Invasive breast cancer is the endpoint of complicated evolutionary process starting in TDLU of mammary gland. It is the network of multiple-step mechanism including cell proliferation, differentiation, atypical intracellular expression and signaling leading to the misbalance between mammary epithelial cells and breast tissue microenvironment. The disruption of epithelial-stromal equilibrium can lead to the epithelial carcinogenesis, progressive stromal invasion and metastatic spread in the final stages. Although we know some of the histopathologic features in these mechanisms, the molecular profile of these events is still not adequately responded, and remains the scope for future research.

Background: Preclinical data show that complete estrogen blockade by both down regulating estrogen receptor and inhibiting estrogen synthesis, has greater effect on tumor growth than either treatment alone. Combination of an aromatase inhibitor and fulvestrant may be an optimal second line therapy by preventing activation of growth factor pathways and possible cross talk with ER. One clinical study has shown no benefit of adding anastrozole to fulvestrant at first relapse. No clinical data on combination letrozole and fulvestrant in the second line or more metastatic beast cancer setting is available.

Methods: Estrogen receptor (ER) positive, progesterone receptor (PgR) positive or negative metastatic breast cancer patients with prior chemo and/or non-aromatase inhibitor (non-AI) endocrine therapy were treated with letrozole and fulvestrant. Patients with complete response(CR) partial response(PR), or stable disease(SD) were considered to have clinical benefit (CR+PR+SD). The predictive effects of age, number of prior regimens, ER/PgR status, histology, sites of metastatic disease were examined using Chi-square test.

Results: Thirty-two patients received oral letrozole 2.5 mg daily plus fulvestrant 250 mg intramuscular injection monthly. Mean age was 70 (range: 35-92), median number of prior treatments was 2 (range2-6). 25 pts had ER+/ PgR+, 7 pts had ER+/PgR- tumors. Twenty-five patients had prior non-AI endocrine therapy. Eight patients had lobular histology. Overall clinical benefit rate was 71% (3 CR, 7 PR, and 13 SD). Mean duration of the clinical benefit was 15 months (range 2-38). Nine patients progressed under therapy. Age more than 65 versus younger (89% vs 46%, P=0.007), prior treatments less than 4 versus more (87% vs 25%, P=0.0007) and ER+/PgR+ versus ER+/PgR- (84% versus 42%, P<0.05) were predictive of clinical benefit; lobular histology, bone versus visceral metastases and prior endocrine therapy did not have affect clinical benefit rate (P>0.05) .

Conclusions: In previously treated metastatic breast cancer patients, combination of letrozole and fulvestrant can be effective with a mean clinical benefit duration of 15 months. Older age, less than four prior lines of therapy, and expression of both ER/PgR are predictive of clinical benefit while lobular histology, site of metastatic disease and prior non-AI endocrine therapy are not. Letrozole and fulvestrant combination can be a reasonable option in selected group of previously treated metastatic breast cancer patients and should be further evaluated in larger studies utilizing recently approved high dose (500 mg) fulvestrant schedule.

A major challenge to breast cancer research is the identification of alterations in the architecture and composition of the breast that are associated with breast cancer progression. The aim of the present investigation was to characterize the mammary adipose phenotype from Brca1 mutant mice in the expectation that this would shed light on the role of the mammary tissue environment in the early stages of breast tumorigenesis. We observed that histological sections of mammary tissue from adult Brca1 mutant mice abnormally display small, multilocular adipocytes that are reminiscent of brown adipose tissue (BAT) as compared to wildtype mice. Using a marker for BAT, the uncoupling protein 1 (UCP1), we demonstrated that these multilocular adipose regions in Brca1 mutant mice stain positive for UCP1. Transcriptionally, UCP1 mRNA levels in the Brca1 mutant mice were elevated greater than 50-fold compared to age-matched mammary glands from wildtype mice. Indeed, BAT has characteristics that are favorable for tumor growth, including high vascularity. Therefore, we also demonstrated that the multilocular brown adipose phenotype in the mammary fat pad of Brca1 mutant mice displayed regions of increased vascularity as evidenced by a significant increase in the protein expression of CD31, a marker for angiogenesis. This Brca1 mutant mouse model should provide a physiologically relevant context to determine whether brown adipose tissue can play a role in breast cancer development.

Background: Endocrine therapy is an essential modality in patients with hormone receptor positive breast cancer. Even with high therapeutic efficacy of first-line hormonal treatment, most patients with metastatic breast cancer will develop resistance. It appeals, that a factor contributing to the resistance may be a transforming factorbeta (TGF-beta). It is highly immunosuppressive factor that inhibits the natural and specific immunity against tumors and stimulates vascular endotelial growth factor (VEGF). The purpose of the study was to monitor immune responses in patients with hormone receptor positive breast cancer, particularly the examination of cellular (CD4, CD8) as well as humoral immunity, as well as TGF beta and VEGF production. Materials and Methods: Patients included into the research project were implemented routine cancer teratment with hormonal therapy. Basic parameters (histological type and grade, the degree of expression of ER and PR, HER2, and the proliferative marker) were established . Patients were evaluated by a cancer clinical immunologist to exclude immune disorders, allergic or autoimmune origin. 12 healthy age matched persons served as control group.TGF beta, VEGF were mesured by ELISA and antitumor cellular immunity (CD4, CD8, antigen presenting cells) was measured by flow cytometry. Results: In patients with resistance to endocrine therapy mainly depression in cellular immunity was found, CD 8, cytotoxic T lymphocytes were significantly [p<0.05] decreased. Immunglobuline plasma level was decreased as well (mainly IgG4 subtype [p<0.05]). Most patients have shown clinical symptoms of immunodeficiency (frequent infections of respiratory or urinary tract, herpetic infections). TGF beta as well as VEGF plasma level were significantly increased as compared with healthy person. Conclusion: Correlation of these factors with resistance to endocrine therapy could help in the future with the prediction of therapy response and contribute to the selection of targeted therapy in breast cancer patients. Dedication: This project was supported by govermental grant IGA NT11168-3/2010.

In recent years there has been a growing interest on enhancing the cosmetic and functional aspects of the oncological surgery of the breast, which resulted in ongoing development of oncoplastic surgery. This method presents several advantages, including the possibility of treating larger tumors with conservative procedures, better tumor-free margins, less carcinogenic risk in the future, better results with radiotherapy and finally, a better psychological profile of the patients. The most important factor regarding the oncological safety of conservative surgery of the breast is the capacity of each procedure in providing tumor-free margins after resection. Therefore, we know that procedures that provide larger free margins are safer from the oncological point of view. In this study, we aimed to verify the oncological safety of the oncoplastic procedures in comparison with the traditional procedures, by comparing variables measured in two groups of patients surgically treated in the Breast Service of the HUAP. We could conclude that since the group operated with oncoplastic procedures had significant larger margins than the group operated with traditional techniques, and that the other variables measured were alike, it is possible to say that the oncological safety of the oncoplastic surgery of the breast is, at least, equal to the safety of the conservative surgery with traditional techniques, and probably better.