Co-Management of Hormonal Agents in Breast Cancer

Co-Management of Hormonal
Agents in Breast Cancer
Tina Kaczor, ND, FABNO
Clinic of Natural Medicine
Eugene, OR
Editor-in-Chief, naturalmedicinejournal.com
Steroids and their Receptors- Classic View
ER= Estrogen Receptor
There is an ER- alpha and ER-beta
receptor
Binding can be
ER alpha- ER alpha
ER beta- ER alpha
ER beta- ER beta
Each combination may have differing
molecular effects.
Tamoxifen is specific for the ER alpha
receptor.
Phytoestrogens bind preferably to ER
beta
Four Molecular Paths to Steroidal Action
Ex: Estrodiol = Ligand
(Classical View)
TF=
Transcription
Factor
A Transcription Factor
binds to ER and DNA
Outer membrane of cell
has receptor
SM=Second
Messenger
Ex: Insulin-like Growth
Factor (IGF-1)
Heldring N et al. Physiol Rev 2007;87:905-931
©2007 by American Physiological Society
Hormonal agents used in Breast
Cancer
Selective Estrogen Receptor
Modulators (SERM’s)
Tamoxifen citrate (Nolvadex®)
Toremifene citrate
(Fareston®)
Raloxifen (Evista®)
Other mechanisms of action:
Fulvestrant (Faslodex®)
GNRH Agonists (ie, Lupron®)
Aromatase Inhibitors
Non-steroidal:
Anastrazole (Arimidex®)
Letrozole (Femara®)
Steriodal
Exemestane (Aromasin®)
Selective Estrogen Receptor Modulator
Modulators= SERMS
Great Review, Free: Oseni T, Patel R, Pyle J, Jordan VC. Selective Estrogen Receptor Modulators and
Phytoestrogens. Planta Medica. 2008;74(13):1656-1665. doi:10.1055/s-0028-1088304.
Tamoxifen is a Pro-drug-
activity is from metabolites
Equivalent antagonistic
effects on ER’s.
Endoxifen in circulation is
5-10 fold greater than 4
hydroxyTAM
Stearns V et al. JNCI J Natl Cancer Inst
2003;95:1758-1764
© Oxford University Press
TAM
The entire Tamoxifen
metabolic pathway.
https://www.pharmgkb.org/pathway/PA
45011119
Tamoxifen and
CYP2D6 Inhibitors
National Comprehensive
Cancer Network (NCCN) advises
caution with use of strong
inhibitors of CYP2D6
**Women on paroxetine and tamoxiifen had increased risk of mortality that was
dose/duration dependent.**
Kelly CM, Juurlink DN, Gomes T, et al. Selective serotonin reuptake inhibitors and breast cancer mortality
in women receiving tamoxifen: a population based cohort study. BMJ: British Medical Journal. 2010;340
For more known inhibitors:
www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractions
labeling/ucm093664
Raloxifene (Evista)
• More estrogenic on bone vs. TAM
• Has lower risk of thromboembolism. Less
estrogenic on uterus.
• Not activated through CYP systems
• Less antagonist activity on breast cells vs. TAM
• Metabolized in gut and liver- glucuronidation
and sulfation by gut flora. NOT CYP’s.
– No enterohepatic recirculation
ASCO Guidelines on TAM vs. Raloxifene:
http://jco.ascopubs.org/content/early/2013/07/03/JCO.2013.49.3122.full.pdf
Toremifine citrate (Fareston®)
Approved for post menopausal metastatic disease, ER+ or
unknown
Most common: Hot flashes, nausea, sweating and vaginal
discharge
Black box warning
Arrhythmia that may lead to fainting, seizures, death.
Do not take if already have low potassium or
magnesium
Arthralgia reported to be much less than with Tam
Does not use CYP2D6 for activation; Does go through
CYP3A4 and CYP2C9
Very seldom used in my experience.
Fulvestrant
(Faslodex®)
Antagonist
Once monthly injection
“Pure” antagonist of ER
Causes dissolution of ER as well
Side effects:
Nausea, diarrhea/constipation, GI pain
Pharyngitis, cough, dyspnea
Bone pain, peripheral edema
NO agonist effects so no uterine or thromboembolic effects
Rarely: thromboembolic events, hyperbilirubinemia, liver
failure
Aromatase (CYP 19A1)
Where is it up-regulated?
Adipocytes in/around tumor
Liu E, Samad F, Mueller BM. Local adipocytes enable estrogen-dependent breast
cancer growth: Role of leptin and aromatase. Adipocyte. 2013 07/01;2(3):0-4.
Stromal cells, fibroblasts, cancer cells themselves
Miki Y, Suzuki T, Tazawa C, et al. Aromatase Localization in Human Breast Cancer
Tissues: Possible Interactions between Intratumoral Stromal and Parenchymal Cells.
Cancer Research. 2007 April 15, 2007;67(8):3945-54.
Lymph nodes nearby
Shibahara Y, Miki Y, Ishida T, et al. Immunohistochemical analysis of aromatase in
metastatic lymph nodes of breast cancer. Pathology International. 2013;63(1):20-8.
Aromatase Inhibitors
Nonsteroidal:
Reversible inhibition
Anastrozole
(Arimedex)
Letrozole
(Femara)
Steroidal:
Irreversible Inhibition
Exemestane
(Aromasin)
Relative vs. Absolute Risk Reduction
• 40-50% relative risk reduction of recurrence
•
•
•
•
•
Absolute Risk Reduction:
Stage IStage IIStage IIIStage IV-
Proportion with Recurrence %
ATAC (Arimidex,Tamoxifen Alone or in
Combination) Trial
Howell, A.Lancet 365 (2005): 60-62.
5 vs. 10 Years of Tamoxifen
ASCO 2013 Abstract #5: aTTom
Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus
stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.
Lancet. 2013;381:805-16.
Gray R. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in
6,934 women with early breast cancer. J Clin Oncol. 2013;31(suppl):abstr 5.
ATAC Trial Data- Comparing Side Effects
Table from AdjuvantOnline
Tamoxifen-Side Effects prioritized
•
•
•
•
•
•
Uterine bleeding/hyperplasia/cancer
Thromboembolism
High Triglycerides Fatty liver
Cognitive impairment (semantic memory)
Weight Gain
Arthralgia
“Common tamoxifen attributed side effects were hot flashes (64%), vaginal dryness
(35%), sleep problems (36%), weight gain (6%), and depression, irritability or mood
swings (6%).” Lorizio W, et al. Breast Cancer Research and Treatment. 2012;132(3):11071118. doi:10.1007/s10549-011-1893-4.
Aromatase inhibitors low estrogen
effects
Bone loss is universally a concern
Symptoms marked by a lessening of
moisture/lubrication/secretion
Joint Pain
Dry eyes
Dry skin, hair, nails
Loss of subcutaneous fat (“my arms look like my mothers!”)
Mood changes- due to lower neurotransmitter levels, esp.
serotonin/ dopamine
Sleep disturbance
Loss of vaginal lubrication/ UTI’s
Tamoxifen and Hot Flashes
Hot Flashes are associated with reduced risk of
recurrence
Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is
associated with clinical outcomes of efficacy and hot flashes. Journal of clinical oncology :
official journal of the American Society of Clinical Oncology. 2005 Dec 20;23(36):9312-8
Hot flashes may be a surrogate for higher levels of
active metabolite-endoxifen
Single nucleotide polymorphisms (SNP’s) in CYP2D6
gene may affect outcomes- although data to date is
conflicting.
Brauch H, Schroth W, Goetz MP, et al. Tamoxifen Use in Postmenopausal Breast
Cancer: CYP2D6 Matters. Journal of Clinical Oncology. 2013 January 10,
2013;31(2):176-80.
WHEL study results
Hot flashes were a stronger predictor of breast cancer specific outcome than age,
hormone receptor status, or even the difference in the stage of the cancer at diagnosis
(Stage I versus Stage II).
Mortimer JE, Flatt SW, Parker BA, et al. Tamoxifen, hot flashes and recurrence in breast cancer.
Breast Cancer Res Treat. 2008;108(3):421-6.
Soy for hot flashes post breast cancer??
Per Evidence Based Medicine (EBM): No.
•
MacGregor CA, et al. (2005) A randomised double-blind controlled trial of oral soy supplements versus
placebo for treatment of menopausal symptoms in patients with early breast cancer. Eur J Cancer
41(5):708–714.doi:10.1016/j.ejca.2005.01.005
•
Nikander E, et al. (2003) A randomized placebo-controlled crossover trial with phytoestrogens in treatment
of menopause in breast cancer patients. Obstet Gynecol 101(6):1213–1220
•
•
Van Patten CL, et al. (2002) Effect of soy phytoestrogens on hot flashes in postmenopausal women with
breast cancer: a randomized, controlled clinical trial. J Clin Oncol 20(6):1449–1455
•
Quella SK, et al. (2000) Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer
survivors: a North Central Cancer Treatment Group Trial. J Clin Oncol 18(5):1068–1074
Clinically, I have had some patients report improvement… is it the
soy or all of the other healthy changes that go with it?
Soy and Tamoxifen/ Arimidex
Possible potentiation of TAM and/or Arimidex in post
menopausal ER+ women
Shanghai Study—Highest soy intake had less
recurrence than TAM users with lowest soy intake.
Reduced recurrence risk in high soy consumers
taking Arimidex
Kang X, et al.Effect of soy isoflavones on breast cancer recurrence and
death for patients receiving adjuvant endocrine therapy. Canadian Medical
Association Journal. 2010;182(17):1857-1862.
Of Mice and (Wo)Men
• Humans metabolize isoflavones differently than
rodents
– Genistein is almost completely metabolized by humans
(only 1-2% unconjugated genistein in circulation)
– In four rodent models (all used in studies looking at
genistein’s influence on breast cancer), there was
significantly more unconjugated genistein: 20, 23, 58,
and 150 times that in humans.
– Therefore, rodent studies of isoflavones may not
translate to humans at all.
• Setchell KD, Brown NM, Zhao X, et al. Soy isoflavone phase II
metabolism differs between rodents and humans: implications
for the effect on breast cancer risk. The American Journal of
Clinical Nutrition. November 1, 2011 2011;94(5):1284-1294.
Flax Seed for Hot Flashes?
Studies show no improvement in menopausal hot
flashes (non-survivor populations)
Used a bar containing 410mg of lignans
One bar 6 days per week
Pruthi S, Qin R, Terstreip SA, et al. A Phase III, Randomized, Placebo-Controlled,
Double-Blind Trial of Flaxseed for the Treatment of Hot Flashes: NCCTG N08C7.
Menopause (New York, NY). 2012;19(1):48.
Simbalista RL, Sauerbronn AV, Aldrighi JM, Arêas JA. Consumption of a flaxseed-rich
food is not more effective than a placebo in alleviating the climacteric symptoms of
postmenopausal women. The Journal of Nutrition. 2010;140(2):293-7.
Evidence on red clover is limited, however existing studies
suggest that it may not possess breast cancer-promoting effects.
Hops (Humulus lupus)
• Trials suggest improvement in
menopausal symptoms:
hot flashes, sweating, insomnia, palpitations,
sleep disturbance and headaches
Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. A first prospective,
randomized, double-blind, placebo-controlled study on the use of a standardized hop
extract to alleviate menopausal discomforts. Maturitas 2006;54:164–175.
Erkkola R, Vervarcke S, Vansteelandt S, Rompotti P, De Keukeleire D, Heyerick A. A
randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a
standardized hop extract to alleviate menopausal discomforts. Phytomedicine
2010;17:389–396.
Vit E for TAM/AI Hot Flashes
Result: There were statistical significant differences in hot
flashes severity score (2.37 ± 0.74, 1.80 ± 0.87) and their daily
frequency (5.00 ± 3.34, 3.19 ± 2.74) after the treatments
between the placebo and vitamin E therapies (p < 0.0001).
Ziaei, S., A. Kazemnejad, and M. Zareai. "The effect of vitamin E on hot flashes in
menopausal women." Gynecologic and obstetric investigation 64.4 (2007): 204-207.
Also: Barton et al. 1998
Cimicifuga for TAM/AI hot flashes?
Results: Comparing patients assigned to usual- care group with those assigned to
intervention group, the number and severity of hot flushes were reduced after
intervention. Almost half of the patients of the intervention group were free of hot
flushes, while severe hot flushes were reported by 24.4% of patients of intervention
group and 73.9% of the usual-care group (P B/0.01). Conclusions: Hot flushes were the
most frequent adverse reaction to tamoxifen adjuvant therapy in breast cancer
survivors. The combined administration of tamoxifen plus CR BNO
1055Menofem†/Klimadynon†, corresponding to 20 mg of herbal drug) for a period of 12
months allowed satisfactory reduction in the number and severity of hot flushes.
Muñoz, Gerardo Hernández, and Salvatore Pluchino. "Cimicifuga racemosa for the
treatment of hot flushes in women surviving breast cancer." Maturitas 44 (2003): S59-S65.
Cimicifuga in Thrivers-con’t
• 50 patients-isopropanolic extract of black cohosh
(1–4 tablets, 2.5 mg) for 6 months
– “...a reasonable treatment approach in tamoxifen treated
breast cancer patients.”
Rostock, M, et al. "Black cohosh (Cimicifuga racemosa) in tamoxifen-treated breast cancer patients with
climacteric complaints-a prospective observational study." Gyn Endo 27.10 (2011): 844-848.
• ?# of women-40mg/day for 2 months
– No change in freq/severity. Sig improvement in sweating.
Jacobson JS, et al. (2001) Randomized trial of black cohosh for the treatment of hot flashes among
women with a history of breast cancer. J Clin Oncol 19(10):2739–2745
• ?#- 40mg/day for 4 weeks->crossover
– No change in hot flashes
Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of
hot flashes: NCCTG Trial N01CC1. J Clin Oncol 24(18):2836–2841. doi:10.1200/ JCO.2005.05.4296
Black cohosh-NOT estrogenic, but…
In vitro, inhibited formation of 4-hydroxy-tamoxifen by
66.3%, N-desmethyl tamoxifen by 74.6% and α-hydroxy
tamoxifen by 80.3%
Inhibition of CYP2D6 and CYP3A4
Cimicifuga racemosa extracted roots/rhizomes in 75%
ethanol
Li J, Gödecke T, Chen S-N, et al. In vitro metabolic interactions between black
cohosh (Cimicifuga racemosa) and tamoxifen via inhibition of cytochromes P450
2D6 and 3A4. Xenobiotica. 2011;41(12):1021-30.
Clinically, must weigh this risk against the patient stopping
TAM altogether
If on aromatase inhibitor, this is not an issue
Thromboembolism and TAM
FVL mutations were identified in 23 (18.5%) case and 12 (4.8%) control subjects
(OR = 4.66, 95% confidence interval = 2.14 to 10.14, P < .001). In the
multivariable model, FVL mutation was associated with TE (OR = 4.73, 95%
confidence interval = 2.10 to 10.68, P < .001). Other statistically significant
factors associated with TE risk were personal history of TE and smoking.
Garber JE, Halabi S, Tolaney SM, et al. Journal of the National Cancer Institute. 2010
July 7, 2010;102(13):942-9. PMCID: PMC2897879
Lowering Risk of Thromboembolism
MOVEMENT/HYDRATION. Watch platelets (<300,000/mm3); no
smoking/no 2nd hand; consider mixed tocopherols/tocotrienols,
enzymes, fish oil (1-3 grams total daily), garlic, botanicals?
Test FactorII/V with conventional lab
Garlic and Tamoxifen
“Allicin, 10mg/kg orally, enhanded the efficacy of TAM in mice... TAM
intoxication resulted in a significant decline in SOD, GSH, and total
protein with significant elevation in TBARS, ALT and AST, ALP, LDH, total
bilirubin, γGT, and TNF-α levels. These changes are abrogated by allicin
treatment.”
Arthralgias- induced by Tam or AI’s
Can switch drugs until one is found that is tolerable. Each AI has a
different reactions/side effects in patients
Vitamin D (>66 ng/dL found to reduce arthralgias from letrozole.
Khan QJ., et al. ] Breast Cancer Res Treat. 2009, Aug 5.
Acupuncture
Treat much like osteoarthritis
Remove inflammatory foods
Fish oil – 1-3 grams total omega 3’s daily
Glucosamine sulfate- 1500mg/day
Curcumin, Boswellia, Enzymes (ie, Wobenzym-N) may reduce some
discomfort
Exercise- Reduction of Arthralgia
Over 12 months, women randomly assigned to exercise (n = 61) attended 70% (±
standard deviation [SD], 28%) of resistance training sessions and increased their exercise
by 159 (± SD, 136) minutes per week. Worst joint pain scores decreased by 1.6 points
(29%) at 12 months among women randomly assigned to exercise versus a 0.2-point
increase (3%) among those receiving usual care (n = 60; P< .001). Pain severity and
interference, as well as DASH and WOMAC pain scores, also decreased significantly at
12 months in women randomly assigned to exercise, compared with increases for those
receiving usual care (all P < .001).
41
Sexual Dysfunction in Breast
Cancer Thrivers
(1) decreased libido, arousal, or lubrication;
(2) dyspareunia (vaginal dryness->atrophy)
(3) anorgasmy
(4) body image concerns
(5) decreased nipple sensation
AI’s < TAM
65% of those under 45 years old had some form of
sexual dysfunction during tx. 44% had continuing
dysfunction after treatment ceased.
Kedde H, Wiel HBM, Weijmar Schultz WCM, Wijsen C. Sexual dysfunction in young
women with breast cancer. Support Care Cancer. 2013 2013/01/01;21(1):271-80.
Conclusion Increased testosterone level did not translate into improved
libido, possibly because women on this study were estrogen depleted.
Local Prasterone, through local androgen and estrogen formation, causes a rapid
and efficient reversal of all the symptoms and signs of vaginal atrophy with no or
minimal changes in serum steroids, which remain well within the normal
postmenopausal range.
Labrie F, Archer D, Bouchard C, et al. Intravaginal dehydroepiandrosterone (Prasterone), a
physiological and highly efficient treatment of vaginal atrophy. Menopause.
2009;16(5):907–22.
Dew J, Wren B, Eden J. A cohort study of topical vaginal estrogen therapy in women
previously treated for breast cancer. Climacteric. 2003;6(1):45-52.
Is Vaginal Estrogen Safe?
Lubricants: ex: Good Clean Love, PRN
Moisturizers: ex: Replens, daily
Topical estrogens? Okay with SERMs. Last resort with
AI’s. Always use lowest possible dose...
Estriol cream can be used
Kendall A, et al. Caution: vaginal estradiol appears to be contraindicated in postmenopausal
women on adjuvant aromatase inhibitors. Annals of oncology. 2006;17(4):584-7.
Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital
atrophy: a preliminary study. Gynecological Endocrinology. 2010;26(6):404-12
Other considerations
• Counseling
– Referral to specialists
• Oxytocin
– 200 units/ml. 10mL. Intranasal 0.5ml/pump. One
pump into each nostril daily, or as needed.
• Pelvic Floor relaxation/therapy
– PT referral
CNS Effects--Cognitive Changes
• SERM’s effects are relative to endogenous estrogen levels
• Older pts. with BrCA receiving TMX post chemo tx have better
verbal ability and processing speed.
• TMX has been shown to slow cognitive decline in postmenop.
women with Alzheimer’s disease
– “APO ɛ4+ women showed a greater beneficial effect of TMX on reversing the
cholinergic impairment than APO ɛ4- women on most tasks. This study
provides evidence that TMX may act as an estrogen-like agonist to enhance
cholinergic system activity and hippocampally mediated learning.”
*Newhouse P. et al. Neuropsychopharmacology. 2013;38(13):2632-43
11 randomized clinical trials...no change in hot flushes...ginseng
group showed more improvement in sexual dysfunction, overall
health status, depression and physical well-being compared to
the placebo group in the other 4 studies, suggesting limited
relief effect of ginseng on menopause symptoms
CNS Effects--Depression
Exercise improves depressive symptoms, particularly when…
Supervised, or partially supervised
More than 30 minutes in duration each time
Done outside one’s home
Craft LL, et al. KS. Exercise effects on depressive symptoms in cancer survivors: A
systematic review and meta-analysis. Cancer Epidemiology Biomarkers & Prevention.
2012;21(1):3-19.
This meta-analysis only included moderate intensity, not low
or high
9/14 RCT’s were on in breast cancer patients
Exercise and/or Therapy for tx induced
menopausal symptoms
Reduction in most symptoms of treatment induced
menopausal symptoms
422 women randomized to cognitive-behavioral therapy
(n=109), physical exercise (n=104), CBT/PE (n=106) or wait
list group/control
Intervention groups (all): sig. decrease in endocrine and GU
symptoms, improvement in physical functioning
Those including CBT had sig. decrease in perceived burden
of hot flashes, and increase in sexual activity
Most effects seen at 12 weeks and 6 month follow up.
Duijts SFA, et al. Efficacy of Cognitive Behavioral Therapy and Physical Exercise in Alleviating
Treatment-Induced Menopausal Symptoms in Patients With Breast Cancer: Results of a
Randomized, Controlled, Multicenter Trial. Journal of Clinical Oncology. 2012;30(33):4124-33.
Bone Health
Bone Health- Exercise
recommendations
Table 3. American College of Sports Medicine Exercise Guidelines to Preserve Bone
Health During Adulthood in the General Female Population
Mode
Weight-bearing endurance activities
(tennis; stair climbing; jogging, at least
intermittently during walking)
Activities that involve jumping (volleyball;
basketball) Resistance exercise targeting all
major muscle groups
Intensity
Moderate to high in terms of bone-loading
forces (ie, ground reaction forces >2 times
body weight)
Duration
30-60 min/d of a combination of weightbearing endurance activities, activities that
involve jumping, and resistance exercise
Frequency
Weight-bearing endurance activities 3-5
times per week
Resistance exercise 2-3 times per week
Winters-Stone KM, et al. A prospective model of care for breast cancer
rehabilitation: Bone Health and Arthralgias. Cancer. 2012;118(S8):2288-99.
54
Bone health
Calcium-Age specific, but generally about 1500mg
total from diet and supplements
Magnesium- At least half the dose of the calcium,
perhaps more if no loose stool
Vitamin D- ideal serum level debatable, my bias: mid
to high range (45-65 ng/dL)
Other bone minerals/trace minerals- silica, manganese,
boron (<3mg) ,etc. (okay in dietary amounts)
Collagen support- adequate protein intake, adequate
bioflavonoids
Consider home-made soup stocks using grass finished
beef, wild game, etc
Bone Health
Vitamin K2 (as MK-4) at high doses, esp. for
young women or those with
osteopenia/osteoporosis
Minimum, 15 mg/day. Therapeutic dose: 15mg tid (45mg/day)
Contraindication: Use of Coumadin/Warfarin
DOES NOT RAISE RISK OF CLOTTING
See summary :: Sept 2009 issue of Natural Medicine Journal
(www.naturalmedicinejournal.com)
K2 as MK-7? Less evidence for OP.
Potentiation of TAM/AI’s?
Melatonin and ER+ cancers
1. Dowregulates gonadal
Estrogen synthesis
2. Decreases ERα expression
And inhibits E2-ER complex
Binding to ERE in DNA = SERM
3. SEEM (selective estrogen
Enzyme modulator): decreases
Aromatase activity
Sanchez-Barcelo EJ, et al. J Pineal Res, 2005 May;38(4):217-22.
57
Melatonin, TMX & Breast Cancer
14 patients with metastatic breast cancer:
3 were non-responders to TMX
11 progressed after initial disease stabilization with TMX
Patients received TMX 20mg/d +
MLT 20mg QHS [mean duration of treatment = 8 mo.]
IGF-1 decreased in
responders
Partial response in 4/14 patients (28.5%)
Lissoni P, et al. Br J Cancer, 1995 Apr;71(4):854-6.
Mechanisms of melatonin’s pro-apoptotic effects: 2013, full text:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645656/
58
Melatonin and
Tamoxifen Resistance
Strikingly, our results also showed that melatonin acted both as a tumor metabolic inhibitor
and a circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to
tamoxifen and tumor regression. Together, our findings show how dLEN-mediated
disturbances in nocturnal melatonin production can render tumors insensitive to tamoxifen.
dLEN= dim Light Exposure at Night
59
Coriolus/ PSK and Breast Cancer: clinical data
• RCT of 914 women with breast cancer receiving Tamoxifen
as an addition to the then-conventional chemotherapy.
• Randomized subgroups received PSK immune therapy
(3000 mg/day for 24 months) in addition to
chemotherapy.
• PSK significantly extended survival in ER-negative, stage
IIA patients without lymph node involvement.
• A five-year, post-operative, RCT comparing chemotherapy to
PSK immune therapy in 376 women with stage II ER
negative breast cancer.
• The 5-year overall and relapse-free survival rate for ER
negative receptor patients was the same regardless of
whether they had received chemotherapy alone (a prodrug of 5-fluorouracil) or PSK (3000 mg/day) alone.
Toi M, et al. Cancer, 1992 Nov;70(10):2475-83
Morimoto T, et al. Eur J Cancer,1996 Feb;32A(2):235-42
60
Reducing Inflammation may
enhance therapies
Baumgarten SC, Frasor J. Minireview: Inflammation: An
Instigator of More Aggressive Estrogen Receptor (ER) Positive
Breast Cancers. Molecular Endocrinology. 2012 March 1,
2012;26(3):360-71.
deGraffenried LA, Chandrasekar B, Friedrichs WE, et al. NF-κB
inhibition markedly enhances sensitivity of resistant breast
cancer tumor cells to tamoxifen. Annals of Oncology. 2004
June 1, 2004;15(6):885-90.
Riggins RB, Zwart A, Nehra R, Clarke R. The nuclear factor κB
inhibitor parthenolide restores (Faslodex; fulvestrant)–
induced apoptosis in antiestrogen-resistant breast cancer
cells. Molecular Cancer Therapeutics. 2005 January 1,
2005;4(1):33-41.
Fish oil
Necessary, so should be part of all patients’ diets/supplements
Dietary equivalent dose is approximately 1.0-3.0 grams daily
Example: One can sardines in oil/ one serving of salmon
(wild)
Vegans: Use algae for DHA
May be therapeutic for joint pain, dry eyes, skin, and hair.
May lessen risk of thromboembolic events with TAM
May lessen bone loss through its anti-inflammatory effects
CONCLUSION
The clinical and experimental findings demonstrate various anticancer properties of
caffeine and caffeic acid against both ER+ and ER− breast cancer that may sensiJze
tumor cells to tamoxifen and reduce breast cancer growth.
What if there is no anti-estrogen Rx?
•
•
•
•
•
•
•
•
Soy is good in moderation (1-2 servings/day)
Cruciferous veggies-daily
Flaxseed- 2tbls or more, most days
Calcium-D-Glucarate: 500mg bid
MUST exercise (Risk reduction=25-50%)
Melatonin-20mg qhs
Vitamin D in range of 40-60ng/dL
Foundational measures,
bioflavonoids/polyphenols
Balunas MJ, Su B, Brueggemeier RW, Kinghorn AD. Natural Products as Aromatase
Inhibitors. Anti-cancer agents in medicinal chemistry. 2008;8(6):646-682.
GNRH Agonist with Aromatase
inhibitor
• Used in young women to shut down ovarian
production.
• goserelin (Zoladex®)
• leuprolide (Lupron®)
• Newly approved use (2015): GNRH agonist
with aromatase inhibitor in premenopausal
women
Muñoz E, González N, Muñoz L, Aguilar J, Velasco JAG. Ovarian stimulation in
patients with breast cancer. ecancermedicalscience. 2015;9:504.
doi:10.3332/ecancer.2015.504.