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San Antonio Breast Conference News: Supplements

The San Antonio Breast Conference is the biggest, most important breast cancer-related conventional conference for medical providers for breast cancer in the world. New research and treatment options are revealed at San Antonio, and sometimes we see a presentation about integrative therapies or other disciplines.

This year, my Bastyr classmate and head of the Integrative Medicine department at Fred Hutch, Dr. Heather Greenlee, was one of the speakers. Her presentation, about the use of supplements for breast cancer patients, has been picked up by major media outlets and social media pages, so you may have seen or heard about this from your friends or providers.

I have concerns about Dr. Greenlee’s role in setting the tone for integrative oncology—take me out for a cup of tea sometime—but I can unpack her statements for you so that you have a  better understanding of the data and the inherent concerns about them.

Points made by Dr. Greenlee:

• 50-80% of breast cancer survivors use supplements, and up to 30% use cannabis, to manage side effects
• Patients are looking for holistic options. However, natural compounds can interact with treatment efficacy (and responses can vary person-to-person)
• Vitamin D is good for the immune system, bones, and mood and may improve breast cancer outcomes
• Good News: Lavender aromatherapy is effective for anxiety
• Good News: Wisconsin ginseng (up to 2000mg daily) is effective for managing fatigue
• Good News: Great clinical outcomes for Exercise, Acupuncture, Cognitive Behavioral Therapy, and Mindfulness-based interventions for depression and anxiety
• Caution: Multi-vitamin Injection (MVI) may interfere with absorption
• Caution: Iron, B12 may worsen cancer outcomes
• Caution: Turmeric and melatonin may interfere with tx CYP enzyme interference
• Caution: Mushrooms may cause liver damage and bleeding
• Ineffective/harmful: Aloe vera and hyaluronic acid for radiation dermatitis; glutamine for  chemo-nausea; guayana and acetyl-l-carnitine for fatigue; soy for hot flashes. Acetyl-L-carnitine (ALC) may worsen neuropathy
• Cannabis: data is lacking (true), chemo-induced nausea (not strong efficacy data), may interact with CYP enzymes and or P-glycoprotein

Dr. Greenlee is accurate in citing data from published studies regarding breast cancer survivor use of supplements and cannabis, and in some of her reporting of data about particular compounds. If you are interested in more scientific details, I would like to give you some points to consider and some background on her claims. Please read on…

Yours in Health,

Dr. Laura

Scientific Details/Background
Good news: Lavender, American ginseng, acupuncture, exercise, cognitive behavioral therapy, and mindfulness-based practices all have good strong data and can be encouraged.

Ineffective or Harmful Compounds
Dr. Greenlee’s points about aloe vera and hyaluronic acid being ineffective for radiation dermatitis is correct. For glutamine being ineffectual for nausea, correct, but also, I have NEVER seen glutamine used for this purpose. Acetyl-L-carnitine potentially  worsening peripheral neuropathy is also correct. Soy, however not my first choice for hot flashes with breast cancer, is not harmful. HUGE retrospective analyses have shown soy’s benefit as a SERM (like Tamoxifen) for women with ER+ breast cancer.

Cannabis
Finally, regarding cannabis, stay tuned for next month’s blog because I will take a deep dive into what we know about cannabis and cancer and what we don’t.

Background
Several of Dr. Greenlee’s points stem from one 2020 SWOG study that looked at multivitamins,  B12, iron, and antioxidants in breast cancer patients. This study reports that B12 and iron use before and during chemotherapy (cyclophosphamide, doxorubicin, and paclitaxel) led to poorer outcomes; antioxidant use (vitamins A, C, E, and CoQ10) was not significant in terms of interference with the protocol; and that multivitamins were benign. It is interesting to note that  this study was conducted on women with high-risk breast cancer with high BMIs and positive nodal status. The results are correlative at best; not causal. There is nothing in this study that  shows a direct line from vitamin use to death, but the language sure makes it out to be that way. Additionally, Dr. Greenlee did not cite this same study regarding the use of MVI’s, rather she discussed a different one that contradicts it. Why not take data from the same study?

Ambrosone CB, Zirpoli GR, Hutson AD, McCann WE, McCann SE, Barlow WE, Kelly KM,  Cannioto R, Sucheston-Campbell LE, Hershman DL, Unger JM, Moore HCF, Stewart JA, Isaacs  C, Hobday TJ, Salim M, Hortobagyi GN, Gralow JR, Budd GT, Albain KS. Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a  Cooperative Group Clinical Trial (SWOG S0221). J Clin Oncol. 2020 Mar 10;38(8):804-814. doi:  10.1200/JCO.19.01203. Epub 2019 Dec 19. PMID: 31855498; PMCID: PMC7062457.

Multi-Vitamins
Multi-vitamins, probably the most benign of all supplements, “may interfere with absorption of  treatment drugs.” Multi-vitamins, however, are not all created equal. Many over-the-counter MVI’s are loaded with binders and fillers–magnesium stearate—to name one, and binders and fillers are indigestible. Each MVI also has varying levels of vitamins and minerals, and many contain plant compounds. If you have a favorite MVI, you can ask your doctor or pharmacist to check on each ingredient to see if there is an interaction. However, MVIs are really only useful if you are not getting enough good quality food, or if you have a known deficiency. Many of the vitamins and minerals in MVIs can be tested for in easy-to-do bloodwork.

Iron and Vitamin B12
Iron is useful if you have a known iron deficiency, best evaluated with a ferritin lab test. If your  ferritin is <20, you should probably take iron. However, if you don’t have documented iron  deficiency, iron can indeed feed cancer cell growth. MVI’s also often contain iron, and this is unnecessary.

Vitamin B12 can be measured in the blood and should be replaced if there is deficiency of it, but also a low methyl malonic acid (MMA) value. MMA is the functional form of B12. B12 has been  shown in clinical trial to improve peripheral neuropathy with chemotherapy, but it’s vernacular use to improve fatigue is ineffectual unless there is deficiency. Vitamin B6 is another useful vitamin, and improves peripheral neuropathy as well. B6 is shown to reduce breast cancer risk; and vitamin B9 to increase it. A recent systematic review of 24 articles describes how B vitamins affect different cancer outcomes. Dr. Greenlee’s citing of the 2020 SWOG study, while powerful in terms of number of subjects, should be read with a grain of salt when also looking at the  systematic review of 24 studies.

Van de Roovaart HJ, Stevens MM, Goodridge AE, Baden KR, Sibbitt BG, Delaney E, Haluschak  J, Kathula S, Chen AMH. Safety and efficacy of vitamin B in cancer treatments: A systematic  review. J Oncol Pharm Pract. 2024 Apr;30(3):451-463. doi: 10.1177/10781552231178686.  Epub 2023 May 25. PMID: 37231628. 

Turmeric (Curcumin*)
There is mixed information that the active compound in turmeric, curcumin, interferes with the CYP enzymes in the liver where drugs are often metabolized. It is important first to determine which CYP enzymes your drug is metabolized by, then look at your dose of curcumin. Overall standard over-the-counter curcumin is poorly absorbed, so much of it will come out in feces. Nanocurcumin, curcumin broken down into smaller pieces, is more absorbable, and biopterene from black pepper enhances this. Pharmacologically, curcumin has been shown not to interfere with paclitaxel significantly, even at a dose of 2g. Most other drugs have not been studied. Going from CYP pathway by drug and extrapolating is the best anybody can do.

Kalluru H, Mallayasamy S, Kondaveeti S, Chandrasekhar V, Kalachaveedu M. Effect of turmeric  supplementation on the pharmacokinetics of paclitaxel in breast cancer patients: A study with  population pharmacokinetics approach. Phytotherapy Research. 2022;36(4):1761-1769 

We do know that curcumin, through cell and animal studies, interacts with some liver isoenzymes and has been indicated as a potent inhibitor of CYP 1A1/1A2, a less potent inhibitor of CYP 2B1/2B2, and a weak inhibitor of CYP 2E1. Inhibition of CYP has also been demonstrated in vitro and in other animal research. In addition, curcumin has been shown to act as an inhibitor of permeability glycoprotein. A study from 2013 cites this mechanism as the reason the chemotherapy drug irinotecan was increased in the colonic lining of rats pretreated with curcumin, a result that points to possibly enhanced therapeutic benefit in the treatment of colon cancer, although the potential of increasing cytotoxic side effects was not studied. In general, the clinical effects of curcumin metabolism remain unclear.

Melatonin
Melatonin is our body’s natural dark sensor. We make melatonin in the pineal glad during darkness, and it helps us set a circadian rhythm that influences sleep and wakefulness. Melatonin has also been found to be an anti-inflammatory, immune modulator, antioxidant, and mitochondrial regulator. It has also been found to influence hormones throughout the body. Melatonin is also made in the gut, which makes it susceptible to the health of the microbiome. It affects both our cardiovascular system and reproductive systems as well, and can be used as treatments for disorders in these categories. The research on melatonin is vast and comprehensive. Research regarding its use in high doses in the setting of cancer shows its ability to modulate tumor cell growth and progression.

Melatonin is metabolized in the liver by the CYP1A2 enzyme, a cytochrome P450 enzyme utilized by many other compounds and drugs. SNP’s in this pathway can lead to a disordered melatonin metabolism. Estrogens are metabolized by many of the cytochrome P450 enzymes, as well as CYP1A2, and this may be why interference may be possible with breast cancer treatment. However, the primary drug metabolized in this pathway is anastrozole (not the whole category of AI’s), and it is an inhibitor of the pathway. This suggests that if one were taking melatonin as well, that melatonin levels would remain elevated in the system, not that the melatonin would impact the anastrozole. The result would be profound sleepiness. And keep in mind that caffeine— one of our favorite legal drugs—is also metabolized by CYP1A2. Thus wouldn’t it make sense that it would be on the “no” list with anastrozole but isn’t?

A 2023 systematic review of eight clinical trials using 20mg of melatonin in breast cancer patients showed improved quality of life during chemotherapy, improved partial response and improved one-year survival rates.

Ramos E, Egea J, López-Muñoz F, Gil-Martín E, Romero A. Therapeutic Potential of Melatonin Counteracting Chemotherapy-Induced Toxicity in Breast Cancer Patients: A Systematic Review. Pharmaceutics. 2023 May 30;15(6):1616. doi: 10.3390/ pharmaceutics15061616. PMID: 37376065; PMCID: PMC10303424.  

If you want to take a deep dive into melatonin, read this: Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements.

Mushrooms
Isolated reports of liver damage and bleeding do exist in the cancer literature, but generally the use of medicinal mushrooms is considered safe. These isolated incidents are often accompanied by concomitant use of strong pharmaceutical medicines and/or patients in poor health to begin with. The literature supporting the use of medicinal mushrooms in cancer care is vast. In fact, 25% of the national cancer care budget in Japan is spent on medicinal  mushrooms. There are complex immune modulators, nerve and brain modulators, and microbiome enhancers all inherent in mushroom compounds. Several studies support the use of Coriolus versicolor (Turkey Tail) in particular as an immune modulator in breast cancer, because it  increases Natural Killer (NK) cell function and activity.

*Curcumin Citations

1. Oetari S, Sudibyo M, Commandeur JN, Samhoedi R, Vermeulen NP. Effects of curcumin on  cytochrome P450 and glutathione S-transferase activities in rat liver. Biochem Pharmacol.  1996;51(1):39-45.
2. Azuine MA, Bhide SV. Chemopreventive effect of turmeric against stomach and skin tumors  induced by chemical carcinogens in Swiss mice. Nutr Cancer. 1992;17(1):77-83.
3. Ciolino HP, Daschner PJ, Wang TT, Yeh GC. Effect of curcumin on the aryl hydrocarbon  receptor and cytochrome P450 1A1 in MCF-7 human breast carcinoma cells. Biochem  Pharmacol. 1998;56(2):197-206.
4. Firozi PF, Aboobaker VS, Bhattacharya RK. Action of curcumin on the cytochrome P450- system catalyzing the activation of aflatoxin B1. Chem Biol Interact. 1996;100(1):41-51.
5. Nagabhushan M,Bhide SV. Curcumin as an inhibitor of cancer. J Am Coll Nutr.  1992;11(2):192-198.
6. Nayak S, Sashidhar RB. Metabolic intervention of aflatoxin B1 toxicity by curcumin. J  Ethnopharmacol. 2010;127(3):641-644.
7. Thapliyal R, Deshpande SS, Maru GB. Mechanism(s) of turmeric-mediated protective effects  against benzo(a)pyrene-derived DNA adducts. Cancer Lett. 2002;175(1):79-88.
8. Deshpande SS, Maru GB. Effects of curcumin on the formation of benzo[a]pyrene derived  DNA adducts in vitro. Cancer Lett. 1995;96(1):71-80.
9. Allen SW, Mueller L, Williams SN, Quattrochi LC, Raucy J. The use of a high-volume  screening procedure to assess the effects of dietary flavonoids on human cyp1a1  expression. Drug Metab Dispos. 2001;29(8):1074-1079.
10. Volak LP, Ghirmai S, Cashman JR, Court MH. Curcuminoids inhibit multiple human  cytochromes P450, UDP-glucuronosyltransferase, and sulfotransferase enzymes, whereas  piperine is a relatively selective CYP3A4 inhibitor. Drug Metab Dispos.  2008;36(8):1594-1605.
11. Appiah-Opong R, Commandeur JN, van Vugt-Lussenburg B, Vermeulen NP. Inhibition of  human recombinant cytochrome P450s by curcumin and curcumin decomposition products.  Toxicology. 2007;235(1-2):83-91.