الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
In This Prospective Study, 107 Non- Diabetic MBC Females Were Collected from South Egypt Cancer Institute (SECI), Assiut University. The Study Was Carried Out During The Period Extending from June 2020 To July 2021. All Studied Subjects Were Divided Into 2 Groups. group A (N=57) Received Metformin (500 Mg Twice Daily) In Addition To Chemotherapy According To Fixed Protocol At SECI For Six Months. group B (N=50) Received Chemotherapy Alone According To Fixed Protocol At SECI For Six Months.
Even If Chemotherapy Was Changed Or Discontinued Prior To Disease Development Or When The Patient Experienced Unacceptable Toxicity, The Treatment Was Continued Until There Was Evidence Of Progressive Disease.
The Aim Of The Study Was To Assess The Effect Of Metformin As An Adjuvant Therapy In MBC Patients Underwent Chemotherapy As Regard To RR After 6 Months And PFS After 1 Year, Additionally, To Estimate The Effect Of Metformin On IGF-1 Which Initiates The Proliferation Of Cancer Cells And The Resistance Of Tumors To Chemotherapy.
Several Demographic And Clinic-Pathological Data Were Collected from Patients Sheets In Both Groups At Baseline Including Age, Pathology (IDC Or ILC), Pathological Grade, Menopausal Status, Body Mass Index (BMI), Tumor Markers (CEA, CA 15-3), Molecular Subtypes As ER, PR, HER2neu And HER2neu Overexpression Routinely Reported from Pathology Department Using Immunohistochemistry, Pathological Types Of Breast Cancer As Luminal A, Luminal B, Triple Negative. Furthermore, The Site Of Metastasis Either Visceral Or Non Visceral Metastasis And Number Of Metastasis.
Patients Were Followed Up On Taking Metformin Tablets By Phone, And They Were Seen When They Came To The Hospital To Take Chemotherapy Doses, As The Remaining Tablets Were Counted And Their Doses Were Completed For Other Days.
Response Rate (RR) Were Assessed At Baseline As Well As After Six Months (Pre And Post-Treatment) Using Computed Tomography Imaging That Was Carried Out For The Chest, Abdomen, And Pelvis To Assess Tumor Status.
Laboratory Tests Such As Kidney Function Test, Liver Function Test And CBC Were Assessed During Schedule Visits Of Studied Participants To Receive Chemotherapy Treatment.
In Addition, Many Adverse Events Including Heartburn, Abdominal Pain, Physical Weakness, Flatulence, Muscle Pain, Upper Respiratory Tract Infection (URTI), Hypoglycemia, Diarrhea, Weight Loss, Headache, Unpleasant Taste, Nausea And Vomiting, Dyspnea, And Anorexia Were Evaluated Among Patients In group A Within Follow Up Period Via Telephone And During Schedule Visits To Receive Chemotherapy Treatment Using Symptoms Checklist (Yes Or No) Done In Excel Sheet.
Furthermore, PFS Which Is Defined As The Time from Random Assignment In A Clinical Trial To Disease Progression Or Death from Any Cause Was Assessed After 1 Year Of Follow Up In Both Groups.
Moreover, IGF-1 Concentrations Were Assessed At Baseline And After 6 Months Of Treatment In Both Groups. ROC Curve Was Used To Show The Ability Of IGF-1 Hormone For The Prediction Of Progression Disease Among MBC Patients. According To The Cut Off Value, IGF Concentrations Were Divided Into High IGF group And Low IGF Group. Also Metformin Dose Level Was Assessed Among group A Patients After 2 Hr Of Administration Of Metformin After 6 Months Of Treatment.
Blood Samples Were Collected from Both Groups At Baseline And After 6 Months, After Allowing The Samples To Coagulate; The Plasma Was Separated By Centrifugation At 4000 Rpm For About 10-15 Minutes And Collected In Eppendorf Tubes. They Were Finally Kept At -80° C For Further Assessments As Detection Of Metformin Dose Level In group A Was Done In The Pharmacology Unit, Tumor Biology Department In The National Cancer Institute (NCI)-Cairo University Using The LC-MS-MS System Consisted Of Agilent 1200 HPLC System (Agilent Technologies, CA, USA) Coupled To ABSCIEX Q TRAP 3200 Mass Spectrometer (ABSCIEX, Dramstadt, Germany) As Well As Assessment Of IGF-1 Level In Both Groups Using ELISA Kits.
In Terms Of All Demographic Data, There Was No Significant Difference Between The Two Groups (P > 0.05). As Regard To RR That Was Assessed In In group A (N=51) And group B (N=47) After 6 Months, Metformin As Adjuvant Therapy Didn’t Show Any Improvement In Response Compared To Controlled group (P = 0.068). After Assessment Of Metformin Concentration In group A (N=51), The Mean Of Metformin Level Was Found To Be 2.41±0.52, 2.13±0.59 And 2.11±0.63 In RD, SD And PD Patients, Respectively With No Significant Difference (P = 0.284).
During The Follow-Up Period, A Symptom Checklist Was Completed. The Most Common Symptoms Were Abdominal Pain (36.8%), Diarrhea (33.3%), Anorexia, Nausea, And Vomiting (24.6%), Weight Loss (17.5%), Heartburn (17.5%), Dyspnea (14%), Headache (12.3%), Unpleasant Taste (12.3%), Muscle Pain (10.5%), Physical Weakness (8.8%), Flatulence (8.8%), And URTI (8.8%), And No Patient Had Hypoglycemia (0%). These Symptoms Persisted For About 2-3 Weeks Before Subsiding With The Passage Of Time. According To The Present Results There Was No Significant Correlation Between Metformin Concentrations And Their Adverse Effects Among Participants (P > 0.05).
During The One-Year Follow-Up Period, The Median Progression-Free Survival For Patients In group A Who Received Chemotherapy And Metformin Was 5 Months Versus 4 Months For Patients In group B, With No Significant Difference (P =0.753).
After Assessment Of IGF-1 Level In Both Groups At Baseline And After 6 Months, We Found That The Mean IGF Concentration At Baseline In group A Was 40.74±36.16, Whereas Mean IGF Concentration At Base Line In group B Was 32.06±20.00, With No Significant Difference Between Two Groups In IGF Concentration At Baseline (P1 = 0.462), While The Mean IGF Concentration After 6 Months In group A Was 37.62±31.35, Whereas Mean IGF Concentration After 6 Months In group B Was 39.12±25.93, With No Significant Difference Between Two Groups In IGF Concentration After 6 Months (P1 = 0.170). Mean IGF Concentration At Baseline In group A Was 40.74±36.16, Whereas The Mean IGF After 6 Months Of The Same group (group A) Was 37.62±31.35, With No Significant Difference Between IGF Concentrations Among The Same group (group A) At Baseline And After 6 Months. (P2 = 0.357), While The Mean IGF Concentration At Baseline In group B Was 32.06±20.00, Whereas Mean The IGF After 6 Months Of The Same group (group B) Was 39.12±25.93, With A Significant Difference Between IGF Concentrations Among The Same group (group B) At Baseline And After 6 Months (P2 = 0.006), It Was Shown That IGF Concentration Of group B Who Received Chemotherapy Alone Increased After 6 Months As Compared With Its IGF Concentration At Baseline.
The Current Study Found No Significant Difference Between The Two Studied Groups In Terms Of IGF Analysis At Baseline And After 6 Months. Metformin Had No Beneficial Effect On IGF Levels In Metastatic Breast Cancer Patients Receiving Chemotherapy, Which Could Be Attributed To An Increased Number Of Progressive Patients In Both Groups. There Is A Link Between Progressive Disease And Higher IGF Levels Because IGF Stimulates Tyrosine Kinase Receptors, Which Then Activate The Mapkinase And PI3K-Akt Pathways, Promoting Cancer Cell Proliferation And Survival As Well As Resistance To Chemotherapy In Breast Cancer.
The ROC Curve Was Used To Assess IGF’s Predictive Ability For Predicting Progression Of Disease In Patients With Metastatic Breast Cancer (MBC). The Area Under The ROC Curve Was 80.1%, Indicating That IGF Was A Significant Predictor Of Progression In Patients With Metastatic BC (P = 0.000).
According To The Above Mentioned Cut Off Value (17.1), We Divided The IGF Concentration Into Two Categories (Low IGF < 17.1, N=25) And (High IGF ≥ 17.1, N=73), As Regard To Demographic Data, We Observed That There Was No Significant Difference Among Both Groups (P >0.05).
The Low IGF MBC Patients With RD Response Were About (24%) Versus (20.5%) In MBC Patients With High IGF, While MBC Patients With SD Response Who Had Low IGF Were About (64%) Versus (37%) In MBC Patients With High IGF, And MBC Patients With PD Response Who Had Low IGF Were About (12%) Versus (42.5%) In MBC Patients With High IGF, With A Significant Difference Between Two Groups (P = 0.017).
Progression Free Survival According To IGF Biomarker, It Was Found That The Mean PFS At 1 Year In The Low IGF group Was Approximately 60.0±9.8% Versus 12.3±3.8% In The High IGF Group, Indicating A Significant Difference Between The Two Groups In Terms Of MBC Patients With Low IGF Having Better PFS Than MBC Patients With High IGF (P = 0.000).
We Divided MBC Patients (Groups A And B) Into Progressive And Non-Progressive Groups And Indicated That The Mean IGF Concentration At Baseline Was About 37.31±30.80 In Progressive Patients Versus 34.52±27.09 In Non-Progressive Patients, With No Significant Difference Between Them (P1 = 0.982), While The Mean IGF Concentration After 6 Months In Progressive Patients Was Approximately 43.91±29.41 Versus 20.72±18.22 In Non-Progressive Patients, With A Significant Difference Between Them (P1= 0.000), While The Mean IGF Concentration At Baseline Was About 34.52±27.09 In Non-Progressive Patients Versus 20.72±18.22 After 6 Months, With A Significant Decrease In IGF Concentration Among Non- Progressive Patients At Baseline And After 6 Months (P2=0.002), While The Mean IGF Concentration At Baseline Was About 37.31±30.80 In Progressive Patients Versus 43.91±29.41 After 6 Months, With A Significant Increase In IGF Concentration Among Progressive Patients At Baseline And After 6 Months (P2= 0.000). When Compared To Baseline And Non-Progressive Patients, All Patients With Progression Disease, Whether In group A Or B, Have A Significant Increase In IGF Levels.
Conclusion
This Prospective Study Found That Using Metformin As An Adjuvant To Chemotherapy In Metastatic Breast Cancer Patients Had No Benefit On RR Or PFS, And More Research Is Needed To Confirm Or Refute The Findings. Metformin Concentrations Were Compared On The Basis Of The Response Status Of The Studied Subjects But Not Statistically Significant Difference. Furthermore, Metformin Use In This Study Was Tolerable, With No Serious Side Effects That Would Have Necessitated Treatment Discontinuation.
Metformin Showed No Significant Effect On IGF-1 Level Among MBC Females. This May Be Attributed To The Increased Number Of Progressive Patients In Both Groups. Also, IGF Was A Significant Predictor Of Progression In Patients With Metastatic BC. As Regard To RR, It Was Found That There Was A Significant Difference Between MBC Patients With High IGF And MBC Patients With Low IGF.
According To PFS, MBC Patients With Low IGF Showed Better PFS Than MBC Patients With High IGF. All Patients With Progressive Disease, Whether In group A Or B, Have A Significant Increase In IGF Levels.