What is Triple-Negative Breast Cancer?
by Barbara MacDonald, ND, LAc
Two out of three breast cancers are ERPR-positive, meaning they have receptor sites that are sensitive to estrogen and progesterone. 1 Around twenty percent of breast cancers are stimulated by a protein called human epidermal growth factor. These are called HER2-positive.
There is a less common type of breast cancer that is not sensitive to, or stimulated by, estrogen, progesterone or HER2. These are called “triple-negative breast cancer” (TNBC) and they make up approximately fifteen percent of all invasive breast cancers diagnosed in the United States. 2
While there are an increasing number of studies being done on TNBC, there are still,many unanswered questions. A few years ago, I began seeing more and more women with TNBC in my practice. However, rates of TNBC actually went down from 2006-2010. 3 This article explains what is known about TNBC, who tends to get it, its risk factors, prognosis,conventional treatments and the little data that is known about natural medicines that have been studied to confront it. It is my hope that more studies will illuminate the nature of this less common and more aggressive form of breast cancer.
The pathology of triple-negative breast cancers
TNBC is considered to be a more aggressive type of breast cancer. It is typically
characterized by a ductal histology, high grade, high proliferation and mitotic rates. It is associated with poorer disease-free survival rates regardless of stage at diagnosis. 4 TNBC has a higher likelihood of local recurrence, especially when multiple nodes are positive. The risk of recurrence in patients with TNBC is higher in the first three years compared to those with the 1 hormone-positive/HER2-negative type.5 There are higher rates of distant metastasis to the lung, liver and brain than non-TNBC and lower rates of metastasis to the bones.6 Rates of BRCA gene mutations tend to be high among women with TNBC, particularly when diagnosed at a young age. 7
It is only in the last few years that pathologists began characterizing breast cancers by their molecular subtypes. In order to delineate each subtype through gene-expression profiling, a new classification system was created. The most common type of breast cancer is called ‘luminal A’ which is ER-positive and/or progesterone-positive, HER2-negative. ‘Basal-like’ breast cancers are ER-negative, PR-negative and HER2-negative, cytokeratin 5/6-positive and/or epidermal growth factor receptor-positive.8 This is helpful for research studies, however, it leaves room for confusion when discussing TNBC. Approximately 75% of TNBCs express basal markers. 9 Basal-like breast cancers are triple-negative but not all TNBCs are basal-like.
Epidemiology of triple-negative breast cancer
Black women of diverse backgrounds are three times more likely than non-black womento have TNBC, regardless of age or weight. In the United States, TNBC makes up 15-20% of the total invasive breast cancers. The prevalence of TNBC among white Americans is 10% and among African-Americans is 33%. The total number of cases of TNBC globally is approximately 170,000. 10 The prevalence of TNBC in Ghana, however is 82% – the highest percentage of breast cancers of this subtype globally.11 The incidence of TNBC, as a particularly aggressive type of breast cancer, may contribute to the lower survival rates among women of color. Younger age, premenopausal status, increased parity, high histological grade and advanced disease have been associated independently with TNBC. 12
2 Genome studies identified 25 known breast cancer susceptibility loci as risk factors for TNBC.13 Among them, there is an association between CYP2C19 deletion; a single nucleotide polymorphism related to estrogen catabolism.14 Immune signatures vary among those with TNBC as well. A cytokine known as IL-5, which plays a role in certain allergic and inflammatory conditions, is particularly high among premenopausal women with TNBC.15 We have also learned from studies of Chinese women, with early stage primary TNBC, that having type 2 diabetes (T2DM) increases ones chances of local recurrence and metastasis (from 4.6% in the non-T2DM group to 23% in the diabetic group). The two year survival rates among TNBC patients without diabetes was 97% compared to 78% in the diabetic group. 16
Etiology of TNBC
The risk factors that contribute to triple-negative breast cancer are varied and not yet fully understood. Associations between TNBC and weight, menopausal status, parity, breastfeeding, cigarette smoking and alcohol have all been studied – most with conflicting results.
Being overweight or obese increases the risk of breast cancer in general. However, among studies of triple-negative breast cancer the studies are contradictory. TNBC incidence was studied within one white, socioeconomically deprived, population in West Virginia. TNBC occurred more frequently among younger women, with later stage at diagnosis, and was associated with obesity. 17 Another study found weight to be a factor in the development of TNBC among premenopausal women.18 While these and other studies did find this association between menopausal status, weight and TNBC, another found the opposite among African- Americans. Stead, et al reported that TNBC was equally common in black women diagnosed 3 before and after age 50, and who were obese and non-obese. Considering all patients in the study, as body mass index increased, the proportion of TNBC decreased. 19
Parity and Breastfeeding
Parity and nursing seems to affect one’s risk of TNBC. One study author determined that TNBC cases tended to be younger at diagnosis and African-American and were more likely to have not breastfed if they three or more children.20 In another study, compared to non-TNBC cases, women with TNBC had a shorter duration of nursing each child and a higher parity.21 Among participants in the Women’s Health Initiative, never having children was associates with decreased risk of TNBC but increased risk of ER-positive breast cancer. Among those who had children, the more births, the higher the risk of TNBC. 22
Oral Contraceptive Use
Studies reporting an association between TNBC and use of oral contraceptives are varied as well. The author of one such study found that using birth control pills for more than one year was associated with a 2.5-fold increased risk of TNBC and no increased risk among non- TNBCs.23 Another study found no such risk association. 24
Cigarette smoking and alcohol consumption
According to a study published using the Women’s Health Initiative, cigarette smoking is not associated with risk of TNBC. Alcohol use was found to reduce the risk compared to those who have never drank alcohol among postmenopausal breast cancer patients. However both exposures increased the risk of ER-positive breast cancer.25
BRCA Gene Mutations 4
Seventy-five to eighty percent of BRCA1-associated breast cancers are basal-like TNBCs. One study of 469 women with TNBC found that 31% had a BRCA mutation; 106 with BRCA1 and 32 with BRCA2 mutations. The rates of TNBC among those with BRCA mutations decreased with age – from 44% among those diagnosed before age 40 compared to only 13% of those in their 60’s who were BRCA-positive with TNBC. 26
Conventional Treatments of TNBC
Conventional treatment of hormone sensitive (luminal A), breast cancer is well established and has specific guidelines based on a well-established criteria. This is not yet the case for triple-negative breast cancer. Due to a lack of research on this type of cancer, there are no established guidelines for the treatment of TNBC. Surgical recommendations currently follow the same guidelines as non-TNBC unless the patient also has a BRCA gene mutation. It is recommended that patients remember, however that there is a higher likelihood of local recurrence in the first three years than in those with non- TNBC. To date, there are no FDA-approved single target therapies for TNBC. In general, oncologists recommend chemotherapy even if the tumor is small and node negative. This is due, in part, because of the higher risk of spread to internal organs and partly because TNBC responds very well to chemotherapy. The studies on which chemotherapy agent(s) work best, however are limited. Future studies appear to be targeting the five subtypes of TNBC based on the signaling pathways unique to each. Some authors recommend molecular testing prior to choosing chemotherapy.27 TNBC responds better to chemotherapy administered prior to surgery 5 (neoadjuvant) than other breast cancer subtypes. Having neoadjuvant chemotherapy has been found to induce a pathological complete response in about 30%, which means that the chemotherapy resolved any evidence of the cancer by the time of surgery. 28 Those who reached pathological complete response correlated with better prognosis in all the neoadjuvant trials. 29 It was also found that among premenopausal women with TNBC, those who were 35 years or younger more often achieved a pathological complete response to neoadjuvant chemotherapy. 30
TNBC, like luminal A breast cancer, has been identified as sensitive to taxanes and anthracycline chemotherapeutic drugs. Standard Adriamycin, Cytoxan followed by Taxol (AC/T) is often prescribed. More recently, it has been observed that Cytoxan and Taxotere are being combined. Platinum agents are effective in TNBC patients with BRCA1-gene mutation, either alone or in combination with poly-adenosine-diphosphate polymerase-1 inhibitors. Combinations of ixabepilone and capecitabine have added to progression-free survival (PFS) without survival benefit in metastatic TNBC.31 The 2013 San Antonio Breast Cancer Symposium reported an improved outcome when veliparib and carboplatin were added to standard AC/T chemotherapeutic regimen.32 Lastly, it was found that those who began chemotherapy within 30 days after surgery, had better overall survival than those who waited longer to start chemotherapy.33
There are no established guidelines for the prescription of radiotherapy among those with TNBC. Standard indications for radiation therapy apply. Unlike those with estrogen receptor-positive breast cancer, who are offered oral medications (to block hormones) after chemotherapy and surgery, there are no post-chemo oral drug therapies recommended for those with TNBC. Three conventional medications that are used for other diseases have been studied in- vitro with TNBC however. Metformin, an anti-diabetic drug, has been found to selectively kill 6 TNBC cell lines. 34
In addition, a proton pump inhibitor used for gastroesophageal reflux, esomeprazole, suppresses growth of TNBC cells independently while sensitizing cells to doxorubicin (Adriamycin). 35 Finally, early in-vitro and animal studies found that aspirin may play a role in the fight against TNBC36 as it slows the growth of TNBC cell lines and reduces tumor growth in mice. 37 However, in a retrospective look at breast cancer patients it was found that regular aspirin use was not associated with any protection from developing TNBC.
Finally, twelve percent of women with metastatic estrogen/progesterone receptor- negative breast cancer tested positive for androgen receptors in one study. Twenty-one percent remained stable for at least 6 months in response to treatment with an anti-androgen drug, called bicalutamide, commonly used for prostate cancer. All but one of these were Her2-negative. 38
Natural Therapies for TNBC
There are several natural therapeutic agents showing promise when studied to retard the growth of TNBC cell lines in-vitro and in animals. The following natural therapies provide us with tools to consider in prevention of recurrence strategies:
- Those with the triple-negative breast cancer phenotype have the lowest average vitamin D levels and the highest percentage of patients that are vitamin D deficient. 39 Vitamin D given to a mouse model suppressed multiple proteins that are required for survival of triple-negative/basal-like breast cancer cells.40
- A product called BreastDefendtm that contains medicinal mushrooms (Coriolus versicolor, Ganoderma lucidum, Phellinus linteus), medicinal herbs (Scutellaria barbata, Astragalus membranaceus, Curcuma longa), and purified biologically active nutritional compounds (diindolylmethane and quercetin), was found to 7 prevent breast-to-lung cancer metastases in an orthotopic animal model of triple- negative human breast cancer.41
- Melatonin showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis in TNBC-induced mouse model.42
- Silibinin, given orally from the milk thistle plant, significantly suppressed tumor volume in a TNBC mice model. 43
- Epigallocatchin-3-Gallate (EGCG), from green tea, induces apoptosis, inhibits cell proliferation and migratory behavior of TNBC cells. 44
- Curcumin induces apoptosis and inhibits the proliferation of TNBC cells. 45
- Ginseng sapogenins are potent inhibitors or MDA-MB-231 human TNBC cell lines. 46
- Piperine, an alkaloid from black pepper, inhibits the growth and motility of TNBC and enhances radiotherapy in vitro. 47
- Omega three polyunsaturated fatty acids have a pronounced inhibitory effect against triple-negative basal breast cancer cell lines in-vitro. 48
Information about triple-negative breast cancer is lacking in general. It is reassuring, however that the interest in studying TNBC appears to be high. The most interesting research, to me, is among those studying individualization of treatment based on gene-expression profiling.
Until more information is available, I recommend that those with TNBC get an opinion from an oncology facility in a major metropolitan area. I encourage patients to request genetic testing from their oncologist and be open to neoadjuvant chemotherapy and mastectomy if recommended. 8
Look for an experienced, licensed, naturopathic physician in your area to help during treatment to reduce side effects and negative interactions between drugs and natural therapeutics.
Complementary care providers can also offer prevention of recurrence strategies. These range from specific dietary and fitness recommendations to individualized treatment plans including vitamins, minerals and botanical medicines found to reduce the risk of recurrence of breast cancer. To find experts in your area, go to the American Association of Naturopathic Physicians (naturopathic.org) or the Oncology Association of Naturopathic Physicians (oncanp.org). For more information on Triple Negative Breast Cancer in general, go to tnbcfoundation.org.
Dr. Barbara MacDonald is a licensed naturopathic doctor, acupuncturist and Chinese herbalist practicing in Camden, Maine. She is the co-author of The Breast Cancer Companion: A Complementary Care Manual: The Practitioner’s Guide to Support Women Through Conventional Cancer Treatment. This article is adapted from a new section of this textbook; fourth edition to be published later this year. Barbara is a 1997 graduate of National College of Naturopathic Medicine, a member of the American Association of Naturopathic Physicians, The Oncology Association of Naturopathic Physicians, the Maine Association of Naturopathic Doctors and Acupuncturists and a charter member of Destination Wellness Midcoast Maine. Dr. MacDonald has a general practice where she facilitates those with chronic illness, cancer and other health challenges to eliminate obstacles to optimal health and inspires them to fully express their highest and best selves.
Contact: www.camdenwholehealth.com or [email protected]; (207) 230-1131.
1 American Cancer Society. Benign breast conditions: not all lumps are cancer. http://www.cancer.org/Treatment/UnderstandingYourDiagnosis/ExamsandTestDescriptions/ForWomenFacingaBr eastBiopsy/breast-biopsy-benign-breast-conditions, 2012.
2 TNBC Foundation. 100 Questions about TNBC. http://www.tnbcfoundation.org/promisegrant.htm 3
3 Desantis C, Ma J, Bryan L, et al. Breast Cancer Statistics 2013. American Cancer Society. Oct 1 2013. Accessed at: http://onlinelibrary.wiley.com/doi/10.3322/caac.21203/full.
4 Bauer KR, Brown M, Cress RD et al. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and Her2-negative invasive breast cancer, the so-called triple-negative phenotype: a population based study from the California Cancer Registry. Cancer 2007; 109: 1721-1728.
5 Qingli Jiao, Aiguo Wu, Guaoli Shao et al. The Latest progress in research on triple negative breast cancer (TNBC): risk factors, possible therapeutic targets and prognostic markers. J Thorac Dis. 2014;6(9):f1329-1335. 9
6 Yu F, Zhang X, Zhang S, et al. Patterns and risk factors of recurrence in triple-negative breast cancer. Zhonghua Yi Xue Za Zhi. 2014 Jul 22;94(28):2180-3.
7 Greenup R, Buchaan A, Loizio W et al. Prevalence of BRCA mutations among women with triple-negative breast cancer (TNBC) in a genetic counseling cohort. Annals of Surg Oncol. 8/22/13.
8Boyle, P. Triple-negative breast cancer: epidemiological considerations and recommendations. Annals of Oncology 23 (Supplement 6):vi7-vi 12, 2012.
9 Carey LA, Perou CM, Livasy CA et al. Race, breast cancer subtypes and survival in the Carolina Breast Cancer Study. JAMA 2006;295:2492-2502.
10 Sorlie T, Wang Y, Xiao C et al. Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer; gene expression analyses across three different platforms. BMC Genomics. 2006;7:127.
11 Stark A, Kleer CG, Martin I et al. African ancestry and higher prevalence of triple-negative breast cancer: findings from an international study. Cancer 2010; 116: 4926-4932.
12 Ibid. Qingli Jiao, Aiguo Wu, et al.
13 Ibid. Qingli Jiao, Aiguo Wu, et al.
14 Tervasmaki A, Winquist R, Jukkola-Vuorinen A, et al. Recurrent CYP2C19 allele is associated with triple-negative breast cancer. BMC Cancer. 2014 Dec 2;2:14(1):902
15 Hong CC, Yao S, McCann SE, et al. Pretreatment levels of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple-negative breast cancers. Breast Cancer Research and Treatment. June 2013, V. 139, Issue 2, pp.477-488.
16 Ma Fj, Liu ZB, Qu L et al. Impact of type 2 diabetes mellitus on the prognosis of early stage triple-negative breast cancer in People’s Republic of China. Onco Target Ther 2014 Nov 27;7:2147-2154.
17 Vona-Davis L, Rose DP, Hazard H et al. Triple-negative breast cancer and obesity in a rural Appalachian population. Cancer Epidemiol Biomarkers Prev 2008;17: 3319-3324.
18 Kwan ML, Kushi LH, Weltzien E et al. Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors. Breast CAcner Res 2009; 11:R31.
19 Stead LA, Lash TL, Sobieraj JE et al. Triple-negative breast cancers are increased in black women regardless of age or body mass index. Breast Cancer Res 2009; 11: R18.
20 Ibid Kwan et al.
21 Shinde SS, Forman MR, Kuerer HM et al. Higher parity and shorter breastfeeding duration: association with Triple-negative phenotype of breast cancer. Cancer 2010; 116: 4933-4943.
22 Dolle JM, Daling JR, White E et al. Risk factors for triple-negative breast cancer in women under age 45. Cancer Epidemiol Biomarkers Prev 2009; 18: 1157-1166.
23 Ibid Dolle et al.
24 Phipps AL, Chlebowski RT, Prentic R et al. Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer. J Natl Cancer Inst 2011; 103: 470-477.
25 Kabat GC, Kim M, Phipps Al et al. Smoking and alcohol consumption in relation to risk of triple-negative breast cancer in a cohort of postmenopausal women. Cancer Causes Control 2-011;22: 775-783.
26 Greenup R, Buchanan A, Lorizio W et al. Prevalence of BRCA mutations among women with triple-negative breast cacner (TNBC) in a genetic counseling cohort. Annals of Surg Oncol. Early online publication August 22, 2013.
27 Elsamany S, Abdullah S. Triple-negative breast cancer: future prospects in diagnosis and management. Med Oncol. 2014 Feb;31(2):834.
28 Balko JMj, Giltnane JM, Shwartz LJ, et al. Profiling of triple-negative breast cancers after neoadjuvant chemotherapy identifies targetable molecular alterations in treatment-refractory residual disease. 2012 San Antonio Breast Cancer Symptosium. Abstract S3-6. Presented 12/6/12.
29Ibid. Qingli Jiao, Aiguo Wu, et al.
30 Loibl S, Jackisch C, Gade S et al. Neoadjuvant chemotherapy in the very young, 35 years of age or younger. 2012 San Antonio Breast Cancer Symposium. Abstract S3.1 Presented December 6, 2012.
31 Budhi Singh Yadav, Suresh C Sharma, Priyanka Chanana et al. Systemic treatment strategies for triple-negative breast cancer. World J Clin Onocol. 2014 May, 10;5(2):125-133.
32 Rita Nanda, MD interview for Living Beyond Breast Cancer; April, 2014. Available at: http://www.lbbc.org/Learning-From-Others/Ask-the-Expert/2014-04-Triple-Negative-Breast-Cancer-Medical- Updates. Accessed on December 6, 2014. 10
33 De Melo Gagliato D, Gonzalez-Angulo AM, Lei X et al. Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. Journ of Clinic Onocol. 1/27/14.
34 Wahdan-Alaswad RS, Cochrane DR, Spoelstra ND, et al. Metformin-induced killing of triple-negative breast cancer cells is mediated by reduction in fatty acid synthase via miRNA-193b. Horm Cancer. 2013=4 Dec;5(6):374- 89.
35 Goh W, Sleptsova-Freidrich I, Petrovic N. Use of proton pump inhibitors as adjunct treatment for triple-negative breast cancers. An introductory study. J Pharm Pharm Sci. 2014;17(3):439-46.
36 Zhang X, Smith-Warner SA, Collins LC, et al. Use of aspirin, other nonsteroidal anti-inflammatory drugs, and acetaminophen and postmenopausal breast cancer incidence. J Clin Oncol. 2012 Oct 1;30(28):3468-77.
37 Maity G, De A, Banerjee S Eta l. Aspirin prevents growth and differentiation of breast cancer cells: Lessons from in vitro and in vivo studies. Presented at the 2013 annual meeting of the American Society for Biochemistry and Molecular Biology and Experimental Biology 2013. Boston, MA April 20-24, 2013. Abstract 606.
38Gucalp A, Tolaney SM, Isakoff SJ et al. Targeting the androgen receptor (AR) in women with AR+ ER-/PR- metastatic breast cancer (MBC). Presented at the 2012 annual meeting of the American Society of Clinical Oncology, June 1-5, 2012, Chicago, IL Abstract 1006.
39 Rainville C, Khan Y, Tisman G. Triple negative breast cancer patients presenting with low serum vitamin D levels: a case series. Cases J. 2009 July 21;2:8390.
40 LaPorta E, Welsh J. Modeling vitamin D actions in triple negative/basal-like breast cancer. J Steroid Biochem Mol Biol.. 2014 Oct;144.
41 Jiang J, Thyagarajan-SAhu A, Loganathan J, et al. BreastDefendtm prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer. Oncol Rep. 2012 Oct;28(4):1139-45.
42 Jardim-Perassi BV, Arbab AS, Ferreira LC, et al. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PLoS One. 2014 Jan 9;9(1):e85311.
43 Kil WH, Kim SM, Lee JE, et al. Anticancer effect of silibinin on the xenograft model using MDA-MB-468 breast cancer cells. Ann Surg Treat Res. 2014 Oct;87(4):167-73.
44 Braicu C, Gherman CD, Irimie A, et al. Epigallocatechin-3-Gallate (EGCG) inhibits cell proliferation and migratory behavior of triple negative breast cancer cells. J Nanosci Nanotechnol. 2013 Jan;13(1):632-7.
45 Sun XD, Liu XE, Huang DS. Curcumin induces apoptosis of triple-negative breast cancer cells by inhibition of EDGR expression. Mol Med Rep. 2012 Dec 6(6):1267-70. 46 Kwak JH, Park JY, Lee D, et al. Inhibitory effects of ginseng sapogenins on the proliferation of triple negative breast cancer MDA-MB-231 cells. Bioorg Med Chem Lett. 2014 Oct 22;24(23):5409-5412.
47 Greenshields AL, Couicette Cd, Sutton KM, et al. Piperine inhibitis the growth and motility of triple-negative breast cancer cells. Cancer Lett. 2014 Nov 13.
48 Pogash TJ, El-Bayoumy K, Amin S, et al. Oxidized derivative of docosahexaenoic acid preferentially inhibit cell proliferation in triple negative over luminal breast cancer cells. In Vitro Cell Dev Biol Anim. 2014 Nov 21. [Epub ahead of print].