Ana Elisa Lohmann1,2, Mira F Liebman3, William Brien4, Wendy R Parulekar5, Karen A Gelmon6, Lois E Shepherd5, Jennifer A Ligibel7, Dawn L Hershman8, Priya Rastogi9, Ingrid A Mayer10, Timothy J Hobday11, Julie Lemieux12, Alastair Mark Thompson13, Kathleen I Pritchard14, Timothy Joseph Whelan15, Som D Mukherjee15, Haji I Chalchal16, Vanessa Bernstein17, Vuk Stambolic18, Bingshu E Chen5, Pamela Jean Goodwin19,20. 1. Department of Medicine, Division of Medical Oncology and Hematology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, 1284-600 University Ave, Toronto, ON, M5G 1X5, Canada. 2. Department of Medicine, Division of Clinical Epidemiology, University of Toronto, Toronto, ON, Canada. 3. Children's Hospital of Eastern Ontario, Ottawa, ON, Canada. 4. University Health Network, University of Toronto, Toronto, ON, Canada. 5. Canadian Cancer Trials Group (CCTG), Cancer Research Institute, Queen's University, Kingston, ON, Canada. 6. British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada. 7. Dana-Farber Cancer Institute, Boston, MA, USA. 8. Columbia University Medical Center, New York, NY, USA. 9. National Surgical Adjuvant Breast and Bowel Project and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. 10. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA. 11. Mayo Clinic College of Medicine, Rochester, MN, USA. 12. Centre Hospitalier Universitaire de Québec, Quebec, QC, Canada. 13. Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. 14. Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, ON, Canada. 15. Juravinski Cancer Centre, Hamilton, ON, Canada. 16. Allan Blair Cancer Center, Regina, SK, Canada. 17. British Columbia Cancer Agency, Vancouver Island Center, University of British Columbia, Vancouver, BC, Canada. 18. Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada. 19. Department of Medicine, Division of Medical Oncology and Hematology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, 1284-600 University Ave, Toronto, ON, M5G 1X5, Canada. pamela.goodwin@sinaihealthsystem.ca. 20. Department of Medicine, Division of Clinical Epidemiology, University of Toronto, Toronto, ON, Canada. pamela.goodwin@sinaihealthsystem.ca.
Abstract
BACKGROUND:Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples. METHODS:VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels <181 pmol/L were considered deficient, 181-221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels <222 pmol/L. Statistical analyses used Spearman's rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables. RESULTS:237 patients receivedmetformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively (p = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm (p = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 <181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) (p = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124-137), and placebo arms, 131 g/L (124-137) (p = 0.38), and at 6 months, metformin, 131 g/L (91-162), and 131 g/L (106-169) in placebo group (p = 0.11). Of the 74 subjects with vitamin B12 <222 pmol/L at either time point (45metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (>15μmol/L). At 6 months, one patient (metformin) had MMA >0.4μmol/L and 3 (2 metformin, 1 placebo) had HC > 15μmol/L. CONCLUSIONS: There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.
RCT Entities:
BACKGROUND:Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples. METHODS:VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels <181 pmol/L were considered deficient, 181-221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels <222 pmol/L. Statistical analyses used Spearman's rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables. RESULTS: 237 patients received metformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively (p = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm (p = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 <181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) (p = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124-137), and placebo arms, 131 g/L (124-137) (p = 0.38), and at 6 months, metformin, 131 g/L (91-162), and 131 g/L (106-169) in placebo group (p = 0.11). Of the 74 subjects with vitamin B12 <222 pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (>15μmol/L). At 6 months, one patient (metformin) had MMA >0.4μmol/L and 3 (2 metformin, 1 placebo) had HC > 15μmol/L. CONCLUSIONS: There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.
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