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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