Breast Cancer

Breast Cancer

1 Introduction

Summary and Quick Facts

  • Breast cancer is the second most common cancer among American women, behind skin cancer. About 250,000 women in the United States are diagnosed each year.
  • In this protocol, you will first learn how breast cancer is typically detected and treated. Next, you will learn about compelling novel and emerging treatment strategies currently being tested in clinical trials.
  • Several natural interventions and dietary considerations may benefit women with breast cancer. For instance, above-average dietary intakes of selenium, omega-3 fatty acids, or lignans have been associated with better outcomes in women with breast cancer. Drinking more than three cups of green tea per day has also been associated with reduced breast cancer recurrence.

Breast cancer is the second-most-common cancer among American women, behind only skin cancer (NCCN 2016; U.S. Cancer Statistics Working Group 2017). About 250,000 women in the United States are diagnosed each year (ACS 2017a).

Although breast cancer research receives enormous funding from public and private sectors, much of the money goes toward studies on prevention and early detection. Thus, treatment options for women with breast cancer have not advanced dramatically in some time. Interventions that form the basis of most breast cancer treatment regimens today—surgery, chemotherapy, radiation, and hormone therapy—were fine-tuned from the 1980s into the early 21st century, leading to marginal outcome improvements. However, few true breakthroughs have emerged (Zurrida 2015).

But promising recent research may soon change the breast cancer treatment paradigm. For instance, immunotherapy—in which the body’s immune system is leveraged to fight cancer—has dramatically improved treatment options for other types of cancer, and results from early trials in breast cancer are promising (Solinas 2017). Many immunotherapy clinical trials are underway, paving the way for this new frontier in cancer treatment, and women with breast cancer may be able to participate in this research.

Other advances in breast cancer diagnosis and treatment are emerging as well. For instance, Oncotype DX and MammaPrint are two recently developed tests that check for molecular changes in tumor tissue and help patients and their medical team fine-tune their treatment plans (Nicolini 2017; Gyorffy 2015).

In addition, intriguing findings suggest off-label use of some cholesterol-lowering statin drugs (including atorvastatin, lovastatin, and simvastatin) may improve chances of survival for women with breast cancer (Liu 2017). And the first-line anti-diabetic drug metformin has shown some promising effects in breast cancer patients, even among non-diabetics (DeCensi 2015; Ko 2015).

Furthermore, several natural interventions and dietary considerations may benefit women with breast cancer (Li 2017). For instance, above-average dietary intakes of selenium, omega-3 fatty acids, or lignans have been associated with better outcomes in women with breast cancer (Harris 2012; Khankari 2015; McCann 2010), and drinking more than three cups of green tea per day has been associated with reduced breast cancer recurrence (Bao 2015).

In this protocol, you will first learn how breast cancer is typically detected and treated. Next, you will learn about compelling novel and emerging treatment strategies currently being tested in clinical trials. The latest recommendations and research on dietary and lifestyle considerations are summarized, highlighting the value of exercise and a diet rich in fruits and vegetables (Heitz 2017; Runowicz 2016). Lastly, you will learn about natural interventions that may improve the body’s ability to fight this disease and manage side effects of conventional treatments (Sinha 2017; Zhang, Haslam 2017; Limon-Miro 2017; Yao 2017).

Note: this protocol should be reviewed along with other relevant, cancer-related protocols:

2 Background

Anatomy of the Breast

Each breast contains 15 to 20 lobes, each made up of several smaller sections called lobules (NCCN 2016; PDQ Adult Treatment Editorial Board 2017). Breast milk is produced in the lobules and travels through the ducts to the nipple (Figure 1).

The tissue around the lobes and ducts is called stroma. Within the stroma, vessels carry a clear fluid called lymph. Lymph delivers immune cells, water, and nutrients to the breast tissue and drains to nearby lymph nodes (NCCN 2016). Healthy breasts also contain fat tissue, connective tissue, nerves, and blood vessels.

low risk drinking limits

Figure 1. Breast Anatomy (OpenStax College 2013)

The hormones estrogen and progesterone are important for the development and function of the breast during puberty and pregnancy (Hilton 2017). Estrogen is primarily produced by the ovaries before menopause, but some is produced by the adrenal glands and, in smaller amounts, in fat tissue and the liver (McNamara 2016). Estrogen can also be produced in the breast tissue itself by a process called aromatization (Yaghjyan 2011). There are two main types of estrogen receptors: estrogen receptor alpha and estrogen receptor beta (McNamara 2016). Activation of estrogen receptors plays a role in breast growth and in many cases of breast cancer.

Non-Cancerous Breast Conditions

The breasts can develop several non-cancerous conditions, some of which may cause symptoms similar to breast cancer. Cysts, fibroadenomas, and calcifications are common benign or non-cancerous breast diseases (Neal 2014; Mayo Clinic 2018). Another condition, hyperplasia, is a condition in which the cells in the duct or lobe are dividing too frequently (Davidson 2016). Women with so called atypical hyperplasias are at increased risk for developing breast cancer (Dion 2016; Farshid 2017).

Breast Cancer

Breast cancer can develop from cells in either the ducts or lobes, but ductal tumors are more common (NCCN 2016; PDQ Adult Treatment Editorial Board 2017). The cells acquire mutations that cause them to divide too rapidly or survive too long. One mutation in breast cancer leads to increased signaling through the HER2 growth factor receptor pathway (Davidson 2016). Cells with extra copies of the HER2 gene can grow more quickly (Petrelli 2017). Some people inherit or develop a mutation in the BRCA1 or BRCA2 genes, which are involved in DNA repair (Takaoka 2017; Davidson 2016). Presence of certain BRCA1 and BRCA2 mutations increase breast and ovarian cancer risk (Toland 2017).

As breast cells acquire more mutations, they begin to look less normal under a microscope. They can divide quickly and are less likely to die when normal cells would (NCCN 2016). Over time, they form a mass or tumor.

Tumors that are small and confined to the lobular or ductal tissue are called non-invasive (Davidson 2016; Posner 1992). Ductal carcinoma in situ (DCIS) is a non-invasive tumor that may become invasive (Rakovitch 2012). DCIS is typically detected by a mammogram (PDQ Screening Prevention Editorial Board 2017b). While some studies found that many DCIS lesions would not progress even without treatment, some of them may become invasive tumors over time. DCIS is normally treated with surgery and radiation, and the prognosis is excellent (NCCN 2017b; PDQ Adult Treatment Editorial Board 2017; Lee 2012; Jones 2006; Vatovec 2014).

Lobular carcinoma in situ (LCIS) is less common than DCIS and less likely to become an invasive tumor (Venkitaraman 2010; Frykberg 1999). LCIS does not normally require standard breast cancer treatments, although these are sometimes used, depending on the patient’s characteristics, but all women diagnosed with LCIS should be carefully monitored and make lifestyle changes to reduce their risk of developing breast cancer (see, “Dietary and Lifestyle Considerations”) (NCCN 2017b; Davidson 2016; Cutuli 2015).

Tumors that have grown into the nearby stromal tissue in the breast are called invasive (NCCN 2016). In some cases, tumor cells are able to move away from the original tumor and invade nearby lymph nodes (Davidson 2016; NCCN 2016). Beyond the lymph nodes, breast cancer may spread to distant sites such as the bones, lungs, liver, or brain (Rostami 2016; Chen 2017).

3 Causes and Risk Factors

Breast cancer occurs almost exclusively in women. About 2,500 men and 250,000 women are diagnosed each year in the United States (ACS 2017a). Age is also a critical risk factor (PDQ Screening Prevention Editorial Board 2017a). At age 40, women have a 1.4% chance of being diagnosed with breast cancer in the next 10 years. By age 70, that chance rises to 3.9% (U.S. Cancer Statistics Working Group 2017).

Family History and Genetics

Women with a family history of breast cancer are at increased risk. Having a first-degree relative diagnosed with breast cancer can increase the risk two- to four-fold (Davidson 2016). A family history of cancer may result from inheritance of a gene mutation. The most well-known genes mutated in breast cancer are called BRCA1 and BRCA2. Women with a mutation in one of these genes have a 50% to 85% lifetime risk of developing breast cancer (Davidson 2016; Antoniou 2003; Kuchenbaecker 2017). Not all women with these mutations develop breast cancer, and most women with breast cancer do not have these mutations.

Other Breast Conditions

Breasts with more stroma and epithelial tissue and less fat are described as dense (ACS 2017b). These characteristics can be seen on a mammogram. Women with very dense breasts have a four-fold or even higher risk for breast cancer (Boyd 2009; McCormack 2006; Cecchini 2012). Also, high breast density can make it harder to detect tumors with a mammogram (Lee, Chen 2017). Benign or non-invasive breast conditions such as atypical hyperplasias can also increase the risk of cancer (Davidson 2016).

Hormonal Exposure

Various factors influencing the level of estrogen exposure to the breast tissue can influence breast cancer risk. Women who start puberty early or enter menopause later have a slightly higher risk (Davidson 2016; Kotsopoulos 2010). In one large analysis, complete pregnancy reduced the risk of breast cancer by about 7%. In the same analysis, every 12 months of breastfeeding also reduced the risk of breast cancer by about 4% (Collaborative Group on Hormonal Factors in Breast Cancer 2002). Women who have a first childbirth later in life are at increased risk (Kotsopoulos 2010).

Women treated with conventional estrogen-progestin hormone replacement therapy (HRT) for menopause have been shown to have an increased risk of breast cancer compared with women using estrogen-only HRT (Davidson 2016; DeBono 2017). However, the increased risk is primarily attributable to forms of HRT containing medroxyprogesterone acetate (MPA), a synthetic form of progesterone (Palacios 2016). In contrast, natural progesterone does not appear to increase the risk of breast cancer (Lieberman 2017). Unopposed estrogen replacement (estrogen therapy without any form of progesterone) also does not appear to increase the risk of breast cancer (Manson 2013; DeBono 2017). In fact, some data suggest estrogen alone may decrease the risk of invasive breast cancer (Nelson 2012). Oral forms of estrogen replacement can increase risk of stroke and coronary artery disease, but estrogen absorbed through the skin (transdermal) is considered to be safer (Cobin 2017).

The type of estrogen used in hormone replacement therapy preparations may also influence risk. There are three primary types of estrogen: estrone, estradiol, and estriol. Estradiol is the dominant estrogen throughout most of a woman’s life, but estriol takes a more prominent role during pregnancy. Some preliminary evidence suggested that estriol may be protective against breast cancer risk (Takahashi 2000; Melamed 1997; Weiderpass 1999), and thus would be a preferable form of estrogen to use in hormone replacement therapy preparations. However, not all older studies supported this notion (Lippman 1977; Marmorston 1965), and more recent studies and analyses appear less conclusive (Ali 2017; Perkins 2017). Overall, more long-term, randomized, controlled trials are needed to test whether hormone replacement with estriol reduces breast cancer risk relative to other forms of hormone replacement therapy.

The association of HRT with breast cancer risk remains a controversial area. More information about the nuances of HRT in the context of breast cancer risk is available in the Female Hormone Restoration protocol. 

The relationship between oral contraceptive use and breast cancer risk is controversial as well. Oral contraceptives may slightly increase the risk of breast cancer (Gierisch 2013; Davidson 2016). A recent study included data from 1.8 million women (Morch 2017). Women who were currently or recently using hormonal contraception were 20% more likely to develop breast cancer than those who had never used hormonal contraception. Although this increased risk was statistically significant, the authors of the study clarify that their analysis suggests only about one additional breast cancer for every 7,690 women using hormonal contraception for one year.

Other Health Parameters

Obesity increases the risk of breast cancer (Davidson 2016; Kabat 2017). In a study of almost 100,000 women, body mass index and weight gain during adulthood were both associated with increased risk of breast cancer (Huang 1997). Most evidence suggests obesity after menopause is particularly problematic, increasing risk two- to four-fold (van den Brandt 2000; Davidson 2016; Cordina-Duverger 2016). Additional related conditions such as high fasting glucose, high cholesterol, diabetes, or high blood pressure may further increase the risk among obese women (Kabat 2017; Park 2017; Michels 2003; Maskarinec 2017; Ronco 2012). Life Extension Magazine® published an article in 2013 summarizing the association between elevated glucose levels and greater breast cancer risk.

Chest Irradiation

Radiation to the chest for another cancer, such as Hodgkin’s lymphoma, may also increase breast cancer risk later in life (Sud 2017; Schaapveld 2015).

4 Signs and Symptoms

Some women have signs and symptoms of breast cancer before diagnosis. Breast cancer can change how the breast or nipple feels. The most common symptom is a lump in the breast or in the armpit. Lumps in the upper, outer quadrant of the breast are most common (Bright 2016). Instead of a lump, women may feel swelling, tenderness, or thickening (Morrow 2000; Smania 2017). Cancer may also change the texture of the skin covering the breast. The pores may become enlarged. Cancer can also cause dimpling, swelling, or shrinking of the breast. Occasionally, women may notice a discharge from their nipples (Lee, Trikha 2017; Yamauchi 2012; Zhang, Cao 2012; Sharma 2010). Many women may not have any of these signs or symptoms before breast cancer diagnosis, and their cancer is detected during a routine mammogram (Davidson 2016; Dixon 2006; Mehrotra 2011).

5 Breast Cancer Screening

Early detection is the best way to improve breast cancer outcomes. Women diagnosed with early-stage breast cancer that has not spread beyond the breast have an excellent prognosis (ASCO 2017). The ideal cancer screening programs find invasive cancers when they can be easily treated, without mistaking them for many of the benign or non-invasive diseases that would never be an immediate danger to the patient’s health.

Familiarity with one’s own breasts is important for breast cancer detection. In fact, many cancers are first detected by patients themselves during normal activities (PDQ Screening Prevention Editorial Board 2017b). However, systematic and routine breast self-examinations have not been shown to help find early breast cancer any better than general familiarity with one’s breasts. Many doctors now make the more general recommendation that women pay attention to their breasts and report any changes in their look or feel. Nevertheless, some women may prefer to conduct more formal and routine self-examinations, so we have included the guide below.

How to Do a Breast Self-Exam (Cleveland Clinic 2015)

  1. Lie down. Flatten your right breast by placing a pillow or towel under your right shoulder. Place your right arm behind your head. Examine your right breast with your left hand.
  2. Use the pads, not the tips, of the middle three fingers on your left hand. With fingers flat, press gently using a circular, rubbing motion and feel for lumps. In small, dime-sized circles without lifting the fingers, start at the outermost top edge of your breast and spiral in toward the nipple.
  3. Press firmly enough to feel the different breast tissues, using three different pressures. First, light pressure to just move the skin without jostling the tissue beneath, then medium pressure pressing midway into the tissue, and finally deep pressure to probe more deeply down to the ribs or to the point just short of discomfort.
  4. Completely feel all of the breast and chest area up under your armpit, up to the collarbone, and all the way over to your shoulder to cover breast tissue that extends outward.
  5. Gently squeeze the nipple and look for discharge.

After you have completely examined your right breast, examine your left breast using the same method. You may want to examine your breasts or do an extra exam while showering. It's easy to slide soapy hands over your skin and feel anything unusual. You should also check your breasts in a mirror, looking for any change in size or contour, dimpling of the skin, or spontaneous nipple discharge. Check for the same changes with your arms raised above your head.

Importantly, self-exams and general breast familiarity cannot replace screening mammography and clinical breast exams.

Clinical Breast Exam

A clinical breast examination may be conducted by a trained health care provider during a routine physical (PDQ Screening Prevention Editorial Board 2017b). Data continue to emerge that support this screening method. In one study, almost nine percent of the cancers were detected by clinical breast examination alone, and they would have been missed if the clinical breast exam performed by a physician had not been conducted (Provencher 2016).

Mammography

A mammogram is an X-ray of the breast that can detect even small tumors that cannot be felt, including DCIS (PDQ Screening Prevention Editorial Board 2017b; Niell 2017). In one study, mammography correctly identified about 90% of the women who truly had breast cancer (Mello 2017). In some cases, a benign breast condition may be detected with a mammogram, and follow-up tests are required to rule out cancer. The BI-RADS classification system was created in 1986 to standardize the reporting of the results of mammograms (Table 1) (Shikhman 2017; Flowers 2013; Neal 2010; Ojeda-Fournier 2009).

Table 1: BI-RADS Categories for Mammogram Results

Category

Description

Follow-up

0

Incomplete

Additional tests may be necessary.

1

Negative

No abnormality was found. Follow-up is routine screening.

2

Benign or non-cancerous finding

A benign condition was detected that should be considered during evaluation of future mammograms.

3

Probably benign finding

The findings are unlikely to be cancer, but are not definitely benign. More frequent follow-ups are recommended to check for any changes.

4

Suspicious abnormality

A biopsy is most often recommended.

5

Highly suggestive of cancer

A biopsy is necessary.

6

Known cancer (diagnosed in previous biopsy)

Follow-up depends on the purpose of the mammogram.

Mammograms expose the breast tissue to very small amounts of radiation (Gennaro 2017). Therefore, screening guidelines consider the risks and benefits of routine mammograms. Guidelines for screening mammography are somewhat inconsistent, but the independent United States Preventive Services Task Force recommends mammography every two years for women aged 50 to 74. Older women may switch to a less frequent schedule. Women at higher-than-normal risk should check with their healthcare providers to see if they may benefit from starting screening earlier (US Preventive Services Task Force 2016). The benefits of mammograms for screening women aged 40 to 49 years with no increased risk of breast cancer are still debated, because the risk of breast cancer in this age group is low and the rate of false positive results is high (Zervoudis 2014; Silva 2014). Importantly, recent data suggest routine mammography screening for any age group may not effectively reduce the rate of advanced breast cancer (Autier 2017). Instead, mammography programs detect many cases of DCIS, and some experts are concerned that patients with DCIS may be overtreated, receiving treatment for a condition that is not likely to become invasive (Seigneurin 2016; Jorgensen 2017). Women should consider their individual risk factors and discuss the risks and benefits of routine screening with their medical providers.

Thermography

Thermography is not an effective alternative to mammograms for breast cancer screening (Omranipour 2016; Gourd 2017). However, researchers are evaluating how this technique can be used to complement mammography (de Jesus Guirro 2017; Wishart 2010). A tumor in the breast typically has increased metabolism and blood flow compared with surrounding areas. These changes make the surface of the breast near the tumor slightly warmer (Ramirez-Torres 2017). The temperature difference may be detected by thermography, which uses infrared imaging (PDQ Screening Prevention Editorial Board 2017b; Garduno-Ramon 2017).

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is a very sensitive test that can find some tumors not detected by a mammogram (PDQ Screening Prevention Editorial Board 2017b). Women who are at especially high risk for breast cancer should get an MRI along with a mammogram every year (Mainiero 2017; Sardanelli 2017; Cho 2017). This includes women with BRCA1 or BRCA2 mutations or women previously treated with radiation to the chest. Routine MRIs are not recommended for women at an average risk of breast cancer because MRI can detect many abnormalities that do not turn out to be cancer, possibly leading to unnecessary invasive diagnostic tests (ie, MRI screening has a high false-positive rate) (PDQ Screening Prevention Editorial Board 2017b).

Ultrasound

Breast ultrasonography is another technique that can be used for breast cancer screening. It is relatively easy to do in the clinic and is well-tolerated. Also, ultrasound does not expose the patient to radiation. Ultrasound can complement mammography, and may be useful in cases where mammography is less sensitive such as in younger women or those with denser breasts. Using breast ultrasound in conjunction with mammography may improve detection rates for early-stage cancers (Guo 2017).

6 Diagnosis

After a suspicious lesion is detected by mammogram or MRI, the medical team must do further tests to diagnose the condition. The follow-up tests often begin with additional imaging. A diagnostic mammogram is a more extensive version of the screening mammogram (Jensen 2010). For some women, an MRI or ultrasound, after abnormal mammography findings, may be helpful (He 2017; Flobbe 2003; Bickelhaupt 2017). An ultrasound uses sound waves to image the area of the breast that looked suspicious on the mammogram (Guo 2017).

Biopsy

After additional imaging, a biopsy is taken so a pathologist can examine some tissue in the suspicious area (John 2016). Most biopsy procedures use a thin needle to remove a piece of tissue (White 2001; Wang, He 2017). Ultrasound, MRI, and X-rays can all be used to guide the placement of the needle depending on the appearance and location of the suspicious area (Chevrier 2016; Klimberg 2016; Omofoye 2017; PDQ Screening Prevention Editorial Board 2017b). Occasionally, a surgical procedure is required to biopsy an area that cannot be reached with a needle (Anonymous 2016).

If cancer is detected in the biopsy, the pathologist will determine the subtype—for instance, ductal or lobular (PDQ Screening Prevention Editorial Board 2017b; Greeley 1997). The tumor is assigned a histological grade that indicates whether the cancer cells still look close to normal (grade 1), have characteristics of both normal and abnormal cells (grade 2), or are quite abnormal and fast-growing (grade 3) (Knuttel 2016; Zhang, Cao 2012). Lastly, the pathologist will assess the molecular characteristics of the cells: first, whether the tumor cells have estrogen and progesterone receptors, and second whether they are overexpressing HER2 (Hammond 2010; Nofech-Mozes 2012). Triple negative breast cancers do not have estrogen receptors, progesterone receptors, or HER2 overexpression (Saraiva 2017). Determining whether the cancer cells express these receptors is important in treatment planning, as some therapies target these receptor pathways.

Prognosis and Staging

After diagnosis, doctors must assess how big the primary tumor is and whether it has spread. This information is described in the cancer stage (Table 2) (Davidson 2016; PDQ Adult Treatment Editorial Board 2017).

Table 2: Breast Cancer Stages

Stage Definition

Stage 0

Non-invasive conditions (DCIS, LCIS, or Paget disease of the nipple)

Stage I

Very small tumors (<2 cm) with either no affected lymph nodes or just a small cluster of cancer cells in one lymph node

Stage II

A large tumor (>5 cm) with no affected lymph nodes or a smaller tumor (2‒5 cm) with 1‒3 affected lymph nodes in the armpit or near the breastbone

Stage III

A large tumor (>5 cm) with a small cluster of cancer cells in one lymph node or any size tumor with many affected lymph nodes

Stage IV

Cancer that has spread to other organs of the body

Blood tests may indicate whether the liver or the bones are being affected by a metastasis (NCCN 2016). If the results are abnormal or if the patient is experiencing pain or any other symptom, the doctor may use a bone scan to check the bones or a computed tomography (CT) scan, MRI, or ultrasound to check the abdomen, chest, or pelvic area (NCCN 2017b).

Newer Molecular and Genetic Tests

Breast cancer stage, hormone receptor status, and cancer subtype can provide information on a patient’s prognosis that can guide treatment decisions. New molecular tests have been developed that provide additional information (Nicolini 2017; Gyorffy 2015). The MammaPrint test is approved by the Food and Drug Administration (FDA) for women with stage I or II breast cancer (Gyorffy 2015). This test examines the expression levels of 70 genes in the tumor (Drukker 2013) and divides women into high-risk and low-risk categories (Viale 2017). Patients in the high-risk category may need chemotherapy after surgery (Drukker 2013; Knauer 2010).

Similarly, the Oncotype DX test examines 21 genes and divides patients into low-risk, intermediate-risk, and high-risk groups (Nicolini 2017). The test can help determine who should have chemotherapy after surgery (Bear 2017; Stemmer 2017). Recently published studies have found that the test is underutilized, particularly among older, poor, or black patients (Kozick 2017; Ricks-Santi 2017). Researchers are investigating how to make this test more universally available (Roberts 2016). Future trials will directly compare the Mammaprint and Oncotype Dx tests along with several newer tests described in the “Novel and Emerging Strategies” section.

Table 3: Molecular Tests for Breast Cancer Prognosis

Test name

Patient population

Result

Clinical application

FDA approval

Selected clinical data

Oncotype Dx

Stage I, II, IIIa
ER positive
HER2 negative
Lymph node negative or positive (1–3 nodes)

Provides a breast cancer recurrence score ranging from 0 to 100

Predicts how likely cancer is to return within 10 years

No

Among patients taking tamoxifen, 3.2% of those with a low-risk score had disease recurrence within 10 years and 39.5% of those with a high-risk score had a recurrence. When a similar group of patients with a high-risk score were treated with chemotherapy along with tamoxifen, only 11.9% had a recurrence (Paik 2006).

Breast Cancer Index Test

Stage I, II, IIIa
ER positive
Endocrine therapy
HER2 negative
Lymph node negative or positive (1–3 nodes)

Classifies patients into low-, intermediate-, and high-risk categories

Predicts how likely cancer is to return late (after five years) and overall (within 10 years)

No

Among patients with positive lymph nodes, 13.4% of those with a high risk score and 3.5% of those with a low risk score had a disease recurrence between five and 10 years after treatment (Sgroi 2013).

Prosigna

Stage I or II
Postmenopausal
ER positive
Endocrine therapy
Lymph node negative or positive (1–3 nodes)

Classifies patients into low, intermediate, and high risk of recurrence

Predicts how likely cancer is to return within 10 years

Yes

Among patients with negative lymph nodes, only 3.5% in the low risk of recurrence group had a disease recurrence within 10 years without any chemotherapy (Gnant 2014).

Endopredict

Stage I, II
ER positive
HER2 negative
Lymph node negative or positive (1–3 nodes)

Molecular score is combined with tumor stage and nodal status to create a risk score ranging from 1 to 6

Predicts how likely cancer is to return within 10 years

No

After 10 years of follow up of breast cancer patients treated with endocrine therapy, 1.8% in the low-risk group and 12.3% in the high-risk group had cancer recurrences (Dubsky 2013).

Mammaprint

Stage I or II
ER positive or negative
HER2 positive or negative
Lymph node negative or positive (1–3 nodes)

Classifies patients into low-risk, high-risk, and borderline categories

Predicts how likely cancer is to return within five years

Yes

Among patients with some high-risk clinical features (eg positive lymph nodes, large tumors) but low Mammaprint risk score, the benefit of chemotherapy was limited: 94.7% were disease free after five years without chemotherapy and 96.2% with chemotherapy (Cardoso 2016).

 

Genetic Testing for BRCA1 and BRCA2 Mutations

BRCA1 and BRCA2 are genes that code for proteins that normally suppress tumors. The proteins normally repair damaged DNA and maintain genetic stability (Toland 2017). When either BRCA1 or BRCA2 are not functioning correctly, the resulting cellular abnormalities increase the risk of breast and ovarian cancer, and that of some other cancers (Davidson 2016; Mehrgou 2016; Scully 2000). Mutations in BRCA1 or BRCA2 can be inherited from either parent.

BRCA1 and BRCA2 mutations that can be passed to offspring play a role in only about 30% of heritable breast cancers (Valencia 2017). As DNA analysis technologies have advanced, more genes can be analyzed to try to identify the contribution of other mutations (Afghahi 2017; Prapa 2017). For instance, for women under 40, inherited changes in a protein that interacts with BRCA2, called PALB2, can increase the risk of breast cancer nine-fold over the average risk (Antoniou 2014; Erel 2014).

Women should consider genetic testing if their family history is suggestive of an increased risk of breast or ovarian cancer (Davidson 2016; Cropper 2017; Moyer 2014). BRCA1 and BRCA2 mutations are more common in people with Ashkenazi Jewish ancestry, women who have cancer in both breasts, or when both ovarian and breast cancer are present in the same woman or the same family (Manchanda 2017; NCI 2018). People considering genetic testing should talk with a genetic counselor before and after testing (NCI 2018; Petrucelli 2016).

Awareness of mutations can help optimize treatment plans (Paterson 2017). Women who test positive for a mutation should be screened for cancer more carefully. Some experts recommend that clinical breast exams and mammograms begin between age 25 and 35 for women with known mutations (NCI 2018; Llort 2015). MRI beginning at age 25 may also improve the chance of detecting cancers early (Llort 2015; Petrucelli 2016). To reduce the risk of developing cancer, some women with mutations choose to have their breasts and/or ovaries surgically removed (Petrucelli 2016; NCI 2018; Llort 2015; Eisemann 2018).

7 Conventional Treatment

With staging information, hormone receptor status, HER2 status, and results of any genetic testing, a treatment plan can be created (NCCN 2017b). For women with stage 0, I, II, or III cancer, the first goal is to remove the cancer surgically (PDQ Adult Treatment Editorial Board 2017; NCCN 2017b). Additional treatments like chemotherapy, endocrine therapy, and radiation can help destroy remaining cancer cells. For women with stage IV cancer, there is ongoing research about the value of surgery for prolonging life and about the best timing of surgery, and while metastatic breast cancer is unlikely to be cured, endocrine therapy, surgery, and radiation are used for long-term disease control (NCCN 2017a).

Surgery

Many breast cancer patients begin their treatment with surgery to remove the tumor and any cancer in nearby lymph nodes (NCCN 2017b). For many women with stage I or II cancer, doctors often recommend a procedure called a lumpectomy. A lumpectomy is also referred to as a breast-conserving surgery, because only the tumor and the normal breast tissue immediately around it are removed (NCCN 2016). During and after the surgery, doctors will inspect the outer edges of the removed tumor to be sure that no cancer was left behind (Moran 2014; Gray 2017; Blohmer 2016). Some women are treated with chemotherapy before surgery to shrink their tumor and make it easier to remove (NCCN 2016).

A mastectomy is a surgery that completely removes the breast. A mastectomy may be necessary depending on the size or location of the tumor and risk factors for additional tumors (NCCN 2016). Some women feel more comfortable choosing mastectomy over lumpectomy (Hamelinck 2017; Gu 2017). If a woman with breast cancer has a family history of breast cancer or a BRCA1 or BRCA2 mutation, doctors may recommend removing both breasts (Eisemann 2018; King 2013; Yi 2010).

A mastectomy is a longer procedure than a lumpectomy (NCCN 2016). Recovery is slower, and the procedure leaves a larger scar. Doctors recommend arm and shoulder exercises to improve strength and mobility (Shamley 2005; Akoochakian 2017). Breast reconstruction is an option for women after surgery (Platt 2018). Please see the sidebar on Breast Reconstruction for more information.

During a lumpectomy or mastectomy procedure, surgeons will also check nearby lymph nodes for cancer (NCCN 2017b). In an axillary (armpit area) lymph node dissection, 10 or more lymph nodes are checked for cancer (NCCN 2016). Removing the lymph nodes may cause swelling called lymphedema if the lymph fluid can no longer drain properly (Dominick 2013). Lymphedema may occur within days of surgery or may develop years later (P.D.Q. Supportive Palliative Care Editorial Board 2002). Symptoms are managed with compression sleeves, physical therapy, bandaging, massage, and laser therapy (NCI 2015).

If there is no lymph node enlargement, then sentinel lymph node biopsy is the standard of care (Esposito 2017). With sentinel biopsy, a dye is used to determine which lymph node the tumor drains to. Then, only that node is dissected and checked for cancer cells (NCCN 2016). Sentinel node biopsies are less likely to cause lymphedema (McLaughlin 2013).

More general information about the use of surgery in treating cancer is available in the Cancer Surgery protocol.

Chemotherapy and HER2 Inhibitors

Some women are treated with chemotherapy before surgery to shrink the tumor or after surgery to try to destroy any remaining cancer cells in the body (NCCN 2016; NCCN 2017b; PDQ Adult Treatment Editorial Board 2017). Chemotherapy may reduce the chances that the cancer will return. The need for chemotherapy is determined by many factors, such as the size of the tumor. Chemotherapy may not be needed for certain histological types of breast cancer or if the tumor is small or has not spread. Molecular testing together with gene panels are often helpful in guiding the need for chemotherapy (NCCN 2016; NCCN 2017b).

For women who do need chemotherapy, the selection of drugs and the dosing regimen can be adjusted based on risk factors (NCCN 2017b). Some studies have suggested that three to six months of chemotherapy is preferable over longer durations (Davidson 2016). Chemotherapy drugs are usually given in combinations to target cancer cells in more than one way and decrease the development of resistance (NCCN 2016; Curigliano 2017; Yardley 2013). Anthracyclines (doxorubicin [Adriamycin], epirubicin [Ellence]), taxanes (docetaxel [Taxotere], paclitaxel [Abraxane; Taxol]), vinca alkaloids (vinorelbine [Navelbine]), 5-fluorouracil, carboplatin (Paraplatin), and cyclophosphamide (Cytoxan) are some of the common types of chemotherapy (Davidson 2016; NCCN 2017b; PDQ Adult Treatment Editorial Board 2017).

Some breast cancers have changes that result in high levels of the growth factor receptor HER2 (Kourie 2017). Signaling through this receptor tells the cells to grow and divide. Trastuzumab (Herceptin) and pertuzumab (Perjeta) are two monoclonal antibody drugs that bind to HER2 and prevent signaling (NCCN 2016). Only women with tumors overexpressing HER2 are treated with these drugs. Trastuzumab emtansine (Kadcyla) is a version of trastuzumab linked to a chemotherapy drug called emtansine (Baselga 2017). The chemotherapy is a second way the drug can kill the target tumor cells (Kourie 2017; Baron 2015; Sau 2017).

Many of these chemotherapy drugs are designed to destroy cells that are actively growing and forming new cells (NCCN 2016). Although cancer cells will be killed, healthy normal cells may also be affected. Side effects are common and can be severe for some women (Davidson 2016). Gastrointestinal side effects include nausea, vomiting, and diarrhea (Fox 2017; Egger 2017). Blood cell counts can drop, leading to fatigue and immunosuppression (Nishijima 2016; Egger 2017). Cells in the hair follicles may be damaged, causing hair loss (NCCN 2016). The side effects will vary depending on the exact regimen of chemotherapy, and some can be managed with other medicines.

More general information about chemotherapy, including strategies to reduce chemotherapy side effects, is available in the Chemotherapy protocol.

Radiation Therapy

Radiation uses high energy rays to damage the DNA inside cells. Treatment usually occurs after chemotherapy, or for women not treated with chemotherapy, soon after surgery (NCCN 2016; Boyages 2017). Modern techniques direct the radiation as much as possible to cancer cells to minimize side effects to healthy tissues. After a lumpectomy, radiation is targeted to part or all of the breast and may also target lymph nodes, depending on the risk of recurrence (NCCN 2017b; Kim, Algan 2017). After mastectomy, radiation is targeted to the chest wall and nearby lymph node sites (NCCN 2017b; Recht 2016).

The main form of radiation used to treat breast cancer is external beam radiation therapy or EBRT. A newer form of radiation delivery, called intensity-modulated radiation therapy, uses many small radiation beams carefully calculated to give the right dose of radiation to the right place, while minimizing radiation to surrounding, healthy tissues (NCCN 2017b; Chan 2017; NCCN 2016). Computed tomography (CT) imaging before the radiation procedure helps guide the radiation to the targeted area (NCCN 2016).

Toward the end of radiation treatment, patients may be treated with a higher dose of radiation, referred to as a radiation boost, to the area where the tumor was (PDQ Adult Treatment Editorial Board 2017; NCCN 2017b; Kindts 2017; Fiorentino 2015; NCCN 2016). The boost can be given by EBRT or internal radiation (also called brachytherapy) (Deng, Wu 2017; NCCN 2016). Internal radiation uses small radioactive seeds implanted directly into the breast tissue. After exposure, the seeds are removed (NCCN 2016).

Radiation therapy for breast cancer can cause a number of side effects such as damage to the skin of the irradiated area, fatigue, pain in the treated area, and damage to the heart or lungs. (Kole 2017; NCCN 2016; PDQ Adult Treatment Editorial Board 2017; Taylor 2017; Recht 2017).

For more complete information on radiation therapy techniques and side effects, see the Radiation Therapy protocol.

Endocrine Therapy

Most breast cancers overexpress receptors for the hormones estrogen and progesterone (Davidson 2016; Howlader 2014; Yip 2014). As with HER2, signaling through these receptors can tell the cancer cell to continue to grow and divide. Endocrine therapies are designed to disrupt this signaling in various ways (NCCN 2016). Endocrine therapy is recommended for most women whose cancer is estrogen-receptor positive (NCCN 2017b; NCCN 2016).

The type of endocrine therapy recommended to a patient will depend in part on her menopausal status. Before menopause, the ovaries are the main source of both estrogen and progesterone (NCCN 2016). Ovarian suppression is a strategy to reduce the amount of hormones in premenopausal women using luteinizing hormone-releasing hormone agonists such as goserelin (Zoladex) and leuprolide (Lupron) (NCCN 2016; Burstein 2016). Alternatively, the ovaries can be surgically removed. This approach is called ovarian ablation (NCCN 2016; Nourmoussavi 2017).

Both premenopausal and postmenopausal women may be treated with a type of drug called an antiestrogen, such as tamoxifen (NCCN 2016). Tamoxifen binds to the estrogen receptor to block estrogen signaling (NCCN 2016; Jameera Begam 2017). Postmenopausal women may also be treated with an aromatase inhibitor (letrozole [Femara], anastrozole [Arimidex], exemestane [Aromasin]). These drugs block the conversion of testosterone to estrogens (Davidson 2016; Olin 2014).

Studies suggested aromatase inhibitors may be more effective than tamoxifen for postmenopausal women (EBCTCG 2015; Xu, Liu 2011). Women diagnosed before menopause may also be candidates for treatment with aromatase inhibitors (NCCN 2016; NCCN 2017b). For these women, the production of estrogen by the ovaries may also be prevented by ovarian suppression (Francis 2015; Pagani 2014).

Women continue endocrine therapy long after diagnosis and initial treatment. A recent meta-analysis with data from over 60,000 women found that after five years of endocrine therapy, breast cancer can still recur. Even women with stage I cancer and no affected lymph nodes had a 13% chance of a distant recurrence (Pan 2017). A large trial involving almost 13,000 women found that 10 years of tamoxifen treatment reduced breast cancer recurrence and mortality compared with five years of treatment. In absolute numbers, breast cancer recurrence was 3.7% less likely among women who continued treatment (21.4% vs. 25.1%) and breast cancer mortality was 2.8% less likely (12.2% vs. 15%) (Davies 2013).   

If cancers become resistant to hormone therapies or recur, another drug called everolimus (Afinitor) may be helpful (NCCN 2017b; Lousberg 2016; Steelman 2016). During endocrine therapy, some cancer cells find ways to proliferate that do not rely on hormone signaling (Fan 2015). Everolimus blocks some of these other pathways, making the cancer cells reliant on hormone signaling once again (Royce 2015). Everolimus in combination with the aromatase inhibitor exemestane (Aromasin) was found to significantly improve progression-free survival (NCCN 2017b; Baselga 2012).

Endocrine therapies may cause side effects similar to the symptoms of menopause, including hot flashes, vaginal dryness, and mood changes (NCCN 2016). Tamoxifen can increase the risk of blood clots and uterine cancer (NCCN 2016; Antimisiaris 2017). Women taking aromatase inhibitors have a higher risk for high cholesterol, high lipids, and high blood pressure than women taking tamoxifen (Foglietta 2017; NCCN 2016). Aromatase inhibitors can also weaken bones (NCCN 2016; Hadji 2017; Kristensen 2017). To protect patients from fractures, doctors may suggest treatment with a drug called denosumab (Xgeva) or a class of drugs called bisphosphonates (Tremblay 2018). Supplemental calcium and vitamin D can also help maintain long-term bone strength (Tremblay 2018; Cepa 2015).

Cyclin-dependent Kinase Inhibitors

Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) are two signaling proteins that may help cancer cells that are resistant to endocrine therapy to proliferate (PDQ Adult Treatment Editorial Board 2017). CDK 4/6 inhibitors include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) (Kwapisz 2017). These drugs may work well in combination with endocrine therapy. Indeed, clinical trial results have been promising. For instance, women with advanced breast cancer taking both palbociclib and the endocrine therapy fulvestrant (Faslodex) had a median progression-free survival time of 9.2 months compared with 3.8 months among women taking fulvestrant plus placebo (Turner 2015). Palbociclib and ribociclib are FDA approved for the treatment of metastatic or advanced breast cancer in combination with endocrine therapies (de Groot, Kuijpers 2017; Zangardi 2017; Ettl 2017). Additional trials have been or are being conducted to see whether these drugs can also help women at a different stage of treatment, such as before surgery (de Groot, Kuijpers 2017; Ma 2017).

Treatment of Bone Metastases

Among women with metastatic breast cancer, 55% have bone metastases (Body 2017). When cancer has spread to the bone, the bone cells called osteoclasts, which normally destroy small amounts of bone, to help keep them healthy, become overactive and cause damage (ACS 2016a). The damage may cause pain and can make the bones susceptible to breaks. Several medications are available to keep the osteoclasts under control and help strengthen the bones and reduce the risk of fractures. Bisphosphonates, including zoledronic acid (Zometa) and pamidronate (Aredia), and the monoclonal antibody denosumab (Xgeva) are both options (de Groot, Appelman-Dijkstra 2017; O'Carrigan 2017; ACS 2016a). In some cases, radiation or surgery are used to treat single sites of bone metastasis (ACS 2016a).

Breast Reconstruction

For many women, restoring their breasts after cancer surgery is important. Reconstructive surgery can either rebuild breasts after mastectomies or restore the appearance of breasts after lumpectomies. Recent studies demonstrated that reconstruction can relieve feelings of stress and anxiety in some women (Fanakidou 2017; McCarthy 2017).

Breast shape can be restored either by inserting implants under the muscle or by a tissue flap procedure, which transplants muscle tissue from another part of the body (PDQ Adult Treatment Editorial Board 2017; Opsomer 2018; Murphy 2018). Neither procedure is simple. In addition, radiation therapy, whether performed before or after surgery, can lead to a higher risk of problems with the implants (Nelson 2017; Ricci 2017; Shankar 2003). The reconstruction often looks and feels more natural after a tissue flap procedure, but this procedure generally requires more surgery than implants and creates more scars (ACS 2016b).

A novel alternative technique, called cell-assisted lipotransfer, has had promising results (Tsekouras 2017; Laloze 2017). The technique, pioneered by Dr. Kotaro Yoshimura in Japan, transplants fat cells enriched with stem cells to the breasts. The stem cells are included to help the fat cells survive and regenerate (Arshad 2016). Actress Suzanne Sommers sought out this treatment a few years ago and is happy with the results (Huget 2012). Life Extension Magazine® published two articles in 2011 titled “Cell-Assisted Lipotransfer Breast Restoration” and “Suzanne Somers Uses Novel Stem Cell Therapy During Breast Rejuvenation” that further explore this groundbreaking procedure. In initial clinical trials, this new procedure appears to be safe and effective (Arshad 2016; Ito 2017; Waked 2017).

A breast reconstruction procedure can be done at the same time as a total mastectomy or after treatment is completed (PDQ Adult Treatment Editorial Board 2017; Thamm 2018). Every patient and every treatment plan is unique. All members of the medical team—the surgeons, radiation oncologist, and medical oncologist—must carefully coordinate all aspects of care, including decisions on what type of reconstruction to use and when it should be conducted (NCCN 2017b; Panchal 2017).

8 Novel and Emerging Strategies

Participating in a Clinical Trial

Researchers continually discover and develop promising new ways to fight breast cancer. Once a new treatment is found to be promising from laboratory studies, it is necessary to conduct a series of several types of clinical trials to demonstrate that the treatment is both safe and effective (NCCN 2016). These studies can take years or decades, and until the treatment is approved by the FDA, participating in a clinical trial may be the only way for patients to access these potentially breakthrough therapies.

Participation in a trial can also help each patient ensure that she has access to high-quality clinical care and personalized attention. Patients’ health is carefully monitored throughout the trial. Clinical trials have some risks, too. The new treatment may have side effects or may turn out to be ineffective.

Many women participating in a clinical trial feel very positive about the experience (Wootten 2011). Every patient in every clinical trial advances our understanding of breast cancer and its treatment, and many patients are motivated to participate in hopes that their contribution will help improve future treatment options (Godskesen 2015; Bidad 2016).

Patients should talk with their medical team about ongoing trials that may be appropriate. Women can also consult online resources to learn about ongoing trials:

  1. National Comprehensive Cancer Network: https://www.nccn.org/patients/resources/clinical_trials/find_trials.aspx
  2. National Cancer Institute: https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/trial-guide
  3. American Cancer Society: https://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/clinical-trials-matching-service-find-trial.html

Screening, Diagnostic, and Treatment Selection Tests

Three-dimensional (3D) mammography. Three-dimensional (3D) mammography, also called digital breast tomosynthesis, is a newer form of X-ray breast imaging (PDQ Screening Prevention Editorial Board 2017b; Sardanelli 2017). This method uses many images taken from multiple angles to make a 3D-like image (Mall 2017). Initial clinical studies of 3D mammography suggest it may detect more tumors than conventional mammography and reduce the number of women called back for additional testing who turn out not to have cancer (Mall 2017; Rafferty 2013; Ciatto 2013; Giess 2017). The Tomosynthesis Mammographic Imaging Screening Trial began in 2017 and will compare conventional and 3D mammography in about 165,000 women (ECOG ACRIN Cancer Research Group 2017).

Scintimammography. Another emerging imaging technique is called breast-specific gamma imaging or scintimammography (Schillaci 2013; Anonymous 2013). A small amount of a drug that emits radioactivity and accumulates in the breast is injected into the patient (O'Connor 2017). Detection is performed using an instrument called a gamma camera. This test is not being developed for screening the general population, but may be helpful for women whose breasts are not easily assessed by mammogram, such as women with dense breast tissue, implants, or benign conditions (Brem 2016; Yu 2016; Holbrook 2015). Currently, MRI is used along with mammography for these women, but breast-specific gamma imaging may be more effective than MRI. In one recent study, breast-specific gamma imaging was far less likely to suggest a false cancer diagnosis for a patient with only benign lesions (Zhang, Li 2017).

Emerging molecular and genetic tests. New molecular tests may also improve early detection of breast cancer (Tang 2016; Bahrami 2018; Harris 2016). The Videssa Beast proteomics test measures levels of specific proteins in the blood to help doctors interpret the results of imaging tests (Lourenco 2017; Henderson 2016; Reese 2017). This test, when used on women with suspicious mammogram findings, may help determine which women do not have cancer and do not need invasive follow-up procedures (Lourenco 2017). This test may be particularly informative for women with dense breasts that are hard to check with mammograms (Reese 2017).

Numerous multigene molecular tests are also being developed to provide patients and their medical teams with information on prognosis and treatment options (Gyorffy 2015; Duffy 2017; Nicolini 2017). Like the Oncotype DX and MammaPrint tests, these tests analyze tissue collected during the biopsy or surgery. The FDA-approved Prosigna or PAM50 test measures levels of 50 genes to estimate the risk of recurrence for postmenopausal women with estrogen receptor-positive cancer (Gyorffy 2015). The more precise prediction of recurrence risk allows for a better basis for treatment decisions (Ohnstad 2017; Prat 2017). Three additional tests that estimate risk of recurrence—Endopredict, Breast Cancer Index test, and Mammostrat—are commercially available but not yet approved by the FDA (Gyorffy 2015; Mislick 2014).

Circulating tumor cell analyses or “liquid biopsies.” Other new tests, referred to as liquid biopsies, analyze tumor cells or cell-free tumor DNA circulating in the blood. Highly sensitive tests can find this rare material (Wang, Li 2017; Cabel 2017). Liquid biopsies may be helpful for predicting metastasis or determining whether cancer has returned after treatment (Zhou 2017; Cheng 2017).

Liquid biopsies may also be used to find markers of treatment resistance. For example, circulating tumor cells may indicate whether the estrogen receptor has mutated during treatment (Beije 2017). A new mutation may make the tumor cells resistant to endocrine therapy. Similarly, mutations in cell-free tumor DNA may also indicate resistance to a new drug called olaparib (Lynparza) used to treat patients with BRCA2-related breast and prostate cancer (Quigley 2017). Although many patients respond to the drug initially, some become resistant. Researchers have analyzed cell-free tumor DNA from patients who have developed resistance and found new changes in the BRCA2 gene or other DNA repair genes that protect the tumor cells from olaparib (Domchek 2017; Quigley 2017). As these assays advance, researchers are beginning to determine how medical teams can use this type of information to improve treatment selection for patients (Schramm 2016; Khatami 2017). Life Extension Magazine® published an article in 2010 titled “Circulating Tumor Cell Assays: A Major Advance in Cancer Treatment” summarizing the benefits of this revolutionary test.

Targeted Therapy

Cancer cells are prone to DNA mutations. Some of these mutations cause changes that can help cancer cells overcome normal processes that stop cells from growing too fast or dividing when they should not. But too many mutations can be dangerous to cancer cells. Inhibitors of the enzyme poly (adenosine diphosphate-ribose) polymerase (PARP) prevent cancer cells from repairing their DNA when they need to (Nickoloff 2017). Tumors from patients with mutations in the DNA repair genes BRCA1 or BRCA2 often rely on PARP to keep their DNA intact. These patients may be great candidates for PARP inhibitors (Nickoloff 2017; Geenen 2017). The PARP inhibitor olaparib is FDA-approved for treating ovarian cancer (Ohmoto 2017; Kim 2015). In a 2017 phase III clinical trial, patients with a BRCA mutation and metastatic breast cancer treated with olaparib lived an average of seven months without disease progression while patients on standard chemotherapy alone lived only 4.2 months without progression (Robson 2017).

Immunotherapy

Advances in immunotherapy have already dramatically improved treatment options for diseases such as melanoma (Amaral 2017). Similar therapies are being developed and tested for the treatment of breast cancer (Yu 2017; Mansour 2017; Gentzler 2016). Some key immunotherapy advances in breast cancer are summarized here, and more general information is available in the Cancer Immunotherapy protocol.

Cancer vaccines are one type of immunotherapy that uses material from tumor cells to encourage the immune system to mount a new attack against the tumor (Benedetti 2017). Some vaccines have been tested that direct the immune cells to attack cells expressing HER2 (Yu 2017; Clifton 2016; Mittendorf 2016). One example, called NeuVax, significantly improved 5-year disease-free survival and is being evaluated in a phase III trial (Clifton 2016). Other vaccines in clinical trials target a different protein on cancer cells called mucin 1 or MUC1 (Yu 2017; Antonilli 2016).

Checkpoint proteins are used by healthy cells to control immune response (Solinas 2017). Cancer cells take advantage of these proteins to prevent the immune system from recognizing them as diseased (Yu 2017). Checkpoint inhibitors are drugs that bind to checkpoint proteins, making the target cell visible to the immune system once again. Clinical trials are evaluating several checkpoint inhibitors in breast cancer patients (Mansour 2017; Yu 2017; Vanpouille-Box 2017). Immune checkpoint inhibitors such as pembrolizumab (Keytruda) were found to be safe in phase I trials, with encouraging early responses (Weiss 2017; Brahmer 2012; Nanda 2016).

Bispecific antibodies act as a link between two cell types. One end of the antibody binds to a protein on a cancer cell, and the other end binds to an immune cell (Yu 2017). The immune cell then recognizes the diseased cancer cell and destroys it. One bispecific antibody called armed activated T cells (aATC), which directs T cells to HER2-positive cancer cells, was found to be safe in a phase I trial (Lum 2015). A phase II study in patients with low levels of HER2 is ongoing as of early 2018 (Jagtap 2014).

Photodynamic therapy uses a drug called a photosensitizer that is retained by cancer cells (Banerjee 2017; Lamberti 2014; NCI 2011). The area of the tumor is then exposed to light. The photosensitizer absorbs the energy of the light and produces oxidizing agents that kill the cancer cells. The damage caused by photodynamic therapy also activates the immune system (Maeding 2016). One study used photodynamic therapy to treat women with breast cancer recurrences in the chest wall after mastectomy. Six of the nine treated patients responded well (Morrison 2014). The technique has been tested in mice as a non-invasive way to treat sentinel-node metastases (Shimada 2017). Life Extension Magazine® published an article in 2015 titled “An Alternative to Conventional Breast Cancer Treatment” that further discusses the benefits of photodynamic therapy.

Antibody-Drug Conjugates

Trastuzumab emtansine, described in the Conventional Treatments section, was the first antibody-drug conjugate (ADC) approved by the FDA for treatment of HER2-positive breast cancer. These drugs use the specificity of the antibody to carefully target chemotherapy to the cancer cells (Deng, Lin 2017; Trail 2017). The ADC sacituzumab govitecan targets a protein called Trop-2, which is an attractive drug target for triple-negative breast cancer cells (Ocean 2017; Sahota 2017; Wu 2011). In a clinical trial of 69 patients who previously tried many different treatments, 30% of participants responded to sacituzumab govitecan. The FDA has granted this drug breakthrough therapy and fast track designations (Bardia 2017; Saha 2016). Another ADC called DS-8201 or trastuzumab deruxtecan targets HER2-expressing cells with a different antibody and chemotherapy than trastuzumab emtansine. In a phase I clinical trial, 43% of participants responded to this drug. Interestingly, even some tumors with only low levels of HER2 responded (Doi 2017). This drug is being tested in additional patients, and the FDA granted it breakthrough status in 2017 (Post 2017).

Endocrine Therapies

Researchers are improving current endocrine therapies (described in the Conventional Treatment section) in several ways. For example, studies are evaluating the optimal length of treatment (Blok 2018) and the best patient groups for each drug (Grossman 2018; Heindl 2018). Other studies are examining mechanisms of resistance to endocrine therapies (Castrellon 2017).

Z-endoxifen is an endocrine therapy in development that is similar to tamoxifen (Goetz 2017). Tamoxifen is converted to endoxifen by the liver, but this conversion is inefficient in some patients, and this is one of the factors that explains the reduced benefit of tamoxifen in certain people (Briest 2009; Baatjes 2017). In a phase I study, 26.3% of participants benefited from Z-endoxifen, including three that previously progressed on tamoxifen (Goetz 2017).

Many breast cancers express the androgen receptor, and this includes some breast cancers that do not have estrogen or progesterone receptors (Mina 2017; Rampurwala 2016; Kono 2017; Doane 2006). For women with these tumors, treatment with drugs targeting the androgen receptor may be helpful. Bicalutamide (Casodex) and enzalutamide (Xtandi) are two examples of such drugs, and enzalutamide is being tested in a phase II trial on women with metastatic breast cancer. These drugs are currently approved for treatment of prostate cancer but not breast cancer (Gucalp 2013; Schwartzberg 2017).  

Repurposing Existing Drugs

Statins, typically used to reduce cholesterol levels, may improve outcomes in some cancer patients (Haukka 2017; Shaitelman 2017; Manthravadi 2016; Mei 2017). In laboratory studies, statins can inhibit signaling in breast cancer cells and cause cell death (Chan 2003; Lin 2017). A recent meta-analysis of seven studies and almost 200,000 women indicated that statins can decrease all-cause mortality and cancer-specific mortality in women with breast cancer. The authors also noted that primarily a type of statins categorized as lipophilic have this effect. Lipophilic statins include atorvastatin (Lipitor), lovastatin (Mevacor), and simvastatin (Zocor) (Liu 2017).  

Metformin is used to treat diabetes, but emerging research suggests it may also mitigate cancer risk and improve outcomes (Sonnenblick 2017; Calip 2015). And metformin has been shown to prevent and reverse drug resistance in breast cancer cells in cell culture and animal models (Davies 2017). One study found that diabetic women taking metformin were less likely to develop breast cancer metastases (Jacob 2016). Another study found that diabetic women with breast cancer who were treated with a diabetes drug other than metformin had worse survival outcomes than those treated with metformin (Sonnenblick 2017). Potential anti-cancer benefits of metformin may not be limited to diabetics (Ko 2015; Pizzuti 2015). In one study, 200 nondiabetic women awaiting breast cancer surgery took either 1,700 mg of metformin or a placebo daily for four weeks. Metformin treatment significantly reduced markers of cellular proliferation in HER-2-positive DCIS in these women (DeCensi 2015). Another study found that cancer cells from non-diabetic breast cancer patients who took metformin before surgery were less active than those from non-treated women (Hadad 2015).

9 Dietary and Lifestyle Considerations

This section will briefly summarize some important dietary and lifestyle considerations for women with breast cancer. However, Life Extension recommends that women fighting breast cancer, and those in remission, consult a credentialed nutrition professional to develop a healthy eating plan, as maintaining a healthy diet is one of the most important considerations for cancer patients. Cancer care centers and oncology medical teams should typically either include a credentialed nutrition professional or be able to offer a referral.

Eat a Minimally Processed Diet Emphasizing Plant-Based Foods

A typical Western diet, characterized by reliance on animal products, refined carbohydrates, and unhealthy fats like processed vegetable oils, may promote an inflammatory environment in the body. A pro-inflammatory diet has been associated with an increased breast cancer risk and a higher risk of death from breast cancer (Fowler 2017; Tabung 2016; Shivappa 2015; Schottenfeld 2006; Cavicchia 2009; Stoll 1998a; Stoll 1998b; Link 2013; Nicholson 1996).

The American Cancer Society and the American Society for Clinical Oncology recommend that women diagnosed with breast cancer drink no more than one alcoholic beverage daily and eat a diet that emphasizes unprocessed vegetables, fruits, whole grains, legumes, and fish (Runowicz 2016). A diet emphasizing unprocessed, plant-based foods has been associated with reduced breast cancer risk in several studies (Penniecook-Sawyers 2016; Chang, Hou 2017; Catsburg 2015; Harvie 2015). This dietary strategy will naturally provide plenty of cancer-fighting phytochemicals. Phytochemicals are specialized compounds found in plants that have health benefits, including anti-cancer effects (Dalasanur Nagaprashantha 2018; Forcados 2017; Kapinova 2017; Shoaib 2016). A diet that emphasizes unprocessed plant-based foods will also be low in saturated fat, high intake of which has been correlated with increased breast cancer risk and worse outcomes for women with breast cancer (Kroenke 2005; Chlebowski 2017; Brennan 2017; Slomski 2017; Kroenke 2013). Finally, an unprocessed diet will contain very little added sugar—greater sugar consumption has been correlated with increased breast cancer risk (Sulaiman 2014).

A good “general” rule to help ensure you are buying healthy ingredients is to obtain most ingredients from the outside isles (or perimeter) of the store. In most stores, the outside isles are where fresh, unprocessed items can be found: produce; dairy; fresh seafood, meat, and poultry; etc.

Cooking Methods – Especially Important for Meat

When meat is cooked at high temperatures with dry heat, cancer-causing compounds such as polycyclic aromatic hydrocarbons are formed (Diggs 2011; Gammon 2004; White, Bradshaw 2016; White, Chen 2016). Consumption of high amounts of grilled, barbecued, or smoked meats has been associated with increased breast cancer risk, especially among women who consume few fruits and vegetables (Steck 2007; Kim, Lee 2017). Furthermore, a recent study found that meat cooked at high temperatures (eg, grilled) may decrease the chances of survival after diagnosis with breast cancer. In that study, women who continued consuming grilled meat after diagnosis were 31% more likely to die during the study’s average 17-year follow-up period (Parada 2017).

Life Extension Magazine® published an article in 2013 titled “Are You Cooking Yourself to Death?” that further explores the potential problems associated with high-temperature cooking and reveals which cooking methods can help avoid these pitfalls.

Soy and Breast Cancer

Soy-based foods, such as edamame, tofu, miso, and soymilk, are a traditional component of many Asian diets. Although soy has not been a significant part of Western diets in the past, soy consumption is steadily increasing in the United States (Soyfoods Association 2014).

The association between soy and breast cancer is very controversial. The controversy arises because constituents in soy, particularly isoflavones, can exert estrogen-like activity in the body. When researchers first discovered these properties of soy, concern arose that soy might promote the growth of estrogen-sensitive breast cancers. Indeed, in some animal models suggested that isoflavones stimulate the growth of implanted breast tumor (Allred 2001; Ju 2006). However, the metabolism of soy isoflavones varies across species (Gu 2006), so findings from animals models of the effects of isoflavone supplementation may not be applicable to humans (Messina 2016).

Moreover, considerable epidemiological and clinical data have found that soy food consumption (not necessarily supplementation with isolated isoflavones) is associated with lower breast cancer risk and better outcomes after diagnosis (Guha 2009; Messina 2016). Several large cohort studies have found that a diet rich in soy is associated with reduced risk of breast cancer recurrence (Nechuta 2012; Shu 2009; Zhang, Kang 2012; Zhang, Haslam 2017). In one study, Chinese women who ate at least 15 grams of dietary soy protein per day were 32% less likely to have a breast cancer recurrence (Shu 2009). A second study enrolled 9,514 Chinese and American women previously diagnosed with breast cancer. Women from either country with at least 10 mg of isoflavones (from soy-based foods) in their diet every day had a 25% lower risk of recurrence (Nechuta 2012).

A meta-analysis that combined data from many studies also found that including soy foods in the diet after a breast cancer diagnosis significantly improved chances of survival and reduced risk of recurrence. The effect appeared to be strongest among postmenopausal women, women with estrogen-receptor-negative tumors, and women with tumors positive for both estrogen and progesterone receptors (Chi 2013).

Each woman should decide for herself whether she is comfortable consuming soy-based foods. It is worth noting that most conventional physicians will advise against consuming soy because not enough data are available from which to draw unequivocal conclusions.

Choose Healthy Beverages

Aside from the importance of drinking plenty of water daily, other beverage choices are also important. As mentioned previously, women concerned with breast health should drink no more than a single alcoholic beverage daily. But other considerations related to beverage choice may influence breast health as well. For instance, coffee contains several compounds such as polyphenols (eg, chlorogenic acid) and diterpenes that may prevent or fight breast cancer (Bhoo-Pathy 2015). Studies suggested drinking 2‒4 cups of coffee per day is associated with reduced breast cancer risk (Oh 2015; Grosso 2017; Jiang 2013). Also, in a large study with almost one million women, a two-cup-per-day increase in coffee consumption was associated with a small reduction in the risk of dying from breast cancer (Gapstur 2017).

Green tea is another good choice. Like coffee, it contains health-promoting polyphenols, the most famous of which is epigallocatechin gallate (EGCG). Green tea is a rich source of EGCG, and 12 months of green tea extract supplementation has been shown to reduce breast density in younger women (Samavat 2017). Many laboratory studies have shown that tea constituents can kill or slow the growth of breast cancer cells, inhibit their metastasis, and reduce their ability to recruit new blood vessels to supply blood and nutrients to metastatic tumors. Also, a number of observational studies has associated green tea consumption with reduced breast cancer risk, and several clinical trials have shown that green tea supplementation reduces biomarkers of breast cancer progression (Sinha 2017).   

Maintain a Healthy Weight and Exercise

Maintaining a healthy weight goes hand-in-hand with a healthy diet. And studies have shown that losing weight reduces breast cancer risk. In a huge meta-analysis of data on over 4 million subjects from 139 studies, weight loss was associated with an 18% relative reduction in breast cancer risk. This same large analysis also found that exercise, which is often part of a weight loss program, led to a 22% relative risk reduction (Hardefeldt 2017). Other studies suggest physical activity can help alleviate some of the side effects of conventional cancer therapy. For instance, 16 weeks of resistance and high intensity interval training reduced cancer-related fatigue and symptom burden in breast cancer patients being treated with chemotherapy (Mijwel 2017). Another study found that exercise one day before chemotherapy (doxorubicin) treatment improved mood and reduced musculoskeletal side effects of the treatment (Kirkham 2017).

The American Cancer Society recommends that adults get 150 minutes of moderate-intensity physical activity (such as walking or leisurely bicycling) or 75 minutes of vigorous physical  activity (such as running or swimming) each week. Ideally, this activity should be spread throughout the week, rather than lumped together.

Managing Stress and Maintaining a Support Group

Receiving a cancer diagnosis and progressing through treatment can be an emotionally tumultuous and highly stressful experience. It is important to not neglect mental health during this time. Maintaining a positive outlook and emotional wellbeing throughout this process is an important but often underemphasized aspect of cancer care. Ongoing stress after breast cancer diagnosis has been shown to predict bothersome physical symptoms and lower quality of life (Harris 2017).

The American Cancer Society recommends that patients include caregivers and family members in consultations with the medical team (Runowicz 2016). This informed support network can help support critical treatment decisions and share the burden with the patient (Wallner 2017). Meditation, mindfulness programs, peer-counseling, and other tools can help reduce stress, anxiety, and depression and improve sleep and quality of life (Yun 2017; Johns 2016; Giese-Davis 2016; Haller 2017). More information about managing stress is available in the Stress Management protocol.

10 Integrative Interventions

Green Tea

Green tea and its components have been associated with numerous health benefits (Rafieian-Kopaei 2017). Consumption of green tea may improve outcomes after breast cancer diagnosis (Sinha 2017; Ogunleye 2010). About 500 Chinese women with triple-negative breast cancer were interviewed about their tea consumption. The risk of breast cancer recurrence was 46% lower among women who drank tea regularly during the five years after diagnosis than among those who did not drink tea. The vast majority of tea drinkers in this study drank green tea (Bao 2015). An earlier study found that consumption of at least three cups of green tea per day dramatically reduced the risk of recurrence of breast cancer, but only for women diagnosed with early-stage disease (Inoue 2001).

Data from these observational studies are encouraging, and randomized controlled trials are now testing whether adding green tea to the diet can improve survival. An exploratory dose escalation study found 600 mg of green tea extract twice daily was well-tolerated by women with a history of stage I-III breast cancer (Crew 2012). A subsequent study, using blood collected during the dose escalation study, found the extract reduced levels of hepatocyte growth factor and vascular endothelial growth factor, two proteins that play a role in tumor growth (Crew 2015).

Another study took a different approach. Women with early-stage breast cancer waiting for surgery took either green tea extract (2,175 mg containing about 940 mg EGCG per day, roughly equivalent to 8‒10 cups of green tea) or received no green tea for an average of 35 days prior to surgery. The women in the green tea extract group had reduced levels of proliferation markers in both benign and malignant cells from specimens obtained during surgery compared with the no tea group (Yu 2013).

Lastly, green tea may have additional benefits for breast cancer patients being treated with radiation therapy. In one study, women with breast cancer undergoing radiotherapy, and taking 400 mg capsules three times per day (total 1,200 mg) of EGCG for two to eight weeks, had several notable changes in growth factors and other growth-related markers in their blood. When serum from these patients was applied to human breast cancer cells in the lab, the cells stopped growing and began to die (Zhang, Wang 2012). Other studies have found that an EGCG-containing topical formula helps prevent progression of radiation-induced dermatitis when applied to the skin of breast cancer patients undergoing radiation therapy (Zhao 2016; Zhu 2016).

Flaxseed

Flaxseed is a source of healthy fibers, omega-3 polyunsaturated fatty acids, and phytoestrogens called lignans (Kajla 2015). In laboratory studies, lignans have anti-cancer properties (Abarzua 2012; Mali 2017). In a Canadian observational study, eating flaxseed or flax bread at least weekly was associated with a reduced risk of breast cancer (Lowcock 2013).

Eating flaxseed may also be beneficial after breast cancer diagnosis (Mason 2014; Seibold 2014). One study followed over 1,000 women with breast cancer for several years. Postmenopausal women who ate the most lignans (at least 318 micrograms of lignans per day) were significantly more likely to have survived than those eating the least (less than 155 micrograms of lignans per day) (McCann 2010).

Lignans are converted in the gut to enterolignans, such as enterolactone (Patterson 2011). One study estimated enterolactone intake among 2,653 German postmenopausal women prior to breast cancer diagnosis who were followed about six years. Among those with the highest dietary enterolactone intake, the overall death rate was about 40% lower than among those with the lowest enterolactone intake (Buck 2011).

Smaller studies are beginning to address whether supplemental flaxseed can fight cancer. In a randomized clinical trial, women newly diagnosed with breast cancer ate either a flaxseed muffin (25 grams of flaxseed) or a placebo muffin daily for approximately one month before surgery. Levels of proliferation decreased and cell death increased in the tumors of those in the flax muffin group but not the control group (Thompson 2005). A second study evaluated secoisolariciresinol, a plant lignan that is converted to enterolactone in the gut. Among 45 women with benign breast hyperplasia, supplementation with 50 mg per day of secoisolariciresinol increased levels of enterolactone in the blood approximately nine-fold and decreased cellular proliferation in the affected breast tissue (Fabian 2010).

Selenium

Selenium is an essential nutrient for humans. Brazil nuts are a particularly rich source of selenium. Other sources include some types of seafood (eg, tuna and crab), poultry, eggs, and wheat (Colpo 2013; Rayman 2000; Tinggi 2008). Comparing food history between 145 breast cancer cases and 148 control women in Iran suggested the women with a nutrient-rich diet, including selenium, may have a reduced risk of breast cancer (Vahid 2018). After breast cancer diagnosis, Polish women with low blood selenium (< 64.4 mcg/L) who were past smokers had higher mortality than women with the highest blood selenium (>81.0 mcg/L). An observational study using diet records showed Swedish women who smoked and had low estimated selenium intake before diagnosis may have reduced chances of survival (Lubinski 2017; Harris 2012). In one study, selenium levels were measured in the blood of 546 patients newly diagnosed with breast cancer. Women with the lowest levels of selenium were more than twice as likely to have died during the five-year follow up than women with the highest levels (Lubinski 2017). A second study found that breast cancer patients with high dietary intake of selenium were significantly less likely to die from the disease (Harris 2012).

Selenium may have interesting benefits for people with some BRCA1 mutations (Bera 2013). Proteins encoded by the BRCA genes are critical for repairing DNA and keeping the genome intact, and mutations in these genes lead to DNA damage and chromosome breaks. When people with BRCA1 mutations took 276 micrograms of supplemental selenium per day, in the form of sodium selenite, for one to three months, the frequency of chromosome breaks in their white blood cells was significantly reduced to the levels seen in non-carrier controls (Kowalska 2005). A second study found that selenium supplementation increased a marker of DNA repair in certain people with BRCA1 mutations (Dziaman 2009).

Se-methylselenocysteine (SeMSC) is a naturally occurring organic compound containing the mineral selenium. SeMSC is abundant in plants such as garlic, onions, and broccoli; it is a source of bioavailable selenium (Suzuki 2008; Lyi 2005). SeMSC has been shown to be an effective inhibitor of breast cell growth in laboratory studies and has significant anticancer activity (Sinha 1999; Sinha 1997). Moreover, in laboratory studies, SeMSC was a very effective selenium chemoprevention compound and caused cancer cells to self-destruct (Jung 2001; Suzuki 2010). In rats, exposure to SeMSC blocks the expansion of premalignant lesions at an early stage by simultaneously modulating pathways responsible for inhibiting cell proliferation and enhancing apoptosis (Ip 2001).

Different Forms of Selenium

The different forms of selenium have been shown to provide various protective properties against cancer, oxidative stress, DNA damage, and even shielding against toxic metal poisoning. For this reason, it is recommended to ingest a 200 microgram “cocktail” daily of various selenium forms to provide broad-spectrum coverage against the diseases of aging (Suzuki 2010; Lunoe 2011).

Here are brief descriptions of well-studied forms, highlighting how each can contribute to selenium-based protection against cancer.

  • Sodium selenite is a simple chemical salt of sodium and selenium. This form of selenium has the ability to ramp up our natural immune system to find and destroy tumor cells (Kiremidjian-Schumacher 2000; Asfour 2006).
  • Selenium-methyl L-selenocysteine triggers cancer cell suicide (apoptosis) and acts on more advanced cancer cells that have lost the fundamental “suicide gene” (Suzuki 2010).
  • Selenium from yeast provides advanced protection against oxidative stress and resulting DNA damage, to reduce the risks that a cell will undergo transformation into a malignancy (Richie 2014).

Because optimum cancer prevention requires protection from DNA damage, enhanced self-destruction of malignant cells, and a boosted immune system, the benefits of using multiple forms of selenium are obvious.

Omega-3 Polyunsaturated Fatty Acids

Long-chain omega-3 fatty acids—abundant in oily fish and flaxseed—are a type of lipid, which make up cell membranes. Greater omega-3 intakes may reduce the chance of breast cancer recurrence. In one trial, 3,081 women with early-stage breast cancer were monitored for about seven years. Women with the highest intakes of omega-3 fatty acids in their diets (at least 153 mg/day) were approximately 25% less likely to have a recurrence than women with the lowest intakes (Patterson, Flatt 2011). A second study followed 1,463 women for almost 15 years. Higher-than-average dietary intake of boiled or baked fish other than tuna (at least 3.85 grams per day) and the omega-3 fatty acid docosahexaenoic acid (DHA) (at least 60 mg per day) were associated with 34% and 27% reductions in risk of death, respectively, compared with those with minimal or no intake (Khankari 2015).

Some laboratory data suggest omega-3 fatty acids integrate into tumor cell membranes and make them more sensitive to chemotherapy (Fabian 2015; Vibet 2008). One phase II clinical trial treated women with metastatic breast cancer with 1.8 grams per day of DHA along with conventional chemotherapy. Although there was no control group in this trial, researchers found that women with the highest levels of DHA in their plasma membranes survived the longest (Bougnoux 2009).

Breast cancers have high numbers of inflammatory cells. The inflammation can contribute to tumor development and progression (Baumgarten 2012; Takeuchi 2017; Ben-Baruch 2003). Omega-3 fatty acids may help reduce inflammation (Fabian 2015). A 30-day randomized trial of 45 women with breast cancer compared markers of inflammation in women taking 1.8 grams per day of omega-3 fatty acids and a placebo group taking 2 grams per day of mineral oil. Levels of high sensitivity C-reactive protein, a marker of inflammation, increased in the placebo group during the course of the study but remained unchanged in the fatty acid group (Paixao 2017).

Omega-3 fatty acids may also help reduce certain side effects of conventional breast cancer treatment (Fabian 2015). Aromatase inhibitors can weaken bones, but a randomized placebo-controlled study on postmenopausal breast cancer survivors revealed that bone loss may be reduced if patients take 4 grams omega-3 fatty acids per day (Hutchins-Wiese 2014). Paclitaxel may cause peripheral neuropathy, or numbness in the hands and feet. In one study, breast cancer patients being treated with paclitaxel took either approximately 2 grams omega-3 fatty acids daily or placebo. The placebo group was twice as likely to experience peripheral neuropathy (Ghoreishi 2012). In addition to reducing the side effects of chemotherapy, omega-3 fatty acids in fish oil may also improve recovery from surgery in general (Heller 2004).

Mushrooms

Various types of mushrooms have traditionally been used by several cultures to treat breast cancer. Modern research is beginning to validate and explore the benefits of these mushrooms for patients (Novaes 2011; Li 2014). In Japan, a component of the Coriolus versicolor mushroom, called polysaccharide K, has been used for decades as a cancer immunotherapy (Sun 2012). In China, several drugs based on Ganoderma sinense or C. versicolor have been approved (Jiang 2017; Chang, Zhang 2017).

Mainstream medicine in other parts of the world has been slower to study this therapeutic approach. In a recent analysis, extracts of the C. versicolor mushroom significantly improved chances of survival among patients with several types of cancer, including breast cancer (Eliza 2012).

Mushrooms may also help manage side effects of conventional treatment. Women taking extracts of Agaricus sylvaticus (2.1 grams per day) had better appetite and nutritional status than women taking a placebo (Valadares 2013). A powder form of Ganoderma lucidum (reishi mushroom) may reduce fatigue and improve quality of life for breast cancer patients (Zhao 2012).

Several studies have investigated the effects of various kinds of mushrooms on the immune system (Guggenheim 2014). The immune system is often suppressed in cancer patients, and some mushrooms may reverse this suppression and allow the immune system to fight the cancer again (Chang, Zhang 2017). G. lucidum was found to increase T cell numbers in cancer patients undergoing treatment (Jin 2012). An extract of Grifola frondosa (maitake) mushrooms (about 700 mg per day) increased the number and activity of natural killer (NK) cells and some types of T cells in breast cancer patients (Deng 2009). An extract of Trametes versicolor mushrooms (6 to 9 grams per day) (Torkelson 2012) or a combined extract of C. versicolor and Salvia miltiorrhiza (Wong 2005) had similar effects.

Melatonin

Melatonin, a hormone that regulates the sleep-wake cycle, is naturally produce by the body at night (Hill 2015; Brown 1994). For women with breast cancer, melatonin supplements may help them sleep while managing the symptoms of the disease itself or the side effects of treatment. For instance, women recovering from breast cancer surgery taking 6 mg melatonin about one hour before bedtime slept significantly better (Madsen 2016). In another study, the same dose of melatonin also reduced depression in a similar group of patients (Hansen 2014).

Disruption of sleep-wake cycles may increase the risk of breast cancer (Samuelsson 2017). For example, studies suggest night shift workers may be at increased risk (Viswanathan 2009; Hansen 2017). This effect may be partly due to reductions in melatonin levels in these workers. In laboratory studies, melatonin has demonstrated many anti-cancer properties (Reiter 2017). Supplemental melatonin slowed tumor growth in animal models (Hill 2015).

Data on supplemental melatonin in breast cancer patients are limited. One study enrolled 14 women with metastatic breast cancer who were not responding well to tamoxifen. The participants took 20 mg melatonin before bed. The cancer was stable in eight of the patients, and four patients responded (Lissoni, Barni 1995). The same research group conducted a follow-up randomized study in 40 patients with estrogen receptor-negative breast cancer. About half of the patients were treated with tamoxifen alone, and the others were treated with tamoxifen plus melatonin (20 mg/d). Seven of 19 patients treated with melatonin responded to treatment, but only two of 21 patients taking tamoxifen alone responded (Lissoni, Ardizzoia 1995).

Lastly, topical melatonin may help prevent skin irritation resulting from radiation therapy. In a phase II trial, melatonin or a placebo was applied to the skin of breast cancer patients during irradiation and two weeks after the end of the radiation therapy. Ninety percent of patients in the placebo group experienced mild or moderate radiation-induced skin irritation, but only 59% of the melatonin group were affected (Ben-David 2016).

Vitamin D

Vitamin D is synthesized in the skin during exposure to sunlight. In the winter, less than half of humans worldwide have the minimum recommended level of vitamin D in their blood (van Schoor 2017). Unfortunately, vitamin D levels may drop during treatment for breast cancer (Charehbili 2016).

Several studies suggest vitamin D is beneficial in women with breast cancer (Sofi 2017; Poole 2013; Hu 2017; Yao 2017). For instance, in a recent study that followed a group of women previously treated for breast cancer, those with high levels of vitamin D in their blood were 28% less likely to have died during the 8-year follow-up period than women with low levels (Yao 2017). A meta-analysis found that every 4 ng/mL increase in vitamin D level decreased the risk of breast cancer death by 6% (Hu 2017).

Data on vitamin D supplementation for women with breast cancer are limited. Several studies have found that supplementation with vitamin D can improve blood levels of vitamin D in patients taking the aromatase inhibitors letrozole or anastrozole (Arul Vijaya Vani 2016; Rastelli 2011; Khan 2010). Letrozole and other aromatase inhibitors may cause side effects in the bones or muscles. These symptoms are worse for women with low vitamin D levels, and supplementation may relieve these symptoms (Arul Vijaya Vani 2016; Khan 2010; Rastelli 2011; Khan 2017). One study found that 50,000 IU of vitamin D3 weekly added to daily standard-dose vitamin D and calcium supplementation reduced joint pain in women undergoing aromatase-inhibitor therapy. Importantly, only women whose 25-hydroxyvitamin D levels were 40 ng/mL or below received the 50,000 IU vitamin D supplementation, and there was no placebo control, only a control group treated with standard calcium plus vitamin D supplements. The beneficial effect was more pronounced in women with higher blood levels of 25-hydroxyvitamin D (more than 66 ng/mL) (Khan 2010).

Vitamin C

Vitamin C, or ascorbic acid, is abundant in fruits and vegetables. Vitamin C is important for immune health and protection of cells from free radicals (Carr 2017; Lobo 2010). Many cancer therapies are designed to destroy cancer cells with free radicals (Lopes 2017). Researchers have hypothesized that vitamin C may protect healthy cells from damage without protecting tumor cells (Greenlee 2009; Nechuta 2011; Greenlee 2012; Wintergerst 2006; Uetaki 2015). After diagnosis, breast cancer patients taking supplemental vitamins, including vitamin C, were 22% less likely to have a breast cancer recurrence after treatment than those not taking supplements (Nechuta 2011). A meta-analysis combining data on 17,696 women with breast cancer found that women taking vitamin C after diagnosis were 15% less likely to die from the disease than those not taking the supplement (Harris 2014).

Carotenoids

Some studies found that breast cancer patients with low plasma levels of vitamin A precursors called carotenoids were more likely to have breast cancer recurrences after treatment (Eliassen 2015; Rock 2005). A pooled analysis of data from 18 prospective cohort studies found that several carotenoids were associated with reduced breast cancer risk. The protective carotenoids included alpha-carotene, beta-carotene, and beta-cryptoxanthin (Bae 2016). The best sources of carotenoids are a variety of fruits and vegetables, and in particular orange and yellow fruits and dark green, leafy vegetables (Maiani 2009).

Cruciferous Vegetables

Researchers encourage the inclusion of vegetables from the cruciferous family, such as broccoli, in the diet of women diagnosed with or at risk for breast cancer (Limon-Miro 2017). A meta-analysis confirmed that women with high amounts of cruciferous vegetables in their diet were less likely to be diagnosed with breast cancer (Liu 2013).

Cruciferous vegetables contain several beneficial compounds (Li 2017). In laboratory studies, a component called indole-3-carbinol (I3C) can slow the proliferation of tumor cells (Popolo 2017; Caruso 2014). I3C may induce favorable changes in the levels of different forms of estrogen, cause degradation of estrogen receptor alpha (the main receptor for estrogen), and reduce the activity of an enzyme that synthesizes estrogen (Marconett 2012; Licznerska 2013). In laboratory and animal models of hormone-dependent cancers, including breast cancer, I3C showed protection against tumor development (Popolo 2017; Tin 2014).

Diindolylmethane (DIM) is a byproduct of the metabolism of I3C (Thomson 2016). As with I3C, there is significant laboratory data suggesting that DIM has cancer-fighting properties. In mice, DIM inhibited breast cancer formation and reduced the growth of existing breast cancers (Thomson 2016; Chang 2005).  

The compound sulforaphane is also abundant in cruciferous vegetables. Sulforaphane is a potent inhibitor of breast cancer cells in laboratory studies (Pawlik 2013). There is growing evidence that sulforaphane’s effects are caused by changes to the DNA that affect the levels of proteins produced from certain genes (Atwell 2015; Gianfredi 2017). For instance, sulforaphane increased levels of the genes encoding two proteins that can slow tumor growth, phosphatase and tensin homolog (PTEN) and retinoic acid receptor-beta-2 (Gianfredi 2017; Lubecka-Pietruszewska 2015). Additionally, sulforaphane may enhance the effectiveness of the chemotherapy drugs 5-fluorouracil and paclitaxel against breast cancer cells (Milczarek 2017; Kim, Park 2017).

Studies of the anti-cancer effects of cruciferous vegetables and their molecular components in women with breast cancer or benign breast conditions are limited, but initial data are encouraging. A study assessed the dietary intake of cruciferous vegetables in 54 women with abnormal mammogram findings. Among women with DCIS, those with the highest levels of cruciferous vegetables in their diet had the lowest levels of a proliferation marker in their biopsy tissue samples (Zhang 2016).

In a randomized trial of women taking tamoxifen, supplementation with DIM (300 mg per day) improved several markers of estrogen metabolism (Thomson 2017). A study of postmenopausal women with early-stage breast cancer had similar beneficial results (Dalessandri 2004). Interestingly, DIM (300 mg per day) increased the expression of the BRCA1 gene among breast cancer patients with BRCA1 mutations (Kotsopoulos 2014). Lastly, in laboratory studies, DIM sensitized human breast cancer cells that were resistant to several drugs to radiation therapy (Wang, Lv 2016).

Milk Thistle

Silymarin, an extract of milk thistle, mainly consists of the lignan silybin (Bijak 2017). In laboratory studies, silymarin blocked proliferation of tumor cells, reduced inflammation, and protected cells from carcinogens (Agarwal 2006; Mahmoodi 2015).

Silybin may also improve the effects of chemotherapy. The chemotherapies paclitaxel and doxorubicin destroy breast cancer cells more effectively in the lab when cells are co-treated with silybin (Molavi 2017). One study in humans confirmed that a preparation of silybin effectively reached breast cancer tissues (Lazzeroni 2016), but the effect of silybin on breast cancer outcomes has not been tested.

Curcumin

Curcumin is a bright yellow component of the spice turmeric. In laboratory studies, curcumin can slow proliferation of breast cancer cells, cause tumor cells to die, and prevent tumors from developing blood vessels to supply nutrients (Wang, Yu 2016; Banik 2017; Khazaei Koohpar 2015). Curcumin may also specifically target cancer stem cells—rare tumor cells that can form new tumors (Mukherjee 2014; Charpentier 2014). Laboratory studies have also found that curcumin can make breast cancer cells more sensitive to chemotherapy drugs, including 5-fluorouracil, paclitaxel, and doxorubicin (Vinod 2013; Wang, Yu 2016; Sinha 2012; Panda 2017). A phase I clinical study using a combination of curcumin and docetaxel for patients with advanced and metastatic breast cancer found the combination to be well tolerated (Bayet-Robert 2010). Scientists looking into these anti-cancer effects of curcumin have found that curcumin alters many signaling pathways that cancer cells heavily rely on (Dandawate 2016).

Inflammation can promote tumor growth. In laboratory studies, curcumin can reduce the levels of inflammatory cytokines in breast cancer cells (Bachmeier 2008). One pro-inflammatory cytokine is tumor necrosis factor-alpha (TNF-α). In laboratory experiments, TNF-α changed the metabolism of tumor cells in a way that provided them with energy to sustain rapid growth. Treating the cells with curcumin blocked this effect of TNF-α (Vaughan 2013).

Curcumin may also help fight the way tumors protect themselves from the immune system (Wang, Yu 2016; Zhang 2007; Banik 2017). NK cells are often impaired in patients with cancer (Leischner 2016; Garner 1983). Mouse breast cancer cells treated with curcumin cannot suppress NK cells as effectively as untreated cells (Zhang 2007).

Tumors can also protect themselves using a type of suppressor T cell called a regulatory T cell or Treg. Treg cells dampen the immune response (Sakaguchi 2009; Ha 2009). When mice with breast cancer were treated with curcumin, the suppressive capacity of Treg cells was reduced and other T cells were able to destroy the tumor cells (Bhattacharyya 2010).

Apigenin

Apigenin, a flavone (ie, a class of flavonoids) present in fruits and vegetables (eg, onions, oranges, tea, celery, artichoke, parsley), has been shown to possess anti-inflammatory, antioxidant, and anti-cancer properties. Many studies have confirmed the cancer chemopreventive effects of apigenin (Sung 2016; Patel 2007).

Apigenin stimulates self-destruction or apoptosis in breast cancer cells (Tseng 2017; Chen 2007). One study showed that apigenin slowed the progression of human breast cancers in mice by inducing cell death, inhibiting cell proliferation, and reducing levels of HER2. Blood vessels responsible for feeding cancer cells were smaller in the apigenin-treated mice compared with untreated mice. Smaller vessels reduce the nutrient flow to the tumors and may deprive the cancer of nutrients (Mafuvadze 2012). Apigenin may also enhance the effects of the chemotherapy drugs paclitaxel and 5-fluorouracil (Seo 2017; Xu, Xin 2011; Choi 2009).

Blueberry Extract and Pterostilbene

Blueberries are rich in cancer-fighting compounds (Jeyabalan 2014). Mice with breast cancer fed a diet supplemented with blueberry extract powder had smaller tumors and fewer metastases than mice fed a control diet (Kanaya 2014). Most laboratory studies have tested the effects of one particular compound in blueberries, pterostilbene. Pterostilbene has been found to increase self-destruction (apoptosis) of breast cancer cells (Hung 2017), reduce proliferation of three subtypes of breast cancer (Wakimoto 2017), inhibit metastasis (Su 2015), and enhance the effects of tamoxifen (Mannal 2010).

Coenzyme Q10

Coenzyme Q10 (CoQ10) helps cellular enzymes turn food into energy. For several decades, it has been known that cancer patients often have decreased blood levels of CoQ10 (Lockwood 1994; Folkers 1996; Ren 1997). These findings sparked interest in the compound as a potential anti-cancer agent (NCCIH 2015).

In a clinical study, 32 patients were treated with CoQ10 (90 mg) in addition to other antioxidants and fatty acids; six of these patients showed partial tumor regression (Lockwood 1994). In one of these cases the dose of CoQ10 was increased to 390 mg and within one month the tumor was no longer palpable; after another month, mammography confirmed the absence of the tumor. A different patient with tumor tissue remaining after surgery took 300 mg of CoQ10, and within three months there was no residual tumor tissue. This complete regression of breast tumors in some patients, coupled with further reports of disappearance of breast cancer metastases (liver and elsewhere) in several other cases (Lockwood 1995) demonstrates the potential of CoQ10 as an adjuvant therapy for breast cancer. Although these promising data were reported more than 20 years ago, research on the effects of CoQ10 on breast cancer has been sparse since then (Tafazoli 2017).

Conjugated Linoleic Acid

Conjugated linoleic acid (CLA), found mostly in dairy and meat products, is a type of fat with some health-promoting properties (Chamruspollert 1999; Shokryzadan 2017). Some case-control studies suggest a diet rich in CLA can reduce the risk of breast cancer (Arab 2016). For instance, in one study, postmenopausal women with the highest CLA intake were 60% less likely to develop breast cancer compared with the group with the lowest intake (Aro 2000).

In one clinical trial, twenty-four women with stage I, II, or III breast cancer scheduled for surgery were treated with 7.5 grams of CLA per day (McGowan 2013). The authors found that a marker of cellular proliferation was decreased in the tumors after treatment compared with before treatment.

Pomegranate

Pomegranate, which is rich in healthy polyphenols, has been used for centuries for medicinal purposes (Li 2017; Sharma 2017). Researchers discovered that treatment with whole pomegranate seed oil and juice concentrate resulted in dramatic growth inhibition of estrogen-dependent breast cancer cells in the lab (Kim 2002). The same study showed inhibition of tumor formation in rodent cells exposed to chemicals known to cause breast cancer. Using different methods, another research group found a 42% reduction in tumor formation in mice with pomegranate juice polyphenols and an 87% reduction with pomegranate seed oil (Mehta 2004).

Pomegranate seed oil is a potent inhibitor of aromatase, the enzyme that converts testosterone into estrogen (Adams 2010). This enzymatic blockade could contribute to the pomegranate seed oil’s ability to inhibit growth of estrogen-dependent breast cancer cells. Pomegranate extract has also been shown to enhance the effects of the estrogen-blocking drug tamoxifen (Banerjee 2011) and reduce levels of estrogen receptors in tumors (Mandal 2015). Pomegranate also increases apoptosis, even in cancer cells that lack estrogen receptors (Kim 2002).

Cancer cells need to grow new blood vessels to support their rapid growth and tissue invasion. They typically do this by ramping up production of certain growth factors, such as vascular endothelial growth factor (VEGF) (Kubota 2012). Pomegranate seed oil powerfully inhibits production of VEGF. In a laboratory model of vessel growth, these modulations translated into a significant decrease in new blood vessel formation (Toi 2003).

Pomegranate seed oil contains a number of unique chemical constituents with potent biological effects. Punicic acid, an omega-5 polyunsaturated fatty acid, inhibited both estrogen-dependent and estrogen-independent breast cancer cell proliferation in lab cultures and induced apoptosis at rates up to 91% higher than those in untreated cell cultures (Grossmann 2010).

Quercetin

Quercetin, a compound belonging to the group of pigments called flavonoids, is found in a broad range of plant foods, from grape skins and red onions to apples, green tea, and tomatoes. Quercetin can protect DNA from cancer-inducing mutations (Yasuda 2017). In breast cancer cells, quercetin stops tumor cells from dividing and causes them to self-destruct (Hashemzaei 2017; Balakrishnan 2017; Nguyen 2017). These effects inhibit the growth of tumors in mice (Hashemzaei 2017; Zhong 2003) and prolong survival of mice with breast cancer (Du 2010). Furthermore, quercetin favorably changes chemical signaling pathways that are abnormal in cancer cells (Morrow 2001; Bach 2010).

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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