Expression of PD-L1 in Locally Advanced Breast Cancer and Its Impact on Neoadjuvant Chemotherapy Response.

OBJECTIVES: Programmed cell death-ligand 1 (PD-L1) is a new target in breast cancer (BC) and its impact on neoadjuvant chemotherapy (NACTH) response is still unclear. The aim of this study was to investigate the prevalence of PD-L1 in locally advanced invasive BC of different molecular subtypes and to elucidate its relation to tumor-infiltrating lymphocytes (TILs) density, established clinicopathological factors, pathological therapy response after neoadjuvant chemotherapy and patients' outcome. MATERIALS AND METHODS: One hundred and five cases of locally advanced invasive BC were enrolled in our study. Cases were classified into five molecular subtypes according to the Immuno-histochemical data. PD-L1 immunostaining was analyzed for all studied cases and its expression was correlated with TILs density, histopathologic parameters, BC molecular subtypes, Pathological therapy response, 7-years disease-free survival (DFS) and overall survival (OS). RESULTS: PD-L1 was expressed in 32.4% of the studied locally advanced BC cases. It showed a significant correlation with old age group (p= 0.010), high tumor grade (p= 0.046) and high pretherapy TILs density (p= <0.001). PD-L1 expression was higher in HER2/neu-enriched group (45.5%) followed by TNBC (44.4%). There were no significant relations between PD-L1 expression and DFS, OS as well as pathological therapy response, although, it revealed more expression in cases with complete and marked therapy response. CONCLUSION: In spite our results fail to prove that PD-L1 is a bad prognostic biomarker in locally advanced BC, but they indicate PD-L1 could be a new target for the treatment of patients with high grade breast carcinoma and TNBC group.

Impact of Molecular Profiling of Breast Cancer on the Rate of Locoregional Recurrence in Young Versus Old Female Patients.

Background Breast cancer (BC) is diverse regarding its natural history and treatment responses. The traditional histopathological classification is unable to confine this diverse clinical heterogeneity. Classically, prognosis and treatment response are influenced by factors including histological grade, lymph node status, and tumour size. Recently, research has diverted from histological classification towards molecular classification. We aim to analyse the locoregional recurrence of breast cancer incidence following surgery across the different molecular subtypes as well as relation to age. Materials and methods Female patients diagnosed with a locoregional recurrence of breast carcinoma in 2012-2014 were identified from our centre histology department. We only included stage I-III patients who were previously treated with surgery achieving negative surgical margins and later developed locoregional recurrence during our study period. These patients were subdivided by age into old (≥40 years old) and young (<40 years old) groups according to their initial diagnosis age. Furthermore, they were categorised according to the molecular subtype of their primary tumour. Results Our study included 184 patients (124 designated to the old age group, 60 to the young age group). In the young group, recurrence occurred after a mean of 4.3 years and the range was one to 23 years, while in the old group, the mean was 3.8 years, and the range was one to 14 years. The most primary cancer subtype recorded was triple-negative (41.85%): 50 old patients and 27 young. Next was the Her-2/neu enriched subtype (27.72%): 35 old patients and 16 young, following this was luminal A subtype (21.19%): 27 old and 12 young. Last was the luminal B subtype (9.24%): 12 old patients and five young. Conclusions To conclude, in our series, the most common molecular subtype found in the recurrent cases was the luminal negative subtypes, with a relatively similar pattern across both age groups. The results of this study can be used as a basis for large prospective studies in our centre to further analyse the effect of molecular subtyping on the recurrence rates of BC.

Secretome of tumor-associated leukocytes augment epithelial-mesenchymal transition in positive lymph node breast cancer patients via activation of EGFR/Tyr845 and NF-κB/p65 signaling pathway.

Epithelial-mesenchymal transition (EMT) is an essential process in breast cancer metastasis. The aim of the present study was to determine the role of secretions of tumor-associated leukocytes (TALs) isolated from negative and positive lymph nodes (nLNs and pLNs, respectively) breast cancer patients in regulating EMT mechanism and the associated signaling pathways. We found an increased infiltration of TALs, which was associated with downregulation of E-cadherin and over-expression of vimentin in the breast carcinoma tissues of pLNs as compared to nLNs patients and normal breast tissues obtained from healthy volunteers during mammoplasty. Furthermore, TALs isolated from pLNs breast cancer patients secreted an elevated panel of cytokines by up to 2-5-fold when compared with those isolated from nLNs patients. Secretome of TALs of pLNs possessed higher TARC, IGF-1, IL-3, TNF-ß, IL-5, G-CSF, IL-4, and IL-1α with more than a fivefold compared to those of nLNs. Using the human breast cancer cell lines MCF-7 and MDA-MB-231, we found that cytokines secreted by TALs isolated from nLNs and pLNs breast cancer patients promoted EMT via upregulation of TGF-ß and vimentin and downregulation of E-cadherin at messenger RNA (mRNA) levels in both cell lines and at protein level in MCF-7. While TGF-ß is over-expressed by MDA-MB-231 seeded in media conditioned by secretome of TALs isolated from nLNs and pLNs breast cancer patients. The downstream TGF-ß signaling transcription factors, Snail, Slug, and Twist, known to be associated with EMT mechanism were over-expressed by MCF-7 and MDA-MB-231 seeded in media conditioned by secretome of TALs isolated from nLNs and pLNs breast cancer patients. Acquisition of EMT in MCF-7 cells is mechanistically attributed to the activation of EGFR(Tyr845) and NF-κB/p65(Ser276) signaling which are significantly highly expressed by MCF-7 cells seeded in media conditioned by secretome of TALs isolated from pLNs compared to nLNs patients. Overall, this study provides implications of secretome of TALs and activated EGFR(Tyr845) and NF-κB/p65(Ser276) in EMT process that may be considered a therapeutic strategy to inhibit lymph node metastasis in breast cancer patients.

Viral genomes and antigen detection of hepatitis B and C viruses in involved lymph nodes of Egyptian non-Hodgkin's lymphoma patients.

Several studies have suggested an association between Hepatitis C and B viruses (HCV and HBV) and non-Hodgkin's lymphoma (NHL). In the present study we have searched for viral genomes and antigens in the malignant lymphoma tissues as well as their seroprevalence. Antibodies against Hepatitis C as well as HCV RNA and hepatitis B surface antigen (HBsAg) were determined for 29 newly diagnosed non-Hodgkin's lymphoma patients using an enzyme linked immunosorbent assay (ELISA), as well as RT-PCR and compared with 36 apparently healthy individuals as a control group for viral markers. Immunohistochemical staining (IHC) was performed on paraffin embedded tissues for the NS3 of HCV and for HBsAg of HBV using the immunoperoxidase technique. Paraffin embedded lymph nodes (LN) were studied for the presence of viral sequences. Ten non-metastatic lymph nodes (LN) from cancer cases other than NHL were used as a control for IHC and molecular studies. HCV was significantly more encountered in patients with NHL when compared to controls for both antibodies (27.6% versus 8.3% of serum controls; p = 0.04), and antigens studied by IHC in the involved LN (41% versus 10% of tissue controls; p = 0.06). Although HBsAg positivity was not different in NHL patients when compared to controls (6.9% and 2.7%); yet it was significantly more encountered in LN of NHL patients (p = 0.04). HBV-DNA was detected in 27.5% of patient's samples and none of the controls. In conclusion, overall our findings confirm the presence of HBV and HCV antigens and viral sequences in the involved LNs of NHL patients, except for HCV RNA which perhaps necessitates fresh and not paraffin embedded tissues. These results strengthen the assumption that these viruses may be involved in the development of NHL.