Cancer risk in long-term users of valproate: a population-based case-control study

Jesper Hallas; Søren Friis; Lars Bjerrum; Henrik Støvring; Sverre Flatabø Narverud; Thomas Heyerdahl; Kirsten Grønbaek; Morten Andersen

doi:10.1158/1055-9965.EPI-08-0646

Cancer risk in long-term users of valproate: a population-based case-control study

Jesper Hallas, Søren Friis, Lars Bjerrum, Henrik Støvring, Sverre Flatabø Narverud, Thomas Heyerdahl, Kirsten Grønbaek, Morten Andersen

25 Citations (Scopus)

Abstract

BACKGROUND: Inhibitors of histone deacetylases (HDAC) have shown promise as targeted cancer therapy. Valproate, an older anticonvulsant, has been shown to possess HDAC inhibitory activity. We undertook this case-control study to clarify whether long-term users of valproate had a reduced cancer incidence. If so, it would support HDAC inhibition as a pharmacologic principle in chemoprevention. METHODS: We identified 149,417 incident cancer cases in Denmark during the study period 2000 through 2005, and 597,668 age- and gender-matched controls. Data on history of cancer, past hospital admission diagnoses, and prescription history were obtained from the Danish Cancer Registry, the Danish National Patient Registry, and the Danish Prescription Registry. Primary exposure to valproate was defined as a cumulative dose of minimum 1,500 g within the past 5 years. Confounders were controlled by conditional logistic regression. RESULTS: Among the cases and controls, 81 (0.05%) and 260 (0.04%), respectively, were long-term users of valproate. For cancer overall, the crude and adjusted odds ratios were 1.25 [95% confidence interval (95% CI), 0.97-1.60] and 1.21 (95% CI, 0.95-1.56), respectively. Subgroup analyses revealed no dose or duration effect for overall cancer incidence, and no specific cancer site was found to be inversely associated with long-term use of valproate. For lung cancer, we found a positive but imprecise association (adjusted odds ratio, 2.32; 95% CI, 1.12-4.79). CONCLUSION: Long-term valproate use is not associated with a reduced cancer risk. Our study does not support HDAC inhibition as a pharmacologic principle for general chemoprevention.

Original language	English
Journal	Cancer Epidemiology, Biomarkers & Prevention
Volume	18
Issue number	6
Pages (from-to)	1714-9
Number of pages	5
ISSN	1055-9965
DOIs	https://doi.org/10.1158/1055-9965.EPI-08-0646
Publication status	Published - 2009

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10.1158/1055-9965.EPI-08-0646

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title = "Cancer risk in long-term users of valproate: a population-based case-control study",

abstract = "BACKGROUND: Inhibitors of histone deacetylases (HDAC) have shown promise as targeted cancer therapy. Valproate, an older anticonvulsant, has been shown to possess HDAC inhibitory activity. We undertook this case-control study to clarify whether long-term users of valproate had a reduced cancer incidence. If so, it would support HDAC inhibition as a pharmacologic principle in chemoprevention. METHODS: We identified 149,417 incident cancer cases in Denmark during the study period 2000 through 2005, and 597,668 age- and gender-matched controls. Data on history of cancer, past hospital admission diagnoses, and prescription history were obtained from the Danish Cancer Registry, the Danish National Patient Registry, and the Danish Prescription Registry. Primary exposure to valproate was defined as a cumulative dose of minimum 1,500 g within the past 5 years. Confounders were controlled by conditional logistic regression. RESULTS: Among the cases and controls, 81 (0.05%) and 260 (0.04%), respectively, were long-term users of valproate. For cancer overall, the crude and adjusted odds ratios were 1.25 [95% confidence interval (95% CI), 0.97-1.60] and 1.21 (95% CI, 0.95-1.56), respectively. Subgroup analyses revealed no dose or duration effect for overall cancer incidence, and no specific cancer site was found to be inversely associated with long-term use of valproate. For lung cancer, we found a positive but imprecise association (adjusted odds ratio, 2.32; 95% CI, 1.12-4.79). CONCLUSION: Long-term valproate use is not associated with a reduced cancer risk. Our study does not support HDAC inhibition as a pharmacologic principle for general chemoprevention.",

author = "Jesper Hallas and S{\o}ren Friis and Lars Bjerrum and Henrik St{\o}vring and Narverud, {Sverre Flatab{\o}} and Thomas Heyerdahl and Kirsten Gr{\o}nbaek and Morten Andersen",

note = "Keywords: Adult; Age Distribution; Aged; Aged, 80 and over; Anticonvulsants; Case-Control Studies; Enzyme Inhibitors; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Incidence; Male; Middle Aged; Neoplasms; Odds Ratio; Risk Factors; Time; Valproic Acid",

year = "2009",

doi = "10.1158/1055-9965.EPI-08-0646",

language = "English",

volume = "18",

pages = "1714--9",

journal = "Cancer Epidemiology, Biomarkers & Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research (A A C R)",

number = "6",

}

TY - JOUR

T1 - Cancer risk in long-term users of valproate: a population-based case-control study

AU - Hallas, Jesper

AU - Friis, Søren

AU - Bjerrum, Lars

AU - Støvring, Henrik

AU - Narverud, Sverre Flatabø

AU - Heyerdahl, Thomas

AU - Grønbaek, Kirsten

AU - Andersen, Morten

N1 - Keywords: Adult; Age Distribution; Aged; Aged, 80 and over; Anticonvulsants; Case-Control Studies; Enzyme Inhibitors; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Incidence; Male; Middle Aged; Neoplasms; Odds Ratio; Risk Factors; Time; Valproic Acid

PY - 2009

Y1 - 2009

N2 - BACKGROUND: Inhibitors of histone deacetylases (HDAC) have shown promise as targeted cancer therapy. Valproate, an older anticonvulsant, has been shown to possess HDAC inhibitory activity. We undertook this case-control study to clarify whether long-term users of valproate had a reduced cancer incidence. If so, it would support HDAC inhibition as a pharmacologic principle in chemoprevention. METHODS: We identified 149,417 incident cancer cases in Denmark during the study period 2000 through 2005, and 597,668 age- and gender-matched controls. Data on history of cancer, past hospital admission diagnoses, and prescription history were obtained from the Danish Cancer Registry, the Danish National Patient Registry, and the Danish Prescription Registry. Primary exposure to valproate was defined as a cumulative dose of minimum 1,500 g within the past 5 years. Confounders were controlled by conditional logistic regression. RESULTS: Among the cases and controls, 81 (0.05%) and 260 (0.04%), respectively, were long-term users of valproate. For cancer overall, the crude and adjusted odds ratios were 1.25 [95% confidence interval (95% CI), 0.97-1.60] and 1.21 (95% CI, 0.95-1.56), respectively. Subgroup analyses revealed no dose or duration effect for overall cancer incidence, and no specific cancer site was found to be inversely associated with long-term use of valproate. For lung cancer, we found a positive but imprecise association (adjusted odds ratio, 2.32; 95% CI, 1.12-4.79). CONCLUSION: Long-term valproate use is not associated with a reduced cancer risk. Our study does not support HDAC inhibition as a pharmacologic principle for general chemoprevention.

AB - BACKGROUND: Inhibitors of histone deacetylases (HDAC) have shown promise as targeted cancer therapy. Valproate, an older anticonvulsant, has been shown to possess HDAC inhibitory activity. We undertook this case-control study to clarify whether long-term users of valproate had a reduced cancer incidence. If so, it would support HDAC inhibition as a pharmacologic principle in chemoprevention. METHODS: We identified 149,417 incident cancer cases in Denmark during the study period 2000 through 2005, and 597,668 age- and gender-matched controls. Data on history of cancer, past hospital admission diagnoses, and prescription history were obtained from the Danish Cancer Registry, the Danish National Patient Registry, and the Danish Prescription Registry. Primary exposure to valproate was defined as a cumulative dose of minimum 1,500 g within the past 5 years. Confounders were controlled by conditional logistic regression. RESULTS: Among the cases and controls, 81 (0.05%) and 260 (0.04%), respectively, were long-term users of valproate. For cancer overall, the crude and adjusted odds ratios were 1.25 [95% confidence interval (95% CI), 0.97-1.60] and 1.21 (95% CI, 0.95-1.56), respectively. Subgroup analyses revealed no dose or duration effect for overall cancer incidence, and no specific cancer site was found to be inversely associated with long-term use of valproate. For lung cancer, we found a positive but imprecise association (adjusted odds ratio, 2.32; 95% CI, 1.12-4.79). CONCLUSION: Long-term valproate use is not associated with a reduced cancer risk. Our study does not support HDAC inhibition as a pharmacologic principle for general chemoprevention.

U2 - 10.1158/1055-9965.EPI-08-0646

DO - 10.1158/1055-9965.EPI-08-0646

M3 - Journal article

C2 - 19505904

SN - 1055-9965

VL - 18

SP - 1714

EP - 1719

JO - Cancer Epidemiology, Biomarkers & Prevention

JF - Cancer Epidemiology, Biomarkers & Prevention

IS - 6

ER -

Cancer risk in long-term users of valproate: a population-based case-control study

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