الفهرس 
TitleOnly 14 pages are availabe for public view
 |  | from | 131 |  |  |
| | | from | 131 | | |
Abstract
Breast cancer is the most common cancer and leading causes of death in females all
over the world. The incidence of breast cancer has increased steadily in past decades, but
the mortality of breast cancer appears to be declining, perhaps as a results of the great
progress that has been made in the management of breast cancer.
The immune suppression/evasion of malignant cancer cells is known as one of the
hallmarks of malignant. A theories of co-inhibitory and co-stimulatory receptors and their
ligands, known as immune checkpoints which control this process. Among them,
programmed cell death-1 (PD-1) and programmed cell death ligand (PD-L1) axis, which
plays a key role in physiological immune homoeostasis and represents a mechanism of
immune escape.
Phosphoinositid 3- kinases are a family of lipid kinases that respond to nutrition,
hormones and other environmental factors, and integrate extracellular stimuli into
intracellular signals that regulate many biological functions, including cell proliferation,
survival, differentiation, metabolism and migration. . Increased activity of the PI3K
pathway has been linked with breast cancer tumorigenesis, drug resistance and clinical
outcome.
Therefore, this study aimed to evaluate the role of programmed death-1 receptor and
programmed death ligand-1 (PD-1/PD-L1) expressing peripheral blood mononuclear cells,
as a potential mechanism of immune escape in breast cancer patients. Also, serum levels of
PI3K were analyzed among patients with different stages of breast cancer. In addition, all
parameters were correlated with each other and with clinicopathological parameters of the
disease.
The study was conducted on a total of sixty females: forty-five of them represented
the breast cancer females at stage I (8 females), stage II (14 females), stage III (16
females), stage IV (7 females) and 15 age matched female donors represented the control
group. Female patients were recruited from the Cancer Research and Management
Department, Medical Research Institute, Alexandria University. Venous blood samples
obtained from all females under study were used for determination of PD-1/PD-L1
expression using flowcytometry technique and measurement of PI3K serum levels using
ELISA technique.
There was no significant difference between patients and control regarding to age.
The majority of patients were stage III and grade II. The lymph node involvement (N1)
was the commonest among all breast cancer patients and the most all patients belonged to
invasive ductal carcinoma (IDC).
Summary, Conclusion and Recommendations
88
Regarding hormonal status (ER, PR and Her-2), our results showed no significant
changes between different stages of breast cancer patients. Concerning the positivity and
negativity of hormonal status in all patients (71.1%) of patients were negative for Her-2
relative to (28.9%) of patients were positive for Her-2.
According to hormonal status of our patients the results showed that (15.6%) of cases
were triple-negative (TNBC), while (84.4) of cases were non-TNBC.
Regarding to the positivity and negativity of PD-1/PD-L1, the flowcytometry results
revealed that, 17.8% of total breast cancer patients were negative for PD-1 relative to 82.2% of
patients were positive for PD-1, while 100% of control subjects were positive for PD-1.
Whereas, 44.4%, of total patients were negative for PD-L1 relative to 55.6% of
patients were positive for PD-L1. While in control group 20% were positive for PD-L1
relative to 80% were negative for PD-L1.
According to the percentage and MFI of positive PD-L1 expression on peripheral
blood mononuclear cells, our results showed a significant increase between the breast
cancer patients and control group regarding the percentage and MFI of positive
PD-L1 expressing peripheral blood mononuclear cells.
According to our results, patients with positive lymph node, advanced tumor stage,
histological grade III, tumor size T3, ER-, PR- and Her-2- tend to have higher PD-L1
expression levels than patients without lymph node metastasis, lower histological grades or
early stage and ER, PR and Her-2 positivity. The former group of patients may benefit
more from treatment targeting the PD-1/PD-L1 pathway.
Regarding PD-1 positive expression, the results revealed that a significant increase
between the breast cancer patients and control group regarding percentage and MFI of
positive PD-1 expressing peripheral blood mononuclear cells. Also the results showed a
significant association between PD-1+ and PD-L1+ expression in early and advanced
breast patients.
In our study, 71.4% of TNBC patients were PD-L1 positive relative to 52.6% of non-
TNBC patients were PD-L1 positive.
The present study showed a significant increase in the mean of PI3K serum
concentration in patients compared to healthy individuals. In addition, there was a
significant increase in the mean of serum PI3K concentration in the advanced stage
compared to that in early stage.
Regarding the association between PI3K serum levels and clinical parameters our
results showed that, there was a positive correlation between PI3K and stage of breast
cancer, tumor size, lymph node involvement and vascular invasion.
Finally, the results showed that PI3K serum concentration correlated positively with
positive PD-1 and positive PD-L1.
However, till now only few studies have reported a possible link between
PD-1/PD-L1 and PI3K among breast cancer patients. Therefore, dysregulation of
PD-1/PD-L1 expression and increased PI3K serum concentration may involved in the
immunopathogenesis of breast cancer. Also, these markers may be used as target of
biological therapy to help in the treatment of breast cancer patients.
Summary, Conclusion and Recommendations
89
Conclusion
(1) Most of breast cancer patients were positive for PD-1 (82.2%) while all control
individuals were positive for PD-1 (100%).
(2) PD-L1 expression was higher in patients (55.6%) than control subjects (20%).
(3) PD-L1 expression increase in late stages of breast cancer.
(4) PD-1 and PD-L1 positive expressions were high in TNBC patients than that of
Non-TNBC patients.
(5) PD-1 and PD-L1 are considered important prognostic indicators of breast cancer
as there was a high significant increase in the percentage and MFI of their
expression in breast cancer patients.
(6) PI3K serum concentration was higher in patients than that of control individuals.
(7) There was significant increase in the mean of serum P13K concentration in the
advanced stages compared to that in early stages that may indicated its role in
tumorigenesis, drug resistant and clinical outcome of breast cancer.
(8) There was a significant positive correlation between P13K serum concentration
and positivity of PD-1 and PD-L1.