JOURNAL CLUB 01/03/2012

DEPARTMENT OF MEDICAL ONCO MADRAS MEDICAL COLLEGE CHENNAI DR. R. RAJKUMAR

METFORMIN AND CANCER 1970-PROFESSOR VLADIMIR DILMAN

METFORMIN AS GEROPROTECTORS (METABOLIC REHABILITATION) & ANTI CANCER DRUGS.

2000-ANISIMOV- PETROV INSTITUTE OF ONCOLOGY -chronic treatment of female transgenic HER2/neu mice -↓mammary adeno carcinomas.

“HYBRID ANTI CANCER PILL”- ↓ INSULIN &GLUCOSE , ↓ AMPK/mtor/S6K1 AXIS

METFORMIN AND CANCER

•BIGUANIDES- metformin, phenformin and buformin- herb GALEGA OFFICINALIS (French lilac)

•MECHANISM OF ACTION- DIRECT-INSULIN INDEPENDENT ACTIVATES AMPK –Energy sensor INDIRECT- INSULIN DEPENDENT

METFORMIN AND CANCER

DANDELION HYPOTHESIS

PATIENTS AND METHODS 3412 patients¹- Neo-adjuvant chemo-Jan 1990-May 2007. 291- Diabetic Exclusion Criteria- Diabetes diagnosed after neo-chemo Resolved GDM Male sex Unknown ER, PR, Her-2 status ˃ 9 months between neo-chemo and surgery Second primary cancer Final study population- 68 Diabetic

population(met) ,87(non met), 2374(Non Diabetic) ¹-Breast Cancer Management Database- University of Texas

PATHOLOGY Diagnosis- Core- needle biopsy Histology- WHO classification Tumor Grade- modified Blacks nuclear

grading IHC- nuclear grading >10%- positive Her-2 status- IHC or FISH HER -2 positive- 3 +

TREATMENT

3-6 courses of Anthracycline based chemo-FAC, AC, FEC

Add Taxane based chemo–1909 patients(75.5%)

Def. Surgery at the end of NACT. All patients- Axillary Staging & SLNB Radiation - Standard Hormonal- ER/PR status

STATISTICAL ANALYSIS χ² test of independence Multivariate logistic regression model

RESULTS

Median Age- 49 years (21- 87) Diabetic Group- Older, Obese , Post-Meno HbA1c- No Difference Insulin Use ˂ Met Group(16%v 33%,

p=.02) Neo-Taxane Use ˃ Diabetic Group

(87%=Met, 84%=Non Met, 75%=Non Diab,p=.01)

90% - Planned cycles of chemo

METFORMIN AND pCR RATES PCR Rate- MetGrop=24%;95%CI,(13%-34%) Non-Met=8.0%;95%CI,(2.3%-14%) Non-Diab=16%;95%CI(15%-18%) ( P=.02 ) Met &Non Met P=.007 Non Met & Non Diab P=.04 Met & Non Diabetic P=.10(non signfi)

SURVIVAL ESTIMATES Median Follow-up- 37 months 3yr RFS-

76%(95%CI),66%(95%CI),73%(95%CI)

P=.66( Not Significant) OS- 81%(95%CI),78%(95%CI),86%(95%CI) P=.02(Significant)

RATE OF PCR Met Group- Insulin v Non Insulin Use 27% v 23%; P=.75 Non Met - Insulin v Non Insulin Use 0% v 12%; P=.05

METFORMIN AND CANCER

ADVANTAGES-1. INEXPENSIVE- GENERIC2. WIDE THERAPEUTIC-TOXIC RATIO3. BROAD SPECTRUM ANTICANCER PILL4. SAFE IN POOR P.S. PATIENTS5. SAFELY COMBINED WITH CHEMO6. METRONOMIC THERAPY7. CHEMO-PREVENTION

HORMETIC PHENOMENON

THANK YOU