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Treating the Oncology Terrain in Breast Cancer Survivors Dr. Jen Green ND FABNO www.emcura.com 248-885-8211 [email protected] 1 Buyers Beware This presentation does NOT cover interactions between Natural Health Products and chemotherapy, hormone blocking medication, radiation & surgery Consider a consult with a FABNO ND during active cancer treatment 2 Treating the Terrain Cancer can behave like an annual or a perennial plant. We need tools like surgery, radiation, and chemotherapy to remove this plant. However, we must also nurture the soil to prevent harmful plants from returning. 3 Inflammation & Hypercoagulability Stress & Hormonal Imbalance Metabolic Syndrome Oncogenic Terrain Immune Incompetence Sustained Angiogenesis Carcinogens 4 Inflammation & Cancer: CRP Cancer is an inflammatory process – inflammatory mediators facilitate cancer growth and metastasis According to a meta-analysis of 11 prospective cohort studies, elevated CRP is associated with increased risk of getting cancer (1) Cancer survivors with high CRP are at greater risk of cancer related mortality (2,3,4) 5 6 CRP & Breast Cancer Survivors CRP in breast cancer survivors correlates with; cancer-related fatigue (1) worse cancer related symptoms (2) reduced health related quality of life (2) A retrospective study shows no link between high CRP & breast cancer recurrence (4) A prospective WHEL study (Women's Healthy Eating and Living Study) of 2,919 early-stage breast cancer survivors with 7 yr follow up showed hsCRP associated with breast cancer death Note: hsCRP threshold was 10.0 mg/L vs. <1 mg/L (3) 7 Post Surgical Inflammation & Breast Cancer Inflammation after surgery a strong prognostic factor for breast, lung, and kidney cancers (1) Peri-operative use of the anti-inflammatory drug ketorolac in early stage breast cancer patients resulted in better 5 year survival, with early relapse events reduced by 5-fold (2) Breast Cancer Death & Aspirin Four large prospective observational studies; Iowa Women’s Health Study : F.U. 8.3 yrs, survivors 9 taking aspirin compared to nonusers, had 47% less risk of death due to breast cancer RR (95% CI) 0.53 (0.300.93) (6) Nurses Health Study : F.U. 30 yrs, aspirin use 2-7 times weekly associated with a decreased risk of distant recurrence & 49% less risk breast cancer death 0.51 (0.41-0.65)(3) LACE : F.U 2.5 yrs, no association with aspirin and breast cancer recurrence, but Ibuprofin use 3x weekly or more associated with a decreased risk of recurrence (4) Swedish National Cancer Register : F.U 2.6 yrs, no association between aspirin & breast cancer death (7) NF-kB: Cancer’s “Master Switch” Protein that produces cytokines Triggered by oxidation, carcinogens, viruses, 10 inflammation, radiation, chemotherapy & stress Signals 400+ genes involved in inflammation, proliferation, anti-apoptosis, angiogenesis, invasion & metastasis Activated in a wide variety of tumors Implicated in radio-resistance & chemoresistance (1,2,3) Inflammation & Cancer: NLR Neutrophil to Lymphocyte Ratio increases with systemic 11 inflammation (a non healing wound drives our surface/neutrophil immunity up and drives deep/cancer immunity down) Cost effective & part of routine testing Predictive of cancer mortality in; colon cancer (1), ovarian cancer (2), non small cell lung cancer (3), gastric (4), breast cancer (5), esophageal cancer (6) and more…. Greater than 3:1, 4:1 or 5:1 ratio a risk factor, depending on tumor type (7) Look at lymphocyte number, multiply by 3 and see if neutrophils are greater than this number Inflammation Evaluation: hsCRP, NLR Targets hsCRP <1.0 mg/L, NLR 3:1 (1) , IL6, COX-2, 5-LOX, NF- kB, PGE2, IL8 Anti-inflammatory Diet Avoid hydrogenated trans-fats Increase omega-3 dietary fats Increase anti-inflammatory foods that lower glucose (cinnamon, blueberries, olive oil, nuts & seeds, leafy greens) Low glycemic-index, whole food diet 12 Natural Anti-inflammatory Tx 13 Fish oil (1-2g EPA, 3-6 g EFA) (5,6,9) Bromelain (1000-2250mg/d) (8) Curcumin (1.5-8 g/d) (1,3,24) Green Tea (EGCG 250-750mg/d) (2) Resveratrol (200-800mg/d) (12,13,14) Boswellia (300-900mg BID-TID) (3) Quercetin (500mg BID-TID) with Vit C (4,11,18) Ginger (400mg TID) (10) Grapeseed Extract (23) NAC (600mg BID-TID) (15,16) Pomegranate juice/ellagic acid (8 oz daily) (17) Vit E Tocopherols/Tocotrienols (200-800IU/d) (19,20) Melatonin (5-40mg nightly) (21,22) Chemoprevention: Soy Soy is another flavonoid that is anti- inflammatory (1,2) In breast cancer survivors, a meta-analysis of prospective trials including over 9,500 breast cancer survivors showed decreased mortality and/or breast cancer recurrence with high soy intake (3,4) 14 http://www2.nau.edu/~bio372/class/cancer/angiogenesis2.jpg 15 Angiogenesis & Cancer Angiogenesis is rate limiting for tumor progression Multiple anti-angiogenic drugs approved for cancer treatment with mixed efficacy Remember that inflammation drives angiogenesis so anti-inflammatory strategies apply (1) In survivors, Vascular Endothelial Growth Factor (VEGF) & elevated copper are modifiable factors that may influence cancer terrain 16 VEGF & Angiogenesis Serum and plasma VEGF (Vascular Endothelial Growth Factor) is correlated with the presence of cancer and metastasis 2,5 In vitro VEGF inhibitors (1-4) Aloe barbadensis, Angelica sinensis Artemisia annua (artemisinin) Green tea (epigallocatechin) Curcuma longa (curcumin) Ganoderma lucidum Ginkgo biloba Glycyrrhiza glabra Hibiscus sabdariffa Matricaria chamomilla (flavonoids: apigenin, fisetin) Magnolia (honokiol), Panax ginseng, Poria cocos 17 Rosmarinus officinalis Scutellaria baicalensis Silybum marianum, Soy isoflavones (genistein, daidzein) Tanacetum parthenium, Viscum album Zingiber officinale Fish oil, Selenium Vitamin D3, Resveratrol, proanthocyanidin (pro & anti-angio) Quercetin Sagar/Yance Anti-Angiogenesis Summary1 18 Herb/Phytoceutical Preventive Dose mg/d Adjuvant Dose mg Turmeric (95% curcumin) 500-1000 1000-2500 TID Green tea (95% phenols; 50% epigallocatechin-3 gallate) (3,4,5) 200-500 1000-1200 TID Quercetin with bromelain 500-1500 500-1000 TID Holy basil and rosemary (2.37% and 10-20 1.5% ursolic acid) 10-20 TID Silibinin (80% silymarin) 200 Up to 2000 TID Resveratrol (2) 30-50 300-500 /d Grape seed extract (95% proanthocyanidin) 100-200 600-1000 /d Copper & Angiogenesis Copper is required for angiogenesis (1-3) Ceruloplasmin is an acute phase reactant that carries copper. Can reflect zinc def, inflammation, elevated copper Locally advanced & advanced solid tumors are associated with increased ceruloplasmin 4,7 & serum copper 5,8 19 Copper in Breast Cancer Breast cancer patients show significantly higher serum copper than controls (1, 5,6,7) as well as increased serum ceruloplosmin (5) Cu/Zn ratio is increased in breast cancer patients compared to controls; 1.91 vs. 0.86 (8), or >1.2 (4) Serum copper may be predictive of survival in premenopausal breast cancer 9 Reducing ceruloplasmin in high risk breast cancer patients with no evidence of disease reduces endothelial progenitor cells (a marker for metastasis in breast cancer)6 20 Sustained Angiogenesis Evaluation Serum copper & ceruloplasmin in survivors controversial Possible ceruloplasmin levels for breast cancer: <15-17 mg/dL (TM study) or 380 mg/L in women as a screening tool for early breast cancer (Senra study) Molecular Targets 21 (1,2) VEGF, PGE2 (Prostaglandin E2), APN (Angiopoietin), HIF (Hypoxia induced factor), PDGF (Platelet derived growth factor), EGF (Epidermal growth factor), Histamine, Insulin, TGF-beta (Transforming growth factor beta) Hypercoagulability Cancer cells can produce fibrinogen (FBG) Peritumoral inflammation stimulates hepatic production of fibrinogen Tumors use FBG to bind and acquire VEGF & other angiogenic growth factors Fibrinogen may contribute to; Hypoxia & angiogenesis (1) Metastasis (4) (via D-Dimer, 3) Radioresistance & chemoresistance (2) 22 Hypercoagulability Evaluation Fibrinogen Normal D Dimer & FDP to rule our DIC Targets: fibrinogen <325, D-Dimer normal range Natural treatment Options Bromelain, Garlic (650mg QD-TID) Curcumin, Fish oil, Ginkgo (80-160mg) Nattokinase (300-600mg), Vitamin E (400-800IU mixed tocopherols) Dan shen, Bai zhu (Atractylodes macrocephala) Chinese peony (Paeonia lactiflora)(in blood stagnation formula) 23 Caution! If low platelets 24 Photos courtesy of Jim MacDonald, herbalist www.herbcraft.org Immunity & Cancer Risk 25 Primary immunodeficiency in humans is associated with increased cancer risk (1) Organ transplant recipients who take immunosuppressive drugs have 2-5x risk of colon, larynx, lung, bladder, prostate, and testicular cancers & 10-30x risk of cancers of the lip, skin, kidney, endocrine glands, cervix, and non-Hodgkin’s lymphoma (2) Acquired immunodeficiency (due to HIV) leads to elevated cancer risk (3) NK cell cytotoxicity is significantly lower (p < .005) in individuals with a high familial incidence of cancer vs low incidence of cancer (4) NK cell activity is significantly reduced in cancer patients compared with controls (5,6,7) Immune Competence & Cancer Survival Quantity and quality of immune cell infiltrate in tumors is an independent prognostic factor for patient survival (4) Activated Circulating T Lymphocytes (CD4+/Thelper & CD8+/Cytotoxic T cells) correlates with better survival in invasive colon cancer (1,2), breast cancer (6,13), lung cancer (11,12) and melanoma (3) Immune system status may predict the risk of primary, metastatic, and relapsed breast cancer (5) In colorectal, liver & breast cancer, tumor infiltration by Th1 cells is particularly advantageous (7,8,9,10) 26 Tumor Evasion of Immune System Tumors create a non healing wound Inflammation makes tumor-associated macrophages & neutrophil granulocytes produce pro-angiogenic factors such as VEGF (1) If the terrain is anti-inflammatory, macrophages signal end of wound repair & stop angiogenesis (1) Tx: Anti-inflammatory & Anti-angiogenic therapies 27 Immune Summary for Solid Tumors Only 28 Evaluation • Post treatment, examine NLR (from CBC w Diff), screen for zinc deficiency Targets • NLR 3-5:1 • Normal CBC w Diff (monocytes, lymphocytes, neutrophils, eosinophils) • -TH1 immunity (vs TH2 dominance), IL2, NK cells, LAK’s, mature dendritic cells • -NK cell activity >60 LU (Lytic Units) or improved from baseline Caution! Do not use botanical immunotherapy agents with hematological cancers unless well researched Turkeytail, I Love You…. Meta-analysis of 13 double blind, placebo- controlled trials (breast, gastric, colorectal, esophageal, nasopharyngeal) on Coriolus/PSK in conjunction with chemo, radiation or surgery Absolute risk reduction of 9% in 5 year mortality, Numbers Needed to Treat (NNT) of 111 Duration of 3-12 months in studies, so continue in survivorship Then consider rotating herbal immunotherapy agents… 29 Herbal Immunotherapy by Tumor Type Tumor Type Breast Prostate Lung Immunotherapy (Positive & Negative Human Studies Only) Coriolus (13, 15,16,17), Maitake (21), Shitake (27), Mistletoe (38-43,45) Reishi (23), Shiitake (35) & Lentinan IM (36) Melanoma Astragalus-based TCM Herbs (3, 4), Coriolus (18,19), Mistletoe (44-46) Coriolus (13,14), Astragalus-based decoction (6), Fermented Wheat Germ Extract (7) Reishi (24,25), Shiitake (26) & SDL -Superfine Dispersed Lentinan (30), Mistletoe (51, 53-56 Fermented Wheat Germ Extract (8), Mistletoe (57-59) Bladder Maitake (22), Mistletoe (60,61) Colorectal Immune Surveillance Increase NK Cell Activity: Avoid un-metabolized folic acid (6) Turkeytail/Trametes/Coriolus (5) Astragalus (7) Maitake (8) Shiitake (8) Agaricus Blazei (3) Aged Garlic (9) Mistletoe/Viscum Album (10,18) Panax Ginseng (17) Combination Homeopathics (19) Lactobacillus casei Shirota (11) Melatonin (4) 31 Bromelain (2) oral Vit C (12) Zinc (13) Fish oil (14) Daily Blueberries (20) Forest Bathing (15) Exercise, Relaxation, Music Therapy, Laughter (1,3) Stress causes decrease in NK activity (16) Avoid toxins such as toluene, atrazine, triclosan (21) Immune Surveillance Boost viral immunity to protect mutation (p53) from EBV, hep B, HPV, T cell leukemia virus etc. Wei Qi formulas, Licorice Root (8), Vit D3 (9), Green Tea/EGCG (10) Mature Dendritic Cells to presents tumor antigen to immune system Low Dose Naltrexone (1), Astragalus (2), Reishi (3), Turkeytail (4), Ginseng (5), Mistletoe (6) 32 Immune Surveillance Steer towards TH1 vsTH2 immunity Agaricus (3), Maitake (3),. Reishi (3), 33 Cordyceps (3), Turkey tail (3) Fermented Wheat Germ Extract (4) Melatonin (1) Serotonin (1) Probiotics (5) Vit A (6) Low dose naltrexone (8) Avoid stress & sleep disturbance (7) Support Glutathione (9) & avoid toxins (10) For Reference: Cancer Immunity 101 34 Dendritic Cells (messengers who present Ag to T cells and B cells, when mature they are like billboards telling T cells to attack cancer, when immature they can increase angiogenesis) Lymphocytes • B cells (humoral, produce antibodies, consider impact with monoclonal antibodies) • T cells (cell mediated) o CD8+/Cytotoxic T Cells (destroy viruses and tumor cells, need Ag presentation, sophisticated assasins) o CD4+/Thelper cells (activate cytotoxic T cells & macrophages, release cytokines that trigger TH1 or Th2 responses) o Treg/T suppressor (induce immune tolerance, involved autoimmunity, tumors can used them for evil) o NK cells (kill tumor cells without the need for antigen presentation, thugs) • Lymphokine-Activated Killer cells (lymphocytes exposed to IL2 that target tumor cells that NK cells cannot kill) (1) 35 http://www.glasbergen.com/stress-management-cartoons/ Metabolic Syndrome & Cancer Patients with MS have greater incidence of: Recurrence - 3-fold recurrence at 5 yrs in breast cancer pts, higher rates of recurrence & liver mets in colon cancer pts Post-Op Complications - rate of post-op complications (40 vs 11%) and longer hospital stay (11 vs 8 days) Immune Suppression - risk of infection in patients undergoing intensive chemotherapy Hormone Dysregulation –High insulin causes elevations in IGF1, VEGF & aromatase activity1 36 Metabolic Syndrome & Breast Cancer 37 Primary Prevention: MS associated with 52% increase in postmenopausal risk of breast cancer (1) Secondary Prevention: Breast cancer patients with MS have 3 times the recurrence rate (1) Metastatic breast cancer: Metastatic breast cancer patients with MS have poorer outcomes (2) MS is highly treatable with natural agents and lifestyle modifications! (3) Diabetes Prevention Program Study - high risk patients; placebo, metformin, or intensive lifestyle intervention. At 3 yrs, diabetes incidence was reduced by 58% with intensive lifestyle intervention and by 31% with metformin compared to placebo (4) Metabolic Syndrome 38 Evaluation: BMI, Blood pressure, HgA1C, Fasting lipids. If suspect early insulin resistance add: Fasting glucose & Fasting insulin. Can download HOMA-IR calculator here: http://www.dtu.ox.ac.uk/Homacalculator/index. php. HOMA-IR ≥ 2.50 indicates insulin resistance Targets in Breast Cancer: BMI 18.5–25 or 30 kg/m2, BP ≥ 130/85 mmHg, HgA1C<5.5%, TG < 100 mg/dL, HDL > 50 mg/dL , Uric acid <5.5 mg/dL, HOMA-IR <2.5 Metabolic Syndrome Anti-inflammatory, Low Glycemic Diet, Sleep hygiene, 39 Cortisol Management, Avoidance of obesogens EXERCISE!! Chromium 400-800mcg/d, Zinc 25-100 mg/d, Vanadium 100-500 mcg/d, Magnesium 250-600mg/d Inositol 2g/d & Alpha Lipoic Acid 100-600mg/d Fish Oil 2-5g/d, CoQ10 200mg/d, Carnitine 1-3g/d, Vit D 2000-5000IU/d Berberine 1500mg/d, Green Tea 3-6 cups/day (organic sencha), Cinnamon 2g/d, Gymnema 100-200mg/d, Bitter melon 100-400mg/d, Fenugreek 100-300mg/d, American Ginseng 450-900mg/d, Holy Basil 400800mg/d Targeting IGF-1 Men with prostate cancer were given 800mg EGCG until radical prostatectomy. Serum IGF-1 decreased significantly (2) Healthy adults given resveratrol 0.5, 1.0, 2.5, or 5.0 g/d for 29 days. 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Circulating IGF-I and IGFBP-3 decreased (P<0.04) in everyone, but most marked at 2.5 g/d (1) Overweight (BMI ≥25kg/m2) postmenopausal women randomized to exercise, dietary weight loss, diet + exercise, or placebo. Higher BMI at onset was associated with higher IGF-I/IGFBinding Protein-3 ratio. After 12 months there was no significant changes in IGF-I or IGFBP3 but the IGF-I/IGFBP-3 ratio increased significantly in the diet & diet + exercise groups compared with control (3) 40 Exercise Deficiency Exercise improves mood, lessens fatigue, improves sleep manages weight, reduces hot flashes, improves immunity, prevents/manages of metabolic syndrome Exercise improves survivorship in patients with breast, prostate and colorectal cancer (1) In one study of 3000 breast cancer survivors , women who exercised 3-5 hrs per week had almost a 50% reduction in recurrence!! (2) 10% of incident breast cancers are attributed to inactivity. Exercise should be used for primary prevention of breast cancer (3) 41 42 http://www.glasbergen.com/stress-management-cartoons/ Cortisol & Cancer Survival • • • 43 Common survivorship issue: Elevated night time cortisol Growing evidence that flattened diurnal cortisol rhythm accelerates tumor progression Flattened cortisol curve is associated with significantly earlier death in: Lung cancer 2 Metastatic Breast cancer (predicts survival up to 7 years later) 1 Renal cell carcinoma 3 Cortisol & Oncology Terrain Flat Cortisol curve is associated with: Poorer ECOG Performance Status 2 Poor cancer immunity 4,5 Fatigue in long term breast cancer 1 Depression in ovarian cancer patients 3 Disrupted melatonin levels Suppressed bone growth Adaptogenic herbs can reverse suppressed immunity in cancer patients 6 44 Cortisol Balance Evaluation: sleep pattern, 4x salivary cortisol, DHEA Targets: Normal cortisol curve, Balance TH1 to TH2 immunity High PM Cortisol: Body Mind Spirit Group (8 weeks1) or Cognitive-behavioral stress management class (10 weeks2), Walking barefoot/Lying on the earth3, Theanine, Phosphatidylserine, Ashwaghanda/Withania, Magnolia/Honokiol, Siberian Ginseng/Eleuthrococcus, Rhodiola, Holy Basil/Tulsi 45 Low Cortisol: B5, Licorice Root, Schizandra Berry Support Group & Survival 227 breast cancer patients randomized to Psychologic Intervention (PI) plus assessment or assessment only. Small groups lead by psychologist to reduce stress, improve mood, alter health behaviors, and maintain adherence to cancer treatment and care. Immune parameters & QOL improved in PI group After 11 years of follow-up, reduced risk of breast cancer recurrence (hazards ratio [HR] of 0.55; P = .034) and death from breast cancer (HR of 0.44; P = .016) Follow-up analyses also demonstrated that Intervention patients had a reduced risk of death from all causes (HR of 0.51; P = .028). 46 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661422/ 47 Supplement Cautions for Survivors Copper – trying to reduce this so please avoid Folic acid supplementation no prevention (1), potential risk (3). Dietary folate strongly advised (2) If supplementing, only use 5MTHF: MTHFR 677TT genotype is associated with a moderate increase in risk of postmenopausal breast cancer (4) Boron 3mg/d increases serum estradiol (5) Beta carotene in smokers or former smokers (6) 48 Putting it all together 49 Individualizing Treatment 6/2012 11/2012 10/2014 302 5.1 64 154 293 5.2 123 362 5.1 39 Cerulopla 44 smin Free 22 Copper hsCRP 2.5 WBC 3.2 (L) 42 - 3 - 6.1 8.6 (N) 1.8 8.5 (N) High cortisol Waking 3am Normal Normal Anxiety Normal V. High “Leslie” fibrinogen HgA1C Vit D Serum JK copper 50 MTHFR C677T & A1298C “Jennifer” fibrinogen HgA1C Vit D hsCRP Lymphocyt es 11/2012 01/2013 10/2014 337 7.1 22 2.1 .4(low) on 6/12 336 6.7 35 1.8 1.8 (N) Digestion Chronic Diarrhea Slight Normal improve ment Arrhythmia Severe Occasio nal 330 6.3 43 1.15 1.8 (N) Normal High 48 yr old with BRCA1. Grade 3 ductal CA, tripple negative, 25/26 nodes + 63 yr old with grade 2 ductal carcinoma, 6 cm, E & P positive, her2neu -, 3/11 nodes + Individualizing Treatment “Leslie” Vitamin D3 5000IU (if drop lower, Vit D below 40) Fish Oil 2 BID Melatonin 10mg Coriolus 3g/d for 1 yr, then a blend of mushrooms Multi BID during reconstruction (now discontinued) CoQ10 100mg (NutrEval) Evening Cortisol Formula prn Curcumin 2 BID Zinc BID prn (based on taste changes) 5HTP 100mg TID, MBSR program Sublingual GABA prn Bromelain with expanders Dietary Green Tea, garlic, brazil nuts 4/d Cu chelation: Molybdenum 1000mcg/d, NAC 600 BID for 8 weeks Carc 58T 200C alt Lach 200C Plussing Method Co Morbidities: Depression. anxiety Meds: None 51 “Jennifer” Vitamin D3 5000IU Fish Oil BID Melatonin 20mg Coriolus 3g/d for 2 yrs, tried switching to Reishi but attached to coriolus) CoQ10 300mg (cardiac toxicity from possible adriamycin overdose) Metabolic Multi 3 qd-BID Mag Glycinate 300 BID Cal-Mag MCHA (Arimidex) Alpha Lipoic 300mg Probiotics Hawthorne Berry Solid extract Dietary Green Tea Carc 58T 200C alt Caust 200C, 2 pellets q 2 weeks Co Morbidities: Uncontrolled type II diabetes, hypertension, epilepsy, diverticulosis, OA, neuropathy Meds: Arimidex, Metformin, Toprol, Phenobarbital, Aspirin 81mg, Simvastatin, weaning from prilosec Questions? 52