Endocrine Therapy in Breast Cancer
Ever since oophorectomy was first shown to cause regression of advanced breast cancer more than a century ago, deprivation of estrogenic signaling has been the mainstay of endocrine management of estrogen receptor-positive and progesterone receptor-positive disease.1 Ovarian ablation can be achieved by way of surgical oophorectomy, radiation to the ovaries, or suppression with agonists of luteinizing hormone-releasing hormone (eg, leuprolide, goserelin). Ovarian oblation can be beneficial in delaying recurrence and in increasing survival in premenopausal women with hormone receptor-positive breast cancer. Data suggests similar benefit from surgical ovarian ablation as there is with the use of the cyclophosphamide/methotrexate/fluorouracil (CMF) chemotherapy regimen possibly due to the endocrine ablative effect of chemotherapy.2
Endocrine therapy for breast cancer is a targeted therapy appropriate for estrogen and progesterone-positive disease. Numerous endocrine agents have been developed in recent years, which include selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs).
Selective Estrogen Receptor Modulators
SERMs inhibit the growth of breast cancer cells through competitive antagonism of estrogen at its receptor. They bind to estrogen receptors and may exert antiestrogenic activity, estrogenic activity, or both. In breast tissue these drugs bind to estrogen receptors and exert an antiestrogenic effect by blocking estrogen from attaching to the receptors. However, SERMs exert an estrogenic effect on the endometrial tissue due to the difference in structure of the tissue receptors.
Tamoxifen, the most commonly used SERM, was approved for the treatment of breast cancer in the 1970s. It was the first SERM to be extensively investigated for its anticancer properties and has historically been considered the gold standard endocrine therapy in hormone-positive disease. Tamoxifen is indicated in hormone receptor-positive disease and is also prescribed preventively for women who are at high risk for breast cancer.
Tamoxifen increases the risk of endometrial cancer by 2.4 times and the risk for thromboembolic disease by 1.9 times.1 These side effects arise from the fact that while tamoxifen acts as an antiestrogen that blocks the effects of estrogen on breast cells, it mimics the actions of estrogen in other tissues such as the uterus. Its estrogen-like effects on the uterus stimulate proliferation of the uterine endometrium and increase the risk of uterine cancer. Tamoxifen resembles estrogen in its ability to lower LDL cholesterol levels. In postmenopausal women, tamoxifen also resembles estrogen in its ability to preserve or increase bone density.
Unfortunately, breast cancer relapses continue even beyond 15 years after therapy. Aromatase inhibitors may play a role in adding further cancer-fighting support without the concerns of endometrial cancer risk and thromboembolic disease.
Since the 1990s aromatase inhibitors have become the new gold standard for first line endocrine treatment in postmenopausal women with advanced breast cancer.
AIs block the peripheral conversion of the adrenal androgen substrate androstenedione to estrogen in the peripheral tissues, which is the primary source of estrogen in postmenopausal women. The third generation AIs, letrozole, exemestane, and anastrozole, are most commonly used due to the potency, selectivity, and lower toxicity concerns. AIs have been shown to reduce estrogen production by more than 90% in postmenopausal women.
Arthralgia and bone fractures were reported significantly more often in patients who received anastrozole, whereas hot flashes, vaginal bleeding, endometrial cancer, ischemic cerebrovascular events, and venous thromboembolic and deep venous thromboembolic events were more common in patients who received tamoxifen.
Prospective studies have demonstrated that bisphosphonates prevent aromastase inhibitor–induced bone loss and should be considered in patients at higher risk of fracture.
Within the last 5 years third generation AIs have become a standard treatment option for postmenopausal patients with estrogen receptor-positive advanced and metastatic disease.
Phase III trials have demonstrated that AIs are more effective and better tolerated than tamoxifen as first-line management of metastatic breast cancer in postmenopausal women. Tamoxifen remains the gold standard for prevention of breast cancer in high-risk groups. However, tamoxifen is no longer considered the standard of care in hormone receptor-positive disease, particularly in postmenopausal women.
Supportive Considerations with Endocrine Therapy
Osteoporosis is one of the most common side effects that occur with the use of aromatase inhibitors. Calcium and vitamin D supplementation as well as weight-bearing exercise is important for the prevention of bone loss. If bone loss is determined prior to treatment, then bisphosphonates should be considered.
Arthralgia is another common side effect observed in patients taking aromatase inhibitors.
Acupuncture may be beneficial in reducing AI-induced arthralgia. Improvement of symptoms was exhibited in a randomized, controlled, blinded study comparing true acupuncture vs sham acupuncture in postmenopausal women with breast cancer. Women with AI-induced arthralgias treated with true acupuncture had significant improvement of joint pain and stiffness, which was not seen with sham acupuncture. Pain scores were significantly lower after 6 weeks in the group who underwent true acupuncture.3
The anti-inflammatory effects of fish oil, Boswellia, and homeopathic Rhus toxicodendron may be helpful in alleviating AI-induced arthralgia.
In a controlled trial comparing NSAIDS with fish oil, patients complaining of arthritic pain were given 1200-2400 mg omega-3 essential fatty acids daily. After an average of 75 days, 59% discontinued their prescription NSAID medications for pain. Sixty percent stated that their overall pain had improved.4
An extract of Boswellia serrata, 5-loxin, was studied for the treatment of osteoarthritis of the knee in a double blind, randomized, placebo controlled study. The 5-Loxin reduced pain and improved physical functioning significantly in patients with osteoarthritis. It was concluded that this effect might be due to the reduction in proinflammatory modulators.5
Homeopathic Rhus tox is indicated when there is stiffness and pain associated with the muscles and joints. Studies suggest that it may interfere with the inflammatory processes involving histamine, prostaglandins and other inflammatory mediators.6
Hesperidin and Vitamin C
In a clinical trial consisting of 94 menopausal women with hot flashes, participants were give hesperidin and vitamin C. After one month the symptoms of hot flashes were completely relieved in 53% of the patients and reduced in 34% of the patients.7 My experience has been that hesperidin is also effective against AI-induced hot flashes.
In a pilot trial involving 25 patients with breast cancer, there was a significant reduction in the frequency of hot flashes when magnesium oxide was given. Eight of the patients were on tamoxifen and 9 of the patients were on aromatase inhibitors.8
Studies indicate that Cimicifuga racemosa does not demonstrate any estrogenic activity and can therefore be safely used in patients diagnosed with breast cancer.9 Cimicifuga has a significant breast cancer protective effect as well as antiestrogenic, antiproliferative, and antoxidant properties.10 In a trial consisting of 136 premenopausal women taking tamoxifen, the number and severity of hot flashes were reduced with the addition of Cimicifuga.11
There are a number of climacteric symptoms that can occur with endocrine therapies for breast cancer. As naturopathic physicians we are equipped with multiple tools to help support our patients through these therapies and improve their quality of life.
The Oncology Association of Naturopathic Physicians (OncANP) was founded in 2004 to enhance the quality of life of people living with cancer through both increasing the collaboration between NDs working with patients with cancer and integrating naturopathic practice into medical oncology care. With its coorganization, the American Board of Naturopathic Oncology (ABNO), the OncANP has set standards, instituted testing and now credentials Fellows in Naturopathic Oncology.
The OncANP welcomes all NDs interested in improving their knowledge and ability to work with oncology patients. For more information see www.OncANP.org.
Aminah A. Keats, ND, FABNO is the director of naturopathic medicine at CTCA at Eastern Regional Medical Center. A Fellow of the American Board of Naturopathic Oncology (FABNO), Keats earned a Doctor of Naturopathic Medicine degree from the University of Bridgeport College of Naturopathic Medicine in Bridgeport, Ct., and completed a two-year residency in naturopathic oncology at CTCA at Midwestern Regional Medical Center in Zion, Illinois.
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2. Casciato DA. Manual of Clinical Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.
3. Crew KD, Capodice JL, Greenlee H, et al. Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer. J Clin Oncol. 2010;28(7):1154-1160.
4. Maroon JC, Bost JW. Omega-3 fatty acids (fish oil) as an anti-inflammatory: an alternative to nonsteroidal anti-inflammatory drugs for discogenic pain. Surg Neurol. 2006;65(4):326-331.
5. Sengupta K, Alluri KV, Satish AR, et al. A double blind, randomized, placebo controlled study of the efficacy and safety of 5-Loxin for treatment of osteoarthritis of the knee. Arthritis Res Ther. 2008;10(4):85R.
6. dos Santos AL, Perazzo FF, Cardoso LG, Carvalho JC. In vivo study of the anti-inflammatory effect of Rhus toxicodendron, Homeopathy. 2007;96(2):95-101.
7. Smith CJ. Non-hormonal control of vaso-motor flushing in menopausal patients. Chic Med. 1964;67:193-195.
8 Park H, Parker GL, Boardman CH, Morris MM, Smith TJ. A Pilot Phase II Trial of Magnesium Supplements to Reduce Menopausal Hot Flashes in Breast Cancer Patients. Richmand, VA: Thomas Palliative Care Unit, Division of Hematology and Palliatiative Care; 2010, 1-13.
9. Lupu R, Mehmi I, Atlas E, et al. Black cohosh, a menopausal remedy, does not have estrogenic activity and does not promote breast cancer cell growth. Int J Oncol. 2003;23(5):1407-1412.
10. Rebbeck TR, Troxel AB, Norman S, et al. A retrospective case-control study of the use of hormone-related supplements and association with breast cancer. Int J Cancer. 2007;120(7):1523-1528.
11. Hernández Muñoz G, Pluchino S. Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer. Maturitas. 2003;44(suppl 1):59S-65S.