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breast-cancer

Should PreMenopausal Breast Cancer Patients Receive Endocrine Therapy?

 

Endocrine Therapy Provides TwentyYear Benefit in ER+ Breast Cancer

Integrative and Individualized cancer care is the best cancer care and yields the best long term outcomes. Making individualized care decisions and including a health model, not just a disease model and following the OutSmart Cancer® Diet Guidelines are core principles of the OutSmart Cancer® System.

Two years of adjuvant endocrine therapy in premenopausal patients with estrogen receptor-positive (ER+) breast cancer can reduce the risk of recurrence at 20 years, according to a study published in the Journal of Clinical Oncology. (2)  This study is meaningful because many oncologists recommend five to ten years of endocrine therapy.  This study clearly demonstrates that only two years is sufficient to significantly reduce risk of breast cancer recurrence 20 years after completion of conventional oncology treatment.  This study also demonstrates that women who are candidates for and who do not receive endocrine therapy have worse outcomes. 

Furthermore this study demonstrates that women with low genomic risk should receive tamoxifen and women with high genomic risk should receive goserilin for best long term outcomes.

By including an integrative approach utilizing the health principles of the OutSmart Cancer® System, we can further manage the side effects of these treatments and support healthy function and quality of life for these women.

OUTSMART CANCER SYSTEM® Integrative Approach and Health Focussed Model

chinese-characterEspecially supportive to management of adverse menopausal effects of endocrine therapy include acupuncture therapy(3), copper free bone mineral formula and optimized Vitamin D as well as traditional Chinese Herbal Tonics

 that nourish yin and blood and support kidney qi to modulate menopausal symptoms without estrogenic effects such as Er Xian Tang (Two Immortals Formula)  and also formulas to address hormone depletion related mood dysregulation, depression and irritability such as Shu Gan Tang (Buplerum and Evodia Combination) to harmonize the liver qi and relieve stagnation of blood and emotions.  Furthermore, patients with estrogenic cancers should be given guidance on restricting estrogenic foods from their diets as part of a lifelong plan to prevent recurrence. For example,  both red meat (7) and alcohol (6) are known carcinogens linked to promotion of breast cancer and should be restricted.  Following the OutSmart Cancer® Diet Guidelines is recommended 

Monitoring for complications of endocrine therapies

Patients receiving Tamoxifen therapy  (an oral selective estrogen receptor modifier) should have semi-annual uterine ultrasound to measure endometrial thickness to assess risk of uterine hyperplasia and neoplasm as a risk of tamoxifen therapy.

Patient receiving goserilin  (an injectabl luteinizing hormone releasing hormone antagonist administered subcutaneously either every month or every 3 months) should monitor bone density by having a baseline DEXA bone density scan at inception and at 2 years and also Urine N-Telopeptide assay to monitor rate of loss of bone minerals due to medical menopause and estrogen blockade.

Results of Study

Researchers observed significant improvements in long-term distant recurrence-free interval (DRFI) for patients who received goserelin alone, tamoxifen alone, or the combination of goserelin and tamoxifen, when compared with patients who did not receive endocrine therapy. 

However, combination goserelin and tamoxifen did not improve DRFI when compared with either agent alone.

Researchers assessed the 20-year benefit of endocrine therapy by analyzing data from the Stockholm trial (1990-1997). The analysis included 584 patients with ER+ breast cancer. The median age at baseline was 47 (range, 26-55) years, 91% of patients had progesterone receptor-positive tumors, and 88% had HER2-negative tumors.

Patients were randomly assigned to 2 years of goserelin (n=155), tamoxifen (n=135), combined goserelin and tamoxifen (n=149), or no adjuvant endocrine therapy (n=145).

In a multivariable analysis, any endocrine therapy was associated with a significant improvement in long-term DRFI, when compared with no endocrine therapy. 

There was a significant improvement in DRFI with goserelin alone (hazard ratio [HR], 0.49; 95% CI, 0.32-0.75), tamoxifen alone (HR, 0.57; 95% CI, 0.38-0.87), and goserelin plus tamoxifen (HR, 0.63; 95% CI, 0.42-0.94). 

However, there was no significant long-term benefit from the combination of goserelin plus tamoxifen, when compared with either agent alone. There was a significant interaction between goserelin and tamoxifen (P =.016). 

The researchers also assessed the long-term benefit of endocrine therapy in patients with low genomic risk (n=305) and those with high genomic risk (n=158). 

Patients with low-risk genomics had a significant improvement in DRFI with tamoxifen (HR, 0.24; 95% CI, 0.10-0.60), and patients with high-risk genomics had a significant improvement in DRFI with goserelin (HR, 0.24; 95% CI, 0.10-0.54).

Patients with high-risk genomics had significantly worse DRFI when tamoxifen was added to goserelin (HR, 3.36; 95% CI, 1.39-8.07). The interaction between goserelin and tamoxifen was significant in high-risk patients (P =.006) but not in low-risk patients (P =.080). 

“This study demonstrates long-term benefit from 2 years of adjuvant endocrine therapy in ER-positive premenopausal patients,” the researchers concluded. “Furthermore, it suggests long-lasting benefit from tamoxifen in genomic low-risk patients with long-term risk of distant recurrence, whereas genomic high-risk patients have early risk and benefit from goserelin.”

Isoflavones genistein and daidizen are phytochemicals derived from soy act  that act as MILD selective estrogen receptor modulators. These isoflavones need to be taken in very high doses on a long term basis to achieve a clinical impact and are mild in comparison to pharmaceuticals.  A recommended daily dose of genistein is 1000mg 3x/day

This study will help us support patients in making educated and informed choices and in making sure that their oncologists are practicing in accordance with the most current research and guidelines and that patients 

 

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Using Phytochemicals

Using Phytochemicals Synergistically with Chemotherapy to Improve Efficacy and Outcomes

 

The role of polyphenols in overcoming drug resistance. 

In a paper published in January 2022, Maleki Dana et al, engage in a thorough review of multiple polyphenols which, when used concurrently with chemotherapy, can inhibit the development of chemo-resistance, rendering treatment more effective and for a longer duration of time.    

Most oncologists are wary of negative drug-herb, drug nutrient interactions. 

 

polyphenols-fruits

This review shows that we can use polyphenol phytochemicals synergistically with chemotherapy treatments to support efficacy and outcomes.

 

The Outsmart Cancer® System is an Integrative Cancer Care model seeking to develop highly individualized care plans that include the best therapeutic approaches and tools from multiple disciplines, combining a disease focused targeted pathology model with a whole biosystem health model to support the best outcomes for patients.

 

Acquired drug resistance has become a challenge that may result in treatment failure.  Multiple factors contribute to chemo-resistance in cancer cells. Acquired drug resistance occurs when cancer cells fail to respond to a previously effective treatment.  Intrinsic  chemo-resistance occurs when a pre-existing factor causes a drug to be inefficient or ineffective.

 

Due to the inherent heterogeneity of tumors, subpopulations of cells may develop resistance while other subpopulations remain sensitive to treatment.  

This is the rationale for using multiple agents which impact multiple signally pathways and receptors to target a wide array of heterogeneous cells.  This is also the rationale for using multiple nutriceuticals, botanicals and phytochemicals concurrently to address multiple signaling pathways and functions.

In this excellent review paper the author focuses on the multiple synergistic functions of polyphenols citing multiple studies.

 

Polyphenols from medicinal plants and food plants form a large part of our Materia Medica. Polyphenols include several subclasses such as catechins, flavonoids, flavones, flavonols, anthocyanins, isoflavones, curcuminoids, chalcones and phenolic acids. These natural compounds are widely found found in deeply pigmented fruits, vegetables, cocoa, seeds and green and black teas,

 

Not only do polyphenols inhibit multiple pathways and mechanisms of drug resistance, but also act to  confront many of the Hallmarks of Cancer, thus inhibiting and controlling the activity and viability of malignant cells.

 

The multiple functional roles of

  • Resveratrol
  • EGCG Epigallocatechin gallate
  • Curcumin 

are discussed and examined in depth examining multiple pathways, mechanisms of action and dosing.

Also discussed are additional well researched polyphenols, many of which are sourced from food plants as well as medicinal plants including

  • Quercetin 
  • Baicalin
  • Baicalien
  • Apigenin
  • Chrysin
  • Luteolin
  • Kaempferol

Mechanisms which lead to drug resistance in tumor cells

Malignant cells are highly adaptive and respond to toxic stressors such as chemotherapeutic drugs in the tumor micro-environment in service to their own survival.  Essential malignant cells are “smart” and they can not only co-opt normal physiologic and metabolic functions within cells to respond to the presence of toxic drug therapies.

  • Decreased Drug Uptake by tumor cells
  • Drug Efflux from tumor cells (membrane pumps)
  • Alterations in drug metabolism
  • Epigenetic Modification and Signaling
  • Inhibition of Programmed Cell death via apoptosis, autophagy and necrosis in tumor cells
  • Alterations in DNA repair 
  • Activity of Cancer Stem Cells
  • Redox Capacity of cells in response to oxidative stress
  • Alterations in Epithelial to Mesenchymal Transition, Invasion and Metastatic Progression

Not only are polyphenols capable of addressing the common Hallmarks of Cancer, but they can also inhibit the multiple ways that malignant cells seek to survive in the face of drug therapies.  

 

Therefore, we should strategically combine chemo-therapeutic  agents with selected polyphenols to both enhance therapeutic effect as well as inhibit the development of drug resistance. 

 

This leads to greater therapeutic benefit, increased duration of action as well as skillful management of adverse effects.

I encourage you to read this paper in detail for a deep and detailed review of the mechanisms of these pleomorphic multitaskers polyphenols.  The polyphenols mentioned in this paper have a history of wide use and safety.

 

Our role is to both eradicate and inhibit neoplastic cells as well as nurture and support the health of the patient.  This is at the heart of the OutSmart Cancer® System.

 

References

 

The Role of Polyphenols in Overcoming Cancer Drug Resistance: A Comprehensive Review 

Maleki Dana et al

Cellular and Molecular Biology Letters (2022) 27:1

https://doi.org/10.1186/s11658-021-00301-9

 

Hallmarks of Cancer: The Next Generation

Douglas Hanahan, Robert A. Weinberg, 2011

https://doi.org/10.1016/j.cell.2011.02.013

 

Revisiting the hallmarks of cancer

Fouad YA, Aanei C.. Am J Cancer Res. 2017 May 1;7(5):1016-1036. PMID: 28560055; PMCID: PMC5446472.

 

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