Aside from non-melanoma skin cancer, prostate cancer is the most common cancer among men in the United States. It is also one of the leading causes of cancer death among men of all races and Hispanic origin populations.(1)

Dietary Boron intake is inversely correlated with prostate cancer incidence. (5)

Prostate risk is  52% lower in men whose diets contain at least 1.8mg boron daily. Prostate cancer risk reduction is correlated with boron intake.  Recommended optimal daily dose of elemental boron is 3 mg/day for health maintenance.

Mechanisms of Action

Boron-containing compounds interfere with the physiology and reproduction of cancer cells through diverse mechanisms, including inhibition of serine proteases, NAD-dehydrogenases, mRNA splicing and cell division, receptor binding mimicry, and induction of apoptosis. (2) 

In several studies Barranco et al (7, 8, 9, 10) demonstrate that increased boron intake is associated with lower levels of Prostate Specific Antigen (a biomarker for prostatitis and prostate cancer) as well as modulation of serum estradiol leading to increased expression of ER-beta receptors and decrease of ER-alpha receptors on tumor cells decreasing proliferation and growth signaling.  Furthermore boron supplementation increased regulation of cell cycle arrest, increased apoptosis, decreased cell adhesion, migration and metastatic progression. 

Boron decreases cancer associated inflammatory factors including hs CRP, TNFa, Interleukin-6 all of which are elevated in the tumor microenvironment.   “Elevated hs-CRP is associated with an increased risk for breast cancer, obesity and metabolic syndrome (MetS) in children, atherosclerosis, unstable angina, insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), metastatic prostate cancer, lung cancer, adult depression, depression in childhood and psychosis in young adult life, coronary heart disease, and stroke." (2)

In  murine study Insulin Like Growth Factor was significantly reduced in the prostate tumor cells in boron dosed animals. The IGF-1 signaling pathway promotes cancer progression and its down regulation is associated with lower risk of prostate cancer. (6)

“Increased intracellular concentration of borate activates borate transporters and leads to growth inhibition and increased apoptosis. “ (2) (3) (11)

Boron may act as a Histone De-acetylase Inhibitor (HDI).  HDI’s act as therapeutic agents for cancer due to their impact on gene expression on growth arrest signaling, cell differentiation and apoptosis in cancer cells. (2)

Boronic Acid has been shown to inhibit hypoxia inducible factor (HIF) which is a physiological stimulus for tumor induced angiogenesis.  Inhibition of HIF leads to inhibition of Vascular Endothelial Growth Factor (VEGF) and the production of capillary blood supply to tumor cells. Angiogenesis leads to exponential tumor growth and to metastatic progression of solid tumors. (11)

Plant foods rich in boron include Avocados, dried apricots, dried prunes, raisins, red kidney beans, lentils, almonds, hazelnuts, brazil nuts, pistachios, cashews and walnuts.

In summary, dietary and supplemental oral boron intake should be optimized to create a tumor microenvironment and cancer terrain that decreases risk of prostate carcinogenesis,proliferation and disease progression through angiogenesis and metastasis. 

Selected References

1. American Cancer Society Statistics https://cancerstatisticscenter.cancer.org/

2. Scorei RI, Popa R Jr. Boron-containing compounds as preventive and chemotherapeutic agents for cancer. Anticancer Agents Med Chem. 2010 May;10(4):346-51. doi: 10.2174/187152010791162289. PMID: 19912103.

3. Romulus Ion Scorei and Radu Popa, Sugar-Borate Esters –Potential Chemical Agents in Prostate Cancer Chemoprevention  DOI: 10.2174/18715206113139990124 Volume 13, Issue 6, 2013 Page: [901 - 909]

4. Kiliccioglu I, Konac E, Varol N, Gurocak S, Yucel Bilen C. Apoptotic effects of proteasome and histone deacetylase inhibitors in prostate cancer cell lines. Genet Mol Res. 2014 May 9;13(2):3721-31. doi: 10.4238/2014.May.9.17. PMID: 24854658.

5. Cui Y, Winton MI, Zhang ZF, et al. Dietary boron intake and prostate cancer risk. Oncol Rep. 2004;11(4):887-892.

6. Pizzorno, L.  Review: Nothing boring about boron. Integrative Medicine Vol. 14, No. 4 August 2015

7. Barranco WT, Hudak PF, Eckhert CD. Evaluation of ecological and in vitro

effects of boron on prostate cancer risk (United States). Cancer Causes Control. 2007;18(1):71-77.

8. Barranco WT, Eckhert CD. Boric acid inhibits human prostate cancer cell proliferation. Cancer Lett. 2004;216(1):21-29.

9. Barranco WT, Eckhert CD. Cellular changes in boric acid-treated DU-145 prostate cancer cells. Br J Cancer. 2006;94(6):884-890.

10. Barranco WT, Kim DH, Stella SL Jr, Eckhert CD. Boric acid inhibits stored Ca2+ release in DU-145 prostate cancer cells. Cell Biol Toxicol. 2009;25(4):309-320.

11. Shimizu K, Maruyama M, Yasui Y, Minegishi H, Ban HS, Nakamura H. Boron-containing phenoxyacetanilide derivatives as hypoxia-inducible factor (HIF)-1alpha inhibitors. Bioorg Med Chem Lett. 2010;20(4):1453-1456.

Today, more and more patients are avoiding toxic chemotherapy in favor of targeted cancer therapies.  Among the many new therapies available are a class of immunotherapy drugs that take the brakes off of the immune system and mobilize T cells against tumor cells.

Because tumor cells have the capacity to disable T cells, this therapy addresses the huge problem of immune resistance in many cancers.  Drugs in the class of PD1 and PDL1 inhibitors were some of the first to be developed.  These drugs bind to PD1 or PDL1 receptors on the tumor surface and unleash the fury of the immune system upon the tumors by removing the inhibitory function of these ligands.

Nature has designed the immune system with both a gas pedal and a brake.  The PD1 and PDL1 inhibitors are the brakes.  Take off the brakes and the immune system is activated.

The best of outcomes with these treatments may result in complete tumor eradication, a truly miraculous outcome for some patients.  I have a patient who came to me with Stage 4 Endometrial Cancer with Lung Metastases some years ago.  After reduction of some of her tumor burden with surgery and rather brutal chemotherapy, her very forward-thinking Gynecologic Oncologist included a course of Keytruda (Pembrolizumab), which was a new immunotherapy treatment at the time. 

The historical prognosis for this patient would have been certain eventual mortality for her metastasized aggressive cancer.  However, she achieved a complete response and has been in remission and designated NED or No Evidence of Disease for many years now.   This is a patient who most likely would not be alive today without the advent of PD1 -PDL-1 inhibitor therapy.

The problem with this class of drugs is that their use is very unskillful and very unpredictable. Some patients will respond with a modicum of mild to moderate systemic autoimmune inflammation while other patients will be disabled by furious, extreme, and damaging autoimmune syndromes.  Some patients may die from extreme autoimmune activity.  I had one patient who developed myocarditis and died within a few days of receiving his first dose.  This was a prostate cancer patient whose sudden death was completely unexpected and not predicted.   

These patients require a health model and safe, effective modulation of extreme auto-immune inflammation not provided by their oncology teams. 

Some patients will have immune activation similar to a nice warm burning ember.  They get the therapeutic benefit without extreme adverse effects.  While other patients will respond with a forest fire of inflammation that must be suppressed aggressively with steroid medications for long periods of time.  The adverse effects of long-term steroid therapy then become part of the clinical picture and challenge for these patients.  In these circumstances, it IS reasonable to ask if the cure is worse than the disease itself? 

My patient developed such severe colitis (a common adverse effect) that she visited the emergency room multiple times for fluid and electrolyte replacement due to extreme persistent watery diarrhea.  Additionally, the nutritional status of this patient was also compromised and she became depleted in both calories and nutrients and developed sarcopenia.

Many cancer patients receiving PD1 and PDL 1 inhibitors are left with lifelong autoimmune disease.   Most common are autoimmune arthritis, colitis, thyroiditis, dermatitis, pneumonitis, and associated loss of normal tissue and organ function.  Some patients suffer ongoing chronic inflammatory pain syndromes.

Less prevalent, but also part of the long list of adverse effects are myocarditis, pericarditis, nephritis, hepatitis, pancreatitis, neuritis, vasculitis. Essentially, any tissue or organ can be impacted with associated loss of function and sequelae.

It is my practice to screen and monitor patients receiving cancer immunotherapies for the development of autoimmune syndromes and intervene early.  If I have a patient with a history of inflammatory or autoimmune disorders I can predict that such patients are more likely to develop adverse effects. 

Additionally, high levels of inflammation not only lead to pain syndromes but are also contributors to ongoing chronic fatigue as well as agitation,  cognitive changes, sleep disruption, anxiety, and depression, and the stress of living not only as a cancer survivor but with a chronic and distressing autoimmune syndrome difficult to control and manage.  It is my firm goal that Quality of Life must be a goal in all treatment plans for cancer patients and survivors.

 If a patient has NO inflammatory adverse effects it is assumed that the patient is not going to benefit from the PD1/PDL1 inhibitor because there is no sign or symptom indicating immune activation.   I always tell patients we should celebrate if they develop a rash or diarrhea because we know the drug is working!   

In fact, it is my observation over many years of following patients who have received these therapies that when the course of immunotherapy treatment is completed those patients who continue to have low levels of inflammation continue to have the therapeutic benefit of tumor control.  This is only an empirical observation on my part.  For example, the endometrial cancer patient described above continues to have mild colitis and has remained in remission.  Before the availability of these therapies, we would expect this patient to have a recurrence and to die of her advanced stage 4 metastatic disease within a few years of her diagnosis.   Patients such as this with lung metastases historically had very poor prognoses and very high mortality rates.  Patients with powerful and manageable responses to PD1 and PDL1 inhibitors may live a long time.  While some patients do recur, some have not.  We have not had decades of time to follow these patients as these treatments are relatively new.  If nothing else, these treatments do extend the life of many patients.

How can we modulate the auto-immune adverse effects of these potentially curative immunotherapy treatments?   I have taken the approach that we employ in Functional and Naturopathic Medicine in the management of auto-immune syndromes to turn down the volume on the immune inflammation just enough to reduce extreme side effects, damage, and loss of function without losing the therapeutic benefit of these immunotherapy treatments.   

While we can rely on studies that have demonstrated that Omega 3 Fatty Acids, Vitamin D3, and Curcumin and a healthy microbiome can modulate auto-immune inflammation, there is a paucity of research on managing autoimmune syndromes related to immunotherapy adverse effects with the exception of steroids. (See selected references below.)

I share with you here my empirical clinical experience.  I have employed this approach with several hundred patients since immunotherapies have come into wider use in oncology.  Clinicians experienced in managing autoimmune syndromes will recognize the basic principles of care.

• Anti-Inflammatory, Low Antigen Diet
• Support for the healthy intestinal microbiome 
• Specific Nutriceutical-Phytochemical Interventions
  • Omega 3 Fatty Acids (EPA DHA)  recommended dose 4-6 grams daily SPMs Specialized ProResolving Mediators can also be considered 1-2grams daily
  • Fat soluble Curcumin recommended dose 2-6 grams daily
  • Vitamin D3 5,000-25,000iu daily  (125mcg-625mcg). 
    • Consider a loading dose of 50,000iu (1.25mg)

I always start at the lower end of the dose range and spread the dosing out into 3-4 doses over the day.  The goal is to MODULATE but not SUPPRESS the therapeutic impact.  It is also important to be mindful of the anticoagulant/platelet aggregation inhibitory effect of such an approach and to determine which patients may NOT be a candidate for high dosing due to thrombocytopenia or anticoagulant pharmaceutical therapies.

This approach has few negative drug-nutrient interactions. I have continued these inflammation-modulating therapies continuously for many years with most patients.  Dosing is highly individualized to each patient towards the goal of supporting and promoting healthy function and quality of life.

For front-line clinicians interested in supporting the health of cancer patients and cancer survivors and learning and implementing my OutSmart Cancer® System developed over 35 years in practice, I encourage you to join our training program, Foundations of Integrative Oncology, self-paced online training with clinical supervision and mentoring.  Go to aiiore.com.  

There is a huge population of patients whose lives have been touched by cancer searching for a health model and skilled and knowledgeable clinicians.

Selected References:

Vitamin D and autoimmune diseases.
Illescas-Montes R, Melguizo-Rodríguez L, et al Life Sci. 2019 Sep 15;233:116744. doi: 10.1016/j.lfs.2019.116744. Epub 2019 Aug 8. PMID: 31401314 

Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis.
Grover S, Dougan M, et al Cancer. 2020 Aug 15;126(16):3758-3767. doi: 10.1002/cncr.32966. Epub 2020 Jun 22. PMID: 32567084

Therapeutic Potential of omega-3 Polyunsaturated Fatty Acids in Human Autoimmune Diseases.
Li X, Bi X, Wang S, Zhang Z, Li F, Zhao AZ.
Front Immunol. 2019 Sep 27;10:2241. doi: 10.3389/fimmu.2019.02241. eCollection 2019.  PMID: 31611873 

Resolvins: Emerging Players in Autoimmune and Inflammatory Diseases.
Abdolmaleki F, Kovanen PT, et al 
Clin Rev Allergy Immunol. 2020 Feb;58(1):82-91. doi: 10.1007/s12016-019-08754-9. PMID: 31267470 

Curcumin in Autoimmune and Rheumatic Diseases.
Yang M, Akbar U, Mohan C.
Nutrients. 2019 May 2;11(5):1004. doi: 10.3390/nu11051004.
PMID: 31052496 

Curcumin and autoimmune disease.
Bright JJ.
Adv Exp Med Biol. 2007;595:425-51. doi: 10.1007/978-0-387-46401-5_19. PMID: 17569223  

Curcumin as an Adjuvant to Cancer Immunotherapy.
Paul S, Sa G.
Front Oncol. 2021 Aug 16;11:675923. doi: 10.3389/fonc.2021.675923. eCollection 2021.
PMID: 34485117 

Gut Bacteria Influence Effectiveness of a Type of Immunotherapy. https://www.cancer.gov/news-events/cancer-currents-blog/2018/gut-bacteria-checkpoint-inhibitors. Feb 2018  NCI Staff