Molecular-guided surgical oncology based upon tumor metabolism ...
Estrogen Metabolism Role in Oncology
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Estrogen MetabolismRole in Oncology
Tom Archie, MD
SLWRMC Tumor Board
June 19, 2008
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• 50yo Caucasian Female
• Early breast cancer – poorly differentiated
• MRI negative for contralateral tumor
• Receptor Status:– Triple Negative (ER, PR, HER2/neu)
• Lumpectomy followed by Taxotere and Cytoxan
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Estrogen Metabolism Testing
• Identify high risk patients for new breast cancer
• Others: prostate cancer, leukemia, olfactory tumors, and Parkinson’s Disease (probably more to come)
• Identify high risk of recurrence in breast cancer patients (and other cancers)
• Modify risk via modification of estrogen metabolism balance
• Future: “pre-mammogram” biomarker
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• Endogenous Estrogens can become carcinogenic via formation of catechol estrogen quinones, which react with DNA to form specific depurinating estrogen-DNA adducts.
• The mutations resulting from these adducts can lead to cell transformation and the initiation of breast cancer.
• Irregardless of ER status• Mechanism: Sheer volume of DNA “apurinic” sites – DNA
repair enzymes make mistakes, leading to single nucleotide polymorphisms (SNP)
Catechol Estrogen Quinones to DNA Adducts
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Catechol Estrogen Quinones to DNA Adducts
• 4-OH-estrone induces DNA Adduct formation in normal breast epithelium (MCF-10F cells)
• Saeed M et al. Int J Cancer. 2007 Apr 15;120(8):1821-4.
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• Human study comparing healthy controls, breast cancer patients, and “high risk” patients (as determined by oncologists in study)
• The levels of the ratios of depurinating DNA adducts to their respective estrogen metabolites/conjugates were significantly higher in high-risk women (p < 0.001) and women with breast cancer (p < 0.001) than in control subjects.
• This mechanism represents the best understood and documented initiation step in the formation of any cancer.
• Gaikwad NW et al. The molecular etiology of breast cancer: evidence from biomarkers of risk. Int J Cancer. 2008 May 1;122(9):1949-57.
Human Study of Urinary Estrogen Metabolites w/ and w/o Breast CA
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COMT and CE (Catechol Estrogen)
• Quantitatively, the most active CE conjugative pathway is methylation. CE methylation is catalyzed by COMT
• Catechol-O-methyltransferase (COMT) a classical phase II enzyme, catalyzes the transfer of methyl groups from S-adenosyl methionine, the enzyme cofactor, to hydroxyl groups of a number of catechol substrates, including the CEs.
• Under normal circumstances, CEs are, for the most part, promptly O-methylated by COMT to form 2- and 4-O-methylethers, which are then excreted.
• While virtually all catechols are substrates for COMT, the highest affinities for the enzyme are exhibited by the CEs
• Journal of the National Cancer Institute Monographs No. 27, 2000
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Low Functioning COMT and Breast Cancer Risk
• Genetic epidemiology studies have proposed a possible correlation between the low activity allele (COMTLL) and increased breast cancer risk
• Lavigne JA, et al. An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer. Cancer Res 1997;57:5493–5497.
• Huang CS, et al. Breast cancer risk associated with genotype polymorphism of the estrogen metabolizing genes CYP17, CYP1A1, and COMT: A multigenic study on cancer susceptibility. Cancer Res 1999;59:4870–4875.
• Yim D-S, et al. Relationship between the val158met polymorphism of catechol O-methyl transferase and breast cancer. Pharmacogenetics 2001;11:1–8.
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COMT and Breast Cancer• COMT protects cells from the genotoxicity and
cytotoxicity of catechol estrogens, by preventing their conversion to quinones
• Adds methyl group (-CH3) at the -OH site that would otherwise be oxidized by peroxidase enzymes
• Low activity of COMT leads to higher levels of depurinating estrogen-DNA adducts that can induce mutations and initiate cancer.– MCF-10F (human breast epithelial cells that are ER
neg) – Estrogen-DNA adducts’ carcinogenicity independent
of ER status
• Zahid M et al. Free Radic Biol Med. 2007 Dec 1;43(11):1534-40.
• Lu F et al.J Steroid Biochem Mol Biol. 2007 ; 105(1-5): 150–158.
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Low Functioning COMT Common
• 25% of US Caucasians are homozygous for the val108/158met polymorphism in the COMT gene
• Lachman HM, et al. Pharmacogenetics 1996;6:243–250.
• Scanlon PD, et al. Science 1979;203:63–65.
• 27% Chinese Americans and 34% Japanese Americans• Wu A et al. Cancer Res 2003;63: 7526–7529
• Val108/158Met SNP associated with 3-4x reduction in functional enzymatic rate of COMT.
• Zhu BT. Curr Drug Metab 2002;3: 321–349
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E2:E16 Ratio - Breast Cancer Risk
• Prospective Study 10,786 women aged 34-69 with 5 ½ yr followup
• Measured urinary estrogen metabolites• 144 breast cancer pts w/ 4 matched controls for
each cancer
• Highest quintile E2:E16 ratio– Premenopausal: OR 0.58 (42% risk red)– Postmenopausal: OR 1.29 (29% risk inc)
Muti et al. Epidemiology. 2000 Nov;11(6):635-40
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Broccoli increases E2:E16 ratio
• Increase E2:E16 ratio 29.5% with broccoli 500gr/day
• Cruciferous vegetables cause the upregulation of Cyp1A2 (19%) and Cyp1A1 and inhibit Cyp2E1– Indole 3 Carbinol (glucocinolate)– Sulforaphane (isothiocyanate)– Diindolylmethane (glucocinolate)– Calcium D Glucarate
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Interpretation
• Low 2-Hydroxyestrone/16α-Hydroxyestrone Ratio– Premenopausal female– Increased risk of ongoing carcinogensis leading to
treatment failure
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Interpretation
• Poor methylation capacity – she is a “slow methylator”– 4-Methoxyestrone is undetectable
• 4-Hydroxyestrone is not being methylated adequately.
– 4-Hydroxyestrone level is high. • This is associated with increased levels of 4-catechol
estrogen DNA adducts, which are strongly associated with the initiation of breast and prostate cancer.
– COMT is likely genetically slow• Principal agent for eliminating catechol estrogens
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Interpretation
• Interestingly, the methylation of 2OHE is adequate, whereas methylation of 4OHE is not
• I find no literature citing methylation preferences for 2OHE vs. 4OHE
• Fact remains that additional methylation support is needed
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Treatment Goals
• Enhance methylation
• Decrease Cyp1B1 activity
• Increase E2:E16 ratio– Cruciferous vegetables
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Improve Methylation• Increase substrate for COMT (SAMe)• Add methyl donors
– Folate, methylcobalamin (B12)– Trimethylglycine (Betaine)– Vit B6 (to discourage the accumulation of
homocysteine and encourage the formation of glutathione via synthesis of cysteine)
• There is no physiological mechanism to suggest an adverse interaction between methylation and the metabolism of either taxotere or cytoxan
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Improve MethylationCOMT
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Cyp1B1 inhibition (ie: reduction of DNA adducts)
• Reduce xenobiotic pollutant exposure• N-acetyl Cysteine• Sulforaphane (glucosinolate from broccoli)
induces quinone reductase, which takes CEQs back to catechol estrogens, reducing the potential for the creating of DNA adducts.
– Hwang. J Med Food. 2005 Summer;8(2):198-203
• Glutathione conjugates are not playing much of a role in protecting against DNA adducts.
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Cyp 1B1 Inhibition to decrease DNA Adduct Formation
• Increased methylation of catechol estrogens leads to feedback inhibition of Cyp1B1
– Dawling et al. Cancer Res. 2003 Jun 15;63 (12):3127-32.
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Cyp 1B1 Inhibition to decrease DNA Adduct Formation
• Reduced Lipoic Acid• N-acetyl Cysteine• Resveratrol• Melatonin (minimal but positive effect)
– Zahid M. et al. Inhibition of depurinating estrogen-DNA adduct formation by natural compounds. Chem Res Toxicol. 2007 Dec;20(12):1947-53. Epub 2007 Nov
– Chen et al. Resveratrol inhibits TCDD-induced expression of CYP1A1 and CYP1B1 and catechol estrogen-mediated oxidative DNA damage in cultured human mammary epithelial cells Carcinogenesis vol.25 no.10 pp.2005--2013, 2004
doi:10.1093/carcin/bgh183
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Synergism b/t Paclitaxel and Broccoli Glucosinolate
• Diindolylmethane in combination with paclitaxel synergistically inhibits growth of Her2 / neu human breast cancer cells through G2M phase cell-cycle arrest and induction of apoptosis / necrosis
• McGuire KP, et al. J Surg Res. 2006 May 15;132(2):208-13. Epub 2006 Mar 31.
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Broccoli and Antitumor Effects
• Sulforaphane inhibits breast cancer growth and induces Quinone Reductase
– Hwang. J Med Food. 2005 Summer;8(2):198-203.
• I3C induces Br CA cell cycle arrest
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Potential Risk
• Uncertain effect on Cyp3A4 – (60% of drugs) – Sulforaphane inhibtis– Diindolylmethane has no effect
• Could affect concentration of these drugs and theoretically increase adverse drug events or decrease efficacy
• Taxotere metabolized by Cyp3A4• Consider avoiding near time of infusion
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Prostate CA
• Small study of urine estrogen metabolites in men with prostate cancer vs. benign urological d/o vs. healthy controls
• 4-OHE1-DNA Adducts detected at higher levels in samples from subjects with prostate cancer and benign urological conditions compared to healthy males
• This is the first demonstration that CEQ-derived DNA adducts are present in urine samples from subjects with prostate cancer.
• Markushkin Y et al. Potential biomarker for early risk assessment of prostate cancer. Prostate. 2006 Oct 1;66(14):1565-71
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Extension to Other Cancers
• This mechanism is also involved in– Initiation of leukemia by benzene– Rat olfactory tumors by naphthalene– Neurodegenerative diseases such as
Parkinson's disease by dopamine. • Estrogens and Human Diseases. Volume 1089 published November
2006 Ann. N.Y. Acad. Sci. 1089: 286–301 (2006). doi:
10.1196/annals.1386.042
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Conclusion• No human intervention trials on manipulation of estrogen
metabolism in patients w/ active breast cancer• Epidemiologic studies support cruciferous vegetables and
methyl donors to decrease breast cancer risk• In vitro studies showing anticancer effects of brassica• Risk of non-action vs. action?
• Enhance methylation now• Increase E2:E16 ratio now but reduce likelihood of
possible interaction w/ metabolism of taxotere by avoiding for 1 week prior and 2 days after administration of taxotere
• Inhibit Cyp1B1 now
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One Last Thought for Future Discussion
Multifocal Angiostatic Therapy
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Silymarin, Glycine, Ginger
VEGFR
EGCG, silymarin, quercetin, resveratrol, soy isoflavones, curcumin, EPA
Cu antagonists
VEGF, AKs, bFGF, IL8, MMPs,
TNF-1, heparinases, collagenases
curcmin, artemsia, mistletoe, ginger scutellaria, resveratrol, grapeseed extract, green tea, gingko, squalamine, Vit D silymarin, glycine,
ginger artemsia mistletoe curcumin scutellaria
curcmin, scutellaria, cartilege, silymarin, green tea
bFGFR and TNF-1:
Cu antagonists
Multifocal Angiostatic
Therapy
Growth FactorsNFkBCOX-2
green tea quercetin magnolia resveratrol, soy, curcumin holy basil rosemary ganoderma licorice Vit E
Anti- NFkB: poria, coriolus, ginger, resveratrol, green tea, artemsia, quercetin, carnosol, panax ginseng, silymarin, salicylates, curcumin, picentannol, basil, Cu antagonists rosemary
Anti-COX-2: quercetin, scutellaria, EPA/DHA, licorice, ginger, resveratrol, grapeseed extract, curcumin, salicylates, garlic, green tea, panax ginseng, silymarin, bilberry, antioxidants, boswellia, aloe