1) This study examined the effect of metformin on chemotherapy-induced toxicities in non-diabetic breast cancer patients receiving an AC-T regimen. 2) Patients receiving metformin plus AC-T experienced significantly less peripheral neuropathy, oral mucositis, fatigue, and liver/heart toxicity compared to the control group on AC-T alone. 3) Metformin may protect against some common toxicities of breast cancer chemotherapy without interfering with the chemotherapy's anti-cancer effects.

1. THE EFFECT OF METFORMIN ON
CHEMOTHERAPY-INDUCED TOXICITIES IN NON-
DIABETIC BREAST CANCER PATIENTS: A
RANDOMIZED CONTROLLED STUDY
-ADNAN SHAIKH
PharmD 5th Year

2. BACKGROUND INFORMATION
• Breast cancer (BC) is the most common type of cancer in females in Egypt and worldwide. In
2020, the prevalence of BC in egypt was 121 per 100,000 Egyptian females.
• Adriamycin (doxorubicin) combined with cyclophosphamide, followed by weekly paclitaxel
(i.e.,AC-T) regimen is commonly used in egypt in the neoadjuvant and adjuvant treatment of
BC.
• Adverse effects:
1) Paclitaxel....peripheral neuropathy,
2) Doxorubicin....Cardiotoxicity is a major life-threatening AE that can progress to
irreversible CHF
3) Toxicity of AC-T.....oral mucositis regimen appears in 77% of the patients.
4) The combination of doxorubicin and cyclophosphamide causes a 3-fold increase in the risk
of oral mucositis compared to individual drugs.
oral mucositis reduces food intake and body immunity, and fatigue.

3. BACKGROUND INFORMATION
• The antidiabetic drug metformin has been shown to
favourably reprogramme molecular and cellular pathways.
• Metformin is largely attributed to the upregulation of
adenosine monophosphate-activated protein kinase
(AMPK)
• Oncology research has established antitumor benefits for
metformin including its ability to reduce metastasis risk.

4. THE NEED FOR THIS STUDY
• To date, NO effective pharmacologic therapies have been identified to prevent to treat the
mentioned chemotherapy-induced toxocities.
• Management of PIPN is limited to symptomatic treatment with painkillers.
• Numerous medication have proposed for chemotherapy-induced oral mucositis,but not has
proven completely beneficial.
• No current therapies has proven effective in alleviating cancer-related fatigue.

5. STUDY OBJECTIVES
In the current randomized clinical trial, they tested the
hypothesis the simultaneous administration of metformin
rectifies the AEs caused by the neoadjuvant AC-T regimen
in chemotherapy-naive non-diabetic BC patients.

6. AUTHORS AFFILIATION/CONFLICTS OF INTEREST
* Manar A. Serageldin
s-manar.serageldin@alexu.edu.eg
1 Department of Pharmacology and Toxicology, Faculty
of Pharmacy, Alexandria University, Alexandria, Egypt
2 Department of Clinical Pharmacy and Pharmacy Practice,
Faculty of Pharmacy, Damanhour University, Damanhour,
Egypt
3 Oncology Department, Medical Research Institute,
Alexandria University, Alexandria, Egypt
4 Department of Pharmacology and Toxicology, Faculty
of Pharmacy, Damanhour University, Damanhour, Egypt
5 Department of Pharmacology and Toxicology, College
of Pharmacy, Arab Academy for Science, Technology
and Maritime Transport, Alexandria, Egypt
6 Department of Pharmacology and Toxicology, College
of Medicine, Kuwait University, Kuwait City, Kuwait

7. Arm Intervention/treatment
Experimental: Metformin group
Patients will recieve AC-T neoadjuvant
chemotherapy in addition to oral metformin HCl
(850mg tab,twice per day, for 6 months) (n=30)
Drug Metformin Hydrochloride 850mg tablets
oral administration of metformin hydrochloride
850mg tablets (1700mg/day) daily until the
completion of neoadjuvant chemotherapy cycles
Drug AC-T chemotherapy regimen
AC: (Doxorubicin 60mg/m2 IV + cyclophosphamide
600mg/m2 IV) for 4 cycles every 3 weeks followed by
taxol cycles (Paclitaxel 80mg/m2 IV) once weekly for
12 weeks.
Other Name: AC (doxorubicin+cyclophosphamide)
followed by paclitaxel
Active Comparator: Control group
Patient will recieve AC-T neoadjuvant chemotherapy
alone (n=30)
Drug AC-T Chemotherapy regimen

8. INCLUSION CRITERIA
• Females greater then equal to 18 years of age and <65
years.
• Unilateral or bilateral primary carcinoma of the breast
confirmed.
• Clinically measured tumor size who are candidates for
neoadjuvant therapy.
• No evidence of distant metastasis.
• Normal liver and renal function.
• Non-Diabetic.

9. Exclusion Criteria
• Pregnant or breast feeding women.
• Prior cancer chemotherapy.
• Heart disease or reduced CO with left ventricular ejection
fraction <50%
• Metastasis breast cancer patients.
• Diabetics
• Patient with hepatic an renal impairment.

11. PRIMARY/SECONDARY ENDPOINTS
Primary outcome Measures:
-Evaluation of the effect on tumor apoptosis[Time Frame:6 months]
Tissue level of apoptosis biomarker in the excised tumor.
- Chemotherapy toxicities [Time Frame: 6 months]
- Monitoring the incidence of the chemotherapy toxicities during neoadjuvant therapy.
Secondary outcome measures:
-Pathologic complete response rate (pCR) (6 months)
-Pathologic complete response rate is defined as the absence of residual invasive cancer in the
resected breast specimen and all sampled regional lymph nodes following completion of
neoadjuvant systemic therapy.

12. STASTICAL ANALYSIS
• All stastical analysis were performed using stata version 14.2
• For interval variables ,Shapiro-Wilk test was used to inspect data normality.
• Levene’s test was used to check the equality of variance between arms.
• Pearson’s Chi-square,or fisher’s exact tests were used as appropriate for categorical
variables.
• To detect the difference in the severity grades of different AEs (i.e..,peripheral
neuropathy,oral mucositis,fatigue,gastrointestinal,and heamatological ADR) between the two
arms at each time point,the Mann-Whitney U test was used.
• The odds ratio (OR) with 95% confidence interval(CI) was reported.

13. PATIENTS BASELINE CHARACTERISTICS

15. RESULTS
• Addition of metformin to AC-T resulted in significantly less incidence and severity of
peripheral neuropathy,oral mucositis,and fatigue (p<0.05) compared to the control arm.
• Moreover the left ventricular ejection fraction (LVEF%) in the control arm dropped from a
mean of 66.69+-4.57 to 62.2+-5.22(p=0.0004)versus a preserved cardiac function in the
metformin arm (64.87+-4.84 to 65.94+-3.44%,p=0.2667)
• Furthermore,fatty liver incidence was significantly lower in the metformin compared with
control arm(8.33%vs 51.85, p=0.001).
• By contrast, heamatological disturbances caused by AC-T were preserved after concurrent
metformin administration (p>0.05)

16. RESULT

17. DISCUSSION
• This is the first randomized controlled trial to endorse a protection effect of metformin on
PIPN, oral mucositis, fatigue, cadiotoxicity, and hepatotoxicity induced by AC-T
chemotherapy regimen.
• Metformin displays on anti-neuroinflammatory effect in spinal cord-injured rats comparable to
that of minocycline,the tetracycline antibiotic with potent neuroprotective properties.
• In another invivo study, metformin reverses the structural brain plasticity that accompanies
neuropathic pain.
• In one clinical study undertaken in patients with stage III colorectal cancer,metformin was
found to reduce peripheral neuropathy induced by oxaloplatin.
• The metformin arm had a significantly lower incidence of and less severe oral mucositis
during the entire neoadjuvant treatment period.

18. LIMITATIONS
• This study was an open-label randomized control study.
• However,the implementation of allocation concealment and the blind outcome assessment
for hematological toxicity,cardiotoxicity and hepatotoxicity may have reduced bias in the
estimated effect of treatment.
• Also, result may have been reinforced by measuring specific confirmatory biomarker for AC-T
induced toxicities.

19. CONCLUSION
• Metformin offers a therapeutic opportinuty for controlling
toxicities caused by neoadjuvant chemotherapy in non-
diabetic breast cancer.