Triple Negative Breast Cancer & Naturopathic Medicine Jake Psenka, ND

PMID? Some of the slides make reference to a PMID number. This number can be copied and pasted into the search bar at www.pubmed.gov to see the research article being referenced.

The Principles of Naturopathic Medicine: Identify and Treat the Cause of Disease Do No Harm Doctor As Teacher Treat the Whole Person The Power of Prevention

Triple Negative Breast Cancer (TNBC) Estrogen Receptor Negative Progesterone Receptor Negative Human Epidermal Growth Factor Receptor (HER2) Negative 15% of Breast Cancers Appear at an earlier age High Histologic Grade Define Cancer

Six TNBC Subtypes: 2 Basal Types Immunomodulatory Mesenchymal Mesenchymal Stem-Like Luminal Androgen Receptor Each subtype has characteristics which may make it more or less susceptible to a particular type of therapy. Hopefully, as research progresses, it will become possible to use more patient-specific treatment strategies. PI3K- phosphatidylinositol-3-kinase, a signaling pathway, plays a role in growth and survival in many mammalian cancers P53- tumor suppressor gene, mutations occur in up to 82% of TNBC BRCA1 MIB-1 IGF-1R: Insulin like growth factor receptor, a tyrosine kinase, binds IGF. Ki67: a measure of cell proliferation, higher # ass. With axillary mets in TNBC mTOR:

Current TNBC Treatment Strategies Cytotoxic Therapy (Adriamycin/Cytoxan/Taxol) Radiation Surgery Chemotherapy is considered a cytotoxic and systemic therapy aimed at destroying rapidly dividing cancer cells. Radiation: kills by ionizing DNA molecule within a cancer cells and the production of free radicals (hydroxyl radicals). At the present time these therapies have a low rate of success and new more efficacious treatments are needed. Adriamycin (docorubicin) Cytoxan (cyclophosphamide) Taxol (Paclitaxel)

Problems Associated with Current TNBC Treatment Strategy Toxicity Immune Suppression Fatigue & Malaise Depression/Anxiety Drug Resistance Lack of Efficacy Ultimately a lack of efficacy. We need new therapies that provide better outcomes.

Naturopathic Treatment Strategies As a way to support the patient: Promoting health of patient- both mind & body Minimizing treatment related side effects As integrative therapy: Anti-Cancer Therapy Improving clinical outcomes Preventing Re-occurrence Not anti-conventional treatments. Prefer integrative approach. Frequent Question: Can a person use CAM treatments with Conventional? Yes, as long as you use the right ones. How many people changed their diet when they were diagnosed? Yes = using CAM

Food As Medicine Dietary habits can play a role in both the development and progression of cancer. A healthy diet supports the body’s natural processes and functions. Inhibiting Unintended Weight Loss Promoting Healthy Elimination Reducing Treatment Related Side Effects Anti-inflammatory Action Energy Balance/Fatigue Reduction Improving Efficacy of Treatments Unintentional weight loss- either via LOA from treatment, or as a consequence of tumor Many tx’s are toxic- want them in and out, if elimination routes are inhibited (aka. Constipation) this can cause more toxicity issues, may also produce additional problems (impaction), additionally many drugs are nephrotoxic and maintaining good hydration keeps the kidneys safe. Tumor lysis syndrome and hydration In addition to bowel and urinary issues, healthy diets can also provide the body with what it needs to process chemicals and remove them from the body(cyp450 system). Some foods promote a decrease in the levels of inflammation present in the body: n-3: PGE2, fish oil: vitamin D3 Nutritionally deficient diets do not provide for sustained energy levels. Simple carbs = transient energy followed by a crash. If a patient does not maintain good health through their therapies then an extended chemo break, or dose-reduction is often needed. This can decrease efficacy.

INSULIN-LIKE GROWTH FACTOR-1 Food As Medicine . INSULIN-LIKE GROWTH FACTOR-1 These results show that IGFs stimulate cell proliferation and promote cell survival in triple-negative breast cancer cell lines and warrant investigation of the IGF signal transduction pathway as a therapeutic target for the treatment of triple-negative breast cancer. Neoplasia. 2011 Jun;13(6):504-15 Randomized controlled trials indicated that the circulating IGF-I level was significantly higher in the milk intervention group. Int J Food Sci Nutr. 2009;60 Suppl 7:330-40. Epub 2009 Sep 9. An unhealthy diet does not provide the same benefits, and instead can have significant negative impact Here is an example of a specific dietary manipulation aimed at inhibiting cancer growth: No dairy on TNBC diet? IGF-1 binds to IGF-1R , a hormone is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and proliferation, and a potent inhibitor of programmed cell death (apoptosis). These data suggest that a plant-based diet is associated with lower circulating levels of total IGF-I. Cancer Epidemiol Biomarkers Prev. 2002 Nov;11(11):1441-8.

Food As Medicine “In vivo, the efficacy of blueberry to inhibit triple-negative breast tumor growth was evaluated. Tumor weight and proliferation (Ki-67 expression) were decreased in blueberry-treated mice, where apoptosis (caspase-3 expression) was increased compared with controls.” “In combination with standard treatments, supplementing the diet with (n-3) fatty acids may be a nontoxic means to improve cancer treatment outcomes and may slow or prevent recurrence of cancer.” Lung metastasis of TNBC was reduced (16-70%) by all treatments, significantly in the flax seed oil group. The distant lymph node metastasis was significantly decreased (52%) only in the flax seed oil group. The total metastasis incidence was lowered (42%). Mouse study. Ki67, a measure of proliferation, higher expressions of this associated with axillary mets.(PMID: 21228363) PMID: 15849746 PMID: 21228363, 15849746

SUGAR/CARBOHYDRATE/GLUCOSE = ENERGY Food As Medicine SUGAR/CARBOHYDRATE/GLUCOSE = ENERGY Higher SUVmax and %Ki67 are associated with higher histologic grades. Histologic grade is a measure of proliferation, Scarff-Bloom-Richardson system most common rage from 3-9. Recall our definition of cancer. Cell reproduction (mitosis) takes energy. GLUT-1 receptors more expressed in TNBC (PMID: 21266827) GLUT1 trasporters are upreg. When a cell is hungry. What are the effects of a high sugar/refined carbohydrate diet? PMID: 20012701 Glucose receptors are upregulated in TNBC (PMID 21266827) Higher sugar uptake by TNBC cells correlates with increased cancer cell proliferation (PMID: 20012701)

Exploiting Metabolism

Supplements for cancer? Reasons for using supplements with conventional therapy: Minimize treatment-related side effects Promote a well functioning immune system Synergize with conventional treatments Are supplements safe with conventional care? Yes, if you take the right ones. Natural does not mean safe. How many capsules can a person eat in one day. Try to maximize effectiveness

L-Glutamine protects against doxorubicin (aka Adriamycin) heart damage Side Effects L-Glutamine protects against doxorubicin (aka Adriamycin) heart damage Glutamine for taxane induced neurotoxicity. Melatonin inhibits Cytoxan-induced leukopenia and anemia Melatonin inhibits taxane-related neuropathy DHA, an n-3 fatty acid, is currently in trials Hormones Glutamine: PMID: 19889810, PMID: 14718801 Melatonin: PMID: 20035269, PMID: 20567633 PMID: 19889810, 14718801, 20035269, 20567633

Immune Enhancement LifeStyle Factors Exercise- but don’t over exercise Stress Reduction yoga, meditation, guided imagery, reiki, acupuncture, religion. Alcohol Elimination Sugar Elimination Supplements Arabinogalactans NK function Melatonin T-cell function Thymic Proteins Beta Glucans NK cells

Synergize Multidrug resistance (MDR): Defined as the ability of a tumor cell to survive exposure to clinically achievable concentrations of structurally diverse chemotherapeutic drugs which act at different intracellular targets.

Propolis (caffeic acid) Synergize Propolis (caffeic acid) Inhibits TNBC tumor growth, both in vitro and in vivo without much effect on normal mammary cells. Decreased malignancy potential of TNBC stem cells. VEGF/Angiogenesis Stem cells implicated with chemoresistance, tumor recurrence, metastasis, and high patient mortality. PMID: 21570765 PMID: 21570765

Inositol Hexaphosphate (IP6): Synergize Inositol Hexaphosphate (IP6): decrease proliferation rates in TNBC cells works synergistically with adriamycin (and Tamoxifen) inhibits metastasis activates natural killer cell function Patient study finds those who took it with chemo had no cytopenia, lowered leukocyte, or platelet levels, increased QOL and better functional status. PMID: 12846414 PMID: 15868430 PMID: 14666664 PMID: 20152024 IP6: P27kip1 tumor suppressor protein PMID: 12846414 PMID: 15868430 PMID: 14666664 PMID: 20152024

Curcumin (extract from tumeric) Synergize Curcumin (extract from tumeric) Modulation of the BRCA1 Protein and induction of apoptosis in TNBC Blocker of COX and LOX Shown to decrease the MDR1 gene through the PI3k/AKT/NF kappa beta pathway Arachidonate metabolites: cycloxygenase and lipoxygenase: anti-inflammatory One study was published stating that found curcumin to antagonize the effects of CTX. Serious methodological errors and misrepresentations of scientific data were found in that study. PMID: 19809577 PMID: 19809577

Synergize Vitamin D3 Potentiates the anti-tumor activities of chemotherapy drugs cisplatin, carboplatin and doxorubicin; 5-fluorouracil, cytarabine, hydroxyurea, cytarabine and gemcitabine; paclitaxel and docetaxel. Vitamin D3 enhances the effect of hydrogen peroxide in cancer cells.

Inhibits TNBC proliferation Synergize Indole-3-Carbinol Inhibits TNBC proliferation Down regulated PGP transmembrane efflux pumps by 80%. Decrease TNBC cell motility Sulphoraphane Inhibits inflammatory cytokines and pro-angiogenic growth factors in TNBC PMID: 21767081 PMID: 19728765 PMID:21767081 PMID:19728765

Resveratrol enhances mTOR inhibitor Synergize Resveratrol Sensitizies tumor to chemotherapy drugs including vincristine*, adriamycin, paclitaxel*, doxorubicin, cisplatin, gefitinib, 5-fluorouracil, velcade, and gemcitabine. Resveratrol enhances mTOR inhibitor NFKB PMID: 21261654 PMID: 21168265 PMID: 21261654 PMID: 21168265

Detoxification: Get Specific Remission Preventing recurrence: NCCN guidelines for breast cancer state “Evidence suggests that active lifestyle, achieving and maintaining an ideal body weight (20-25 BMI) may lead to optimal breast cancer outcomes.” Detoxification: Get Specific National Comprehensive Cancer Network Coffee enemas/colonics- rectal burn

New Ideas Metformin Breast Cancer Res Treat. 2010 Sep;123(2):333-44. Epub 2009 Nov 22. Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy. Phoenix KN, Vumbaca F, Fox MM, Evans R, Claffey KP.

New Ideas

Circulating Tumor Cell Studies New Ideas Chemotherapy Sensitivity and Chemo-resistance Testing Circulating Tumor Cell Studies

New Ideas Prevention