly different (P=0,20). In a multivariate model including basic clinico-pathological parameters, TIMP-1 low and high patients benefited differentially from adjuvant CMF and anthracyclines when compared to untreated patients. In particular, patients with high tumor levels of TIMP-1 had little benefit from adjuvant anthracyclines. Hazard ratios (HR) and 95% confidence intervals (CI) are given in the table for the analysis of DFS. A similar pattern was seen in the analyses of OS. In the CMF-treated group, both TIMP-1 low and high patients had significantly better survival than untreated patients (P&amp;lt;0,01). Among anthracycline-treated patients those with TIMP-1 low tumors appeared to benefit more from the adjuvant therapy than TIMP-1 high patients although these results did not reach significance in the present analyses.&amp;#x2028; &amp;#x2028; Conclusion: This study suggests that high tumor tissue TIMP-1 levels are associated with decreased benefit from adjuvant chemotherapy. Especially in the group treated with anthracycline-based therapy there is a strong tendency for TIMP-1 high tumors to be less sensitive to the treatment. This group, however, is small and should be enlarged to confirm our results. In the group treated with CMF all patients benefit from the therapy with TIMP-1 high patients having slightly less benefit than TIMP-1 low patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6054.</jats:p