الفهرس 
Anatomy and Histology of the breastOnly 14 pages are availabe for public view
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Abstract
Breast cancer (BC) is the second most common type of cancer and the most common cancer in women.
Programmed death ligand-1 (PD-L1) is a transmembrane protein, found in a variety of normal tissue cells and also a wide range of epithelial malignancies, including breast carcinoma. Binding of PD-L1, expressed on tumor cells, to its receptor PD-1, expressed on activated T cells and B cells, disrupts effector immune functions.
Antibodies targeting PD-L1 have been approved for treating a wide range of malignancies including breast cancer especially unresectable and metastatic triple negative breast cancer (TNBC). However, PD-L1 expression and its prognostic role in BC is still the target of several research in order to maximize its therapeutic role in different clinicopathological settings.
The aim of this study is to evaluate immunohistochemical expression of PD-L1 in tumour cells (TCs) and tumour infiltrating lymphocytes (TILs) in different types of breast carcinoma and to correlate between PD-L 1 expression and clinicopathological variables.
In our study, Ninety cases of breast carcinoma mastectomy specimens were collected and stained immunohistochemically for PD-L1, PD-L1 expression was evaluated in TCs and TILs in the two settings of cases; (group A) in which the patients didn’t receive preoperative neoadjuvant chemotherapy (NAC) and (group B) in which the patients received preoperative NAC. The expression of PD-L1 was correlated with clinicopathologic parameters. Survival analysis was conducted to correlate disease-free survival (DFS) with PD-L1 expression.
In our study, the mean age of patients was 51.044 years. As regards the history of neoadjuvant chemotherapy: Sixty-one (61) (67.8%) of cases didn’t receive neoadjuvant chemotherapy (group A), while twenty-nine (29) (32.2%) of cases received neoadjuvant chemotherapy (group B).
Regarding the cases of group A (Those didn’t receive preoperative NAC); (31.1%) of cases showed PD-L1 expression by tumor cells (TCs) and (47.5%) of cases showed PD-L1 expression by tumor infiltrating lymphocytes (TILs).
PD-L1 expression in TCs and TILs were statistically significant associated with histologic type of invasive duct carcinoma, NST (p= 0.01) and (p= 0.001) respectively, grade 2 (p= 0.03) and (p= 0.01) respectively, absence of carcinoma in situ (p= 0.03) and (p= 0.02) respectively, negative ER expression (p= 0.05) and (p= 0.003) respectively, negative PR expression (p= 0.03) and (p=0.003) respectively, high proliferation index (Ki-67) (p<0.001) and (p= 0.02) respectively, molecular subtype of triple negative breast cancer (TNBC) & HER2 positive (p= 0.02) and (p= 0.001) respectively and high level of TILs (p= 0.01) and (p= 0.001) respectively.
Regarding the cases received preoperative NAC (group B); (13.8%) of cases showed PD-L1 expression by tumor cells and (41.4%) showed PD-L1 expression by tumor infiltrating lymphocytes.
PD-L1 expression in TCs was statistically significant associated with high level of TILs infiltration (p= 0.04). While PD-L1 expression in TILs was statistically significant associated with presence of carcinoma in situ (p= 0.01), negative ER expression (p< 0.001), negative PR expression (p= 0.002), high proliferation index (Ki-67) (p=0.05) and molecular subtype of TNBC (p< 0.001).
In this study, The patients were followed up in the Oncology department for a period from 3 months up to 58 months to detect any recurrence of the tumor or death of patients.
During the period of follow up, the mean overall survival (OS) of group A cases was 31.1 months, while the mean of overall survival (OS) of group B was 20.97 months.
During the period of follow up, the mean disease-free survival (DFS) of group A cases was 26.77 months, while the mean disease-free survival (DFS) of group B cases was 20.41 months
In this study, The correlation between PD-L1 expression in TILs, TCs in both groups A & B and DFS was statistically insignificant.
However, Using Cox regression analysis, Only in group B cases, PD-L1 immunohistochemical expression in TILs was the only factor that had an independent prognostic significance (hazard ratio= 4.6, p value= 0.042).
from this work we conclude that:
• Breast carcinoma in both patients who didn’t receive neoadjuvant chemotherapy (NAC) and who received neoadjuvant chemotherapy (NAC) shows PD-L1 immunohistochemical expression on both tumor cells (TCs) and tumor infiltrating lymphocytes (TILs). However, the PD-L1 expression is much more prevalent in tumor infiltrating lymphocytes (TILs) than tumor cells (TCs).
• PD-L1 expression was significantly associated with high TILs level. Thus, The detection of increased TILs in the routine hematoxylin and eosin (H&E) tissue sections is an indicator of possible PD-L1 expression in the tumoral tissue and recommends the importance of immunohistochemical study to detect the PD-L1 in the breast tissue.
• The statistically significant correlation which was detected between PD-L1 expression in TILs and negative hormonal receptors in both group A and group B suggests that hormonal receptor negative breast carcinoma (ER -ve & PR -ve) may be another field for check point inhibitor immunotherapy.
• The significant expression of PD-L1 in both triple negative and Her2 positive molecular subtypes of breast carcinoma suggesting an important role of PD-L1 inhibitors in their management.
• PD-L1 expression in TILs and TCs is significantly correlated with high proliferative activity (Ki-67).
• Although, No statistically significant value was detected in both group A and group B as regarding the expression of PD-L1 in both (TILs and TCs) and the mean disease-free survival (DFS) yet, the mean DFS was rather longer in patients with negative expression of PD-L1 than in patients with positive PD-L1 expression.
• Multivariate Cox regression analysis showed PD-L1 immunohistochemical expression in TILs in patients received neoadjuvant chemotherapy (NAC) was significantly associated with (DFS) indicating that PD-L1 expression in TILs is independent prognostic factor in case of NAC setting.
• Future studies on a larger number of breast cancer patients of different molecular subtypes are recommended to better assess the value of immunotherapeutic agents in treatment regimens for breast cancer patients and to evaluate the impact of PD-1/PD-L1 inhibitors on treatment outcomes in eligible patients.
• We recommend more studies to approve and standardize a scoring system and to set a cut-off value for determining the positivity of PD-L1 expression in breast carcinoma cases to attain the most accurate and objective results.
• Although the increase of the level of PD-L1 expression may be an important risk factor, yet blockage of PD-1/PD-L1 pathway with monoclonal antibodies against PD-1 or PD-L1 may be a promising therapeutic approach that is currently being used in breast carcinoma.
• Because the survival is less good in group B who receive neoadjuvant chemotherapy (NAC), we suggest that immunotherapeutic treatment may be used as a trial could be effective in these patients.
• More studies are recommended to compare between PD-L1 expression in pre-NAC and post-NAC settings of the same patients to study the effect of chemotherapy on PD-L1 expression.
• Our study revealed statistically significant correlation between increase PD-L1 expression in TILs in patient having an associated in situ carcinoma. This is group B; thus, this study recommends immunohistochemical staining for patients with breast carcinoma with in situ component, this is to verify if there is any expression of PD-L1 in in situ carcinoma to suggest any possible role for PD-L1 inhibitor in treatment of early breast cancer.