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Breast Cancer Part 1: Risk Factors, Diagnosis, and Treatment from a Biomedical Perspective
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Breast Cancer Part 1:
Risk Factors, Diagnosis, and Treatment from a Biomedical Perspective


 
"One might say that breast tissue is like the canary in the coal mine, since it acts as a harbinger of a negative environment.
-Tai Lahans, Integrating Conventional and Chinese Medicine in Cancer Care

 

Introduction

          Breast cancer is the most common form of cancer in women and the leading cause of death in women between 40 and 55 years old.  Increasingly patients are using Chinese medicine as an adjunct to their biomedical treatment.  Whether to help relieve symptoms of chemotherapy or to augment their immune system, it is pertinent that the Chinese medicine practitioner understand the elements of Western medicine's breast cancer treatment, from risk factors to hormone therapy. 

          Thus far, the FDA has approved only patented drugs and devices in the treatment of cancer.  Alternative medicine approaches are approved only to treat the symptoms of cancer in the body and the side effects associated with biomedical treatment.  The FDA has been speeding up the approval process for cancer drugs, curtailing the years it takes to get a new drug to the market.  Because of the high volume of new drugs on trial, this course will only cover what is the current standard of care.  To obtain information on the newest cancer drugs, please visit:  http://www.fda.gov.

Definition

          Cancer is a disease in which a group of cells display uncontrolled growth, invasion to adjacent tissues, and sometimes metastasis, which is a spread to other locations in the body via lymph or blood.

          Breast cancer is largely a disease amongst women - only less than one percent of all breast cancer occurs in men (Merck).




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Anatomy

          The female breast is made up of glands that produce milk called lobules.  The tubes that carry the milk from the lobules to the nipple are called ducts.   The fatty tissue and connective tissue that give structure to the breast and surround the ducts, lobules, blood and lymph vessels are called stroma.

          Most breast cancers begin in the ducts or the lobules, while a small number begin in the other tissues of the breast.

          The lymphatic system contains lymph fluid that is made up of tissue fluid, waste products and immune cells connected by vessels and nodes throughout the body, similar to a roadway, where vessels are roads and nodes are round-a-bouts.  The lymph vessels in the breast connect to either the axillary nodes under the armpit, the supraclavicular or infraclavicular nodes above and below the collarbone, or the internal mammary nodes.   Cancerous cells draining from the lymph vessels in the breast can enter any of the above-mentioned nodes and begin to replicate in those nodes.   The prominent diagnostic factor in cancer is lymph node involvement.

 

Breast Cancer Metastasis

          When cancer cells spread to lymph nodes near the primary tumor, it is referred to as a "regional spread." Breast cancer cells that break away from the primary tumor in the breast most often end up in the lung, liver, bone, lymph nodes, or brain via the bloodstream or lymphatic system. 

          When cancer cells spread and form a new tumor in a different organ, the new tumor is considered a metastatic tumor, as the cells come from the original tumor.  For example, breast cancer with lung metastasis means there is a tumor made up of breast cancer cells in the lung.  

          Sometimes a cancer patient will develop a second primary tumor, meaning the new tumor is not a breast cancer metastasis, but has originated in a different organ or tissue. 

     Recent research has concluded that carcimona of the breast is able to metastasize to different organs before it has impaired regional lymph nodes. In other words, breast cancer cells can cause metastasis regardless of size of primary tumor or lymph node involvement.  Certain researchers are now beginning to see breast cancer as a systemic disease from the beginning.1  Chinese medicine has always considered cancer a systemic disease.  (For more on TCM and breast cancer, please refer to Breast Cancer Part 2).

    
 1 National Cancer Institute.  Svetlovksa D, Mardiak J.  "Treatment strategy of early-stage breast cancer."  




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Types of Breast Cancer

          Whether the tumor is "in situ" (meaning "in place") or invasive (spreading to other breast tissue) will determine the course of treatment and often the prognosis.  Non-invasive cancers generally have better outcomes. 

DCIS:  Ductal Carcinoma in Situ

          DCIS is the most common type of non-invasive breast cancer.  Cancer cells are often confined inside the ducts of the breast.

LCIS:  Lobular Carcinoma in Situ

          LCIS begins in the milk-producing glands but does not grow through the wall of the lobules.  It is not tumor-forming and therefore does not show up on mammograms.  

DIC:  Infiltrating Ductal Carcinoma

          DIC is responsible for 75% of all breast cancers.  It starts in the milk duct of the breast, breaks through the wall of the duct, and grows into the fatty tissue and frequently metastasizes to other parts of the body.  There are several types of DIC's, including tubular carcinoma, named after the tubular formation of the cells when seen under the miscroscope, metaplastic carcinoma, a range of cancers of mixed epithelial cells (cells that line the breast) and mesenchymal cells (the connective tissue of the breast), and medullary carcinoma, originating in the milk ducts and characterized by a clear line of demarcation from normal breast tissue.

LIC:  Inflitrating Lobular Carcinoma

          LIC is responsible for 5-10% of all breast cancers and starts in milk-producing lobules.  Metastasis sites are meninges, serosal surfaces, ovaries and the retroperenium (3).

IBC:  Inflammatory Breast Cancer

          IBC accounts for 1%-5% of all breast cancers.  It is characterized by erythema and edema of the breast (caused by the cancer cells blocking the lymph vessels in the skin).  In its early stages, inflammatory breast cancer is often mistaken for mastitis.

Paget's Disease of the Nipple

          This type of cancer starts in the ducts and spreads to the nipple and the areola.  It is rare, accounting for only about 1% of all cases of breast cancer.  The skin of the nipple and areola often appears crusted, scaly, and red, with areas of bleeding or oozing. Symptoms may be burning or itching.

          Paget's disease is almost always associated with either ductal carcinoma in situ (DCIS) or, more often, with infiltrating ductal carcinoma (DIC).

Mucinous Carcinoma

          Also known as colloid carcinoma, this is a rare type of invasive breast cancer formed by the mucus-producing cancer cells.

Adenoid Cystic Carcinoma (adenocystic carcinoma)

          This type of cancer has glandular (adenoid) and cylinder-like (cystic) features when seen under the microscope. Making up less than 1% of breast cancers, they rarely metastasize.

Phyllodes Tumor

          This very rare breast tumor develops in the stroma of the breast, in contrast to carcinomas, which develop in the ducts or the lobules.  These tumors are usually benign but on rare occasions may be malignant.

Angiosarcoma

          This is a form of cancer that starts in the cells that line blood vessels or lymph vessels.  It rarely occurs in the breasts and when it does, it is usually seen as a complication of radiation to the breast developing many years after treatment.


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Risk Factors 

          Risk factors for developing breast cancer can be both genetic and environmental.  The major risk is being female.  It is important to note that 85% of women diagnosed with breast cancer have no family history of the disease (1).

Genetics

Gene:  BCRA1 & BCRA 2

          These are tumor suppressor genes.  With a BRCA1 or BCRA2 abnormality, the chance of getting breast cancer can be as high as 80% (1).  Women that carry mutations of theses genes are often encouraged to have a prophylactic mastectomy and/or ovary removal, and are treated with Tamoxifen (nolvadex).

Gene:  CYP1

         The CYP1 gene has an influence on estrogen production and 40% of women carry it.  A variation of the gene causes estrogen to start being produced earlier in a woman's life (i.e. early puberty).  Women with this gene variation are two and a half times more likely to get breast cancer than those without it (3).

Gene:  ATM / A-T

          A small percentage (1-2%) of American women carry the ataxia-telangiectasis gene which increases their sensitivity to X-rays (including mammograms) and thus their risk for cellular mutation (1).

Gene:  CHEK2

          The CHEK2 gene increases breast cancer risk about twofold when it is mutated (1).

Gene:  p53

          Inherited mutations of the p53 tumor suppressor gene can also increase the risk of developing breast cancer (1).

Gene:  PTEN

          The PTEN gene normally helps regulate cell growth.  Inherited mutations in this gene cause Cowden syndrome, a rare disorder in which people are at increased risk for both benign and malignant breast tumors (1).

Gene:  CDH1

          Women with mutations in this gene have an increased risk of invasive lobular breast cancer (1).




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Risk Factors Continued

Family History
          Breast cancer risk is higher among women whose blood relatives have the disease. 
          Having a first-degree female relative (mother, sister, or daughter) with breast cancer will increase the woman's risk by about two-fold.  Having 2 first-degree relatives with breast cancer increases the woman's risk by about 3-fold.  Women with a family history of breast cancer in a father or brother also have an increased risk of breast cancer.  In all, about 85% of women with breast cancer do not have a family history of the disease (1).

Age, Race & Ethnicity
          Most invasive breast cancer occurs in women over the age of 55.  White women are at a higher risk of developing breast cancer than compared to African-American women, however the mortality rate of African-American women from breast cancer is higher than in white women.  Native American, Asian, and Hispanic women have a lower risk of developing and dying from breast cancer than white women (1).

Estrogen and the Reproductive Cycle
          Estrogen stimulates the growth and development of the uterus at puberty and causes the endometrium to thicken during the first half of the menstrual cycle.  Estrogen also influences breast cell division.
        
            It is generally accepted that the longer one is exposed to estrogen, the greater the risk for developing breast cancer (3).  That is why having multiple pregnancies and breast feeding is considered protective, as the lifetime amount of estrogen - via the total number of menstrual cycles - is reduced.  In addition, blood levels of estriol (the type of estrogen that is considered protective against tumor growth) is elevated during pregnancy.

          Women who have their first child after age 30 and women who have never been pregnant have a higher risk of developing breast cancer (1).  The higher risk for women who have never been pregnant is due to the fact that certain breast cells complete maturation with a full-term pregnancy.  If these breast cells never reach maturation by fully differentiating, they are more susceptible to carcinogenesis (5).

Oral Contraceptives 
          According to the American Cancer Society, there have been studies proving the birth control pill slightly increases breast cancer risk, but that this risk decreases over time once the pill has been stopped.  However, studies from the 1980's show that the risk is long lasting, and does not diminish over time (3).

Combined Hormone Replacement Therapy (CHRT)
          Large studies have found that there is an increased risk of breast cancer related to the use of combined hormone replacement therapy, which is using estrogen and a synthetic form of progesterone, called progestin (6).  The longer the hormone therapy was used was used, the greater the risk. 

          Combined HRT also increases the likelihood that the cancer may be found at a more advanced stage.  This is due to the fact that hormones make breasts more dense,  making the screening mammograms more difficult to identify cancerous lesions. 

Estrogen Replacement Therapy
          For post-menopausal women, taking unopposed estrogen (without progesterone) long-term (more than 10 years) is thought to increase the risk of breast cancer (1).

Alcohol 
          Compared with non-drinkers, women who consume 1 alcoholic drink a day have a very small increase in risk. However, those who have 2 to 5 drinks daily have about 1½ times the risk of women who drink no alcohol (1).




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Risk Factors Continued

Obesity
          Post-menopausal women are at increased risk for breast cancer if they are obese. This is because the ovaries, pre-menopause, produce the majority of estrogen and abdominal fat tissue produces a minority of estrogen. 
          But once ovarian production ceases at menopause, estrogen is still being created by the fat tissue.  Therefore the more fatty tissue, the more estrogen is secreted into the blood stream (1,3).  
 
Hyperinsulinemia
          High blood insulin levels is a risk factor for breast cancer (1,3).

Lack of physical activity 
          Evidence is growing that physical activity in the form of exercise reduces breast cancer risk (1).  One possible explanation for this is that lack of physical activity can cause obesity. 

Night work 
          Women who work at night may have an increased risk of developing breast cancer, several studies have suggested.  This may be due to changes in levels of the hormone melatonin, a hormone that is dependent on the level of light one is exposed to (1). 

Environmental Exposures
          The evidence to date generally supports an association between breast cancer and polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs, vinyl chloride).  Evidence regarding dioxins and organic solvents is also suggestive of an association (7).  

Endocrine Disruptors
          Xenoestrogens are synthetic estrogen-like substances that differ from those produced by living organisms.  They have only recently (less than 70 years) been introduced into the environment and are produced by industrial, agricultural, and chemical companies.

          Pseudo-estrogens are problematic because they convert estradiol into a strong form of estrogen (16-alpha-hydroxyestrone), causing normal breast cells to mutate.  One study showed that women with higher levels of 16-alpha-hydrosyestrone estrogen in their bodies were more at risk for developing breast cancer (8).

          Some examples of xenoestrogens are bisphenol A (called "BPA," a component of some plastics, also found in the lining of canned goods), the insecticide DDT, phthalates (a chemical component often found in plastics), and parabens (a class of petroleum-derived preservatives). 

Food Contaminants
          Red Dye no. 3 is a common food dye and a carcinogen that can influence the DNA of breast cells (3).

Radiation exposure 
          Ionizing radiation is a proven human carcinogen. The evidence for this comes from many different sources, including studies of atomic bomb survivors in Japan.  Examples of ionizing radiation exposure include radiation from the sun, medical radiation from dental and other routine x-rays (including mammograms), CT scans, PET scans, bone scans and non-medical man-made radiation like nuclear weapons testing (1).  In general, the risk of cancer from radiation exposure increases as the dose of radiation increases.

Smoking 
          Smoking cigarettes has been found to increase the risk of breast cancer (9).  

Diet and Stress
          It has been estimated that 35% of cancer deaths may be related to dietary factors, in particular a diet high in fat (10).  Researchers have shown that a diet high in vegetables and fruit and daily exercise down-regulate the Selectin E gene, which promotes inflammation and is elevated in breast cancer (11). 

          Although a direct relationship has not yet been proven in clinical studies, some studies do suggest that psychological stress weakens the immune system, which in turn causes a hypofunctioning of the immune cells that are responsible for destroying cancer cells (1).


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Breast Cancer Detection
          Biomedicine offers advanced diagnostic tools that are instrumental in detecting, diagnosing, staging and tracking the progression of breast cancer and the effectiveness of treatment. These tools include MRI, PET, CT, ductal lavage, tissue biopsy, chest X-rays, blood tests as well as bone and brain scans to look for metastasis.  
 
          Many factors are considered in a breast cancer diagnosis, including invasiveness of surrounding tissue, level of lymph node involvement and tumor size, tumor grade, hormone receptor status, HER2/neu oncogene over-expression, margins of resection (from surgery), and overall health.  
 
          An interesting point to consider is that early breast cancer usually does not cause pain. 

Breast Exam 
          Up until very recently, the self breast exam (SBE) was encouraged by oncologists as an early detection tool for breast cancer.  However, a recent study by the Cochrane Collaboration concluded that there was no beneficial effect in terms of screening or breast cancer mortality from conducting self breast exams (12).  However, it is reasonable that if a woman knows how her breast tissue normally feels and looks, she is better equipped to notice changes in what is normal for her.  
 
       
Mammograms
          Although other imaging tests like the MRI, CT, and PET scans are used, the mammogram is still the first choice for breast cancer screening.  Why this is I am not sure.  A 25 year study done in Canada published March 2014 in Nursing Standard found that regular mammography screenings were no more likely to reduce mortality than physical examination.1  Since a screening mammogram is recommended every year for women over age 40, is it reasonable to suggest that the motive is profit, considering there is no health benefit but rather risk involved in consistent, repeated X-rays of breast tissue?  (For more information on this topic, please refer to the following article written by the Swiss Medical Board found here:  http://acct-blog.com/2014/04/19/abolishing-mammography-screening-programs-a-view-from-the-swiss-medical-board/).  For high risk women, or women with lobular histology, an MRI is sometimes recommended in addition to the mammogram.
 
          Screening mammograms usually involve 2 x-rays of each breast (4 in total).  Overall, false negatives tend to occur more often in younger women than in older women because the dense breasts of younger women make breast cancers more difficult to detect in mammograms. As women age, their breasts usually become more fatty and less dense, so breast tumors become easier to detect.

Thermography
          Although FDA approved, breast thermography is still not widely used as an early diagnostic tool for breast cancer detection.  Totally non-invasive, thermography measures thermovascular temperature and patterns on the surface of the breast tissue.  These temperatures are monitored over time in order to detect changes, possibly due to physiological abnormalities or increased blood flow that could indicate a precancerous growth. 
 
Fine Needle Aspiration
          This is essentially a biopsy of the suspected tumor tissue.  Obtaining results is fast - usually within a matter of days a diagnosis is confirmed. 


1.
Nursing Standard - 28(27):pp. 17; Regular mammography ineffective in addressing breast cancer incidence.  Available online at:  http://rcnpublishing.com/doi/abs/10.7748/ns2014.03.28.27.17.s24

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Laboratory Tests
          No tumor marker has been found to be useful for screening or diagnosing early stage breast cancer.  Blood tests are mostly used to gauge the effectiveness of breast cancer treatment.
 
          In addition to the following tumor markers, the oncologist will usually order a Complete Blood Count (CBC) and liver function tests.  A complete blood count test is done because cancer (and chemotherapy or other medications) can influence bone marrow production of red and white blood cells - either increasing or decreasing the production of one type of cell causing fatigue, anemia, etc.  Liver function tests include bilirubin, ammonia, total protein, albumin, prothrombin, fibrinogen, cholesterol, triglycerides, and the enzymes:  ALT (alanine aminotransferase), AST (aspartate aminotransferase), ALP (alkaline phosphatase), GGT (gamma-glutamyl transferase), and LDH(lactate dehydrogenase).  In a nutshell, these tests monitor whether the liver's function has been impaired, and if there has been damage, to what extent.
 
          Some of your patients may report they have triple negative breast cancer.  This means they are not ER/PR positive and are not HER-2 positive.  Most often these patients are put on chemotherapy as a primary treatment strategy.

Understanding the Results
          The prefix ‘CA’ means cancer antigen.  The following blood tests are commonly ordered if breast cancer is suspected or to monitor patient progress or digression.
 
Test Reference Range Explanation
CEA (carcinoembryonic antigen)
0-3 ng/mL
The CEA protein is found in embryonic tissues and is used to track metastasis. Besides breast cancer metastasis, it is also found in colorectal, pancreatic, gastric and lung metastasis and some non-cancer diseases.
CA 125
<35 U/mL

Normally thought of as an ovarian cancer tumor marker, this cancer antigen can be elevated in breast cancers as well.
CA 27.29 / CA 15.3
<38 U/mL / <22 U/mL
Both of these antigens test for a mucus-containing protein that is produced by the MUC-1 gene that breast cancer cells shed copies of into the bloodstream.  Used to monitor the effectiveness of breast cancer treatment.
Estrogen Receptor Test & Progesterone Receptor Test
Result is either positive or negative, noted as ER/PR + or -
A sample of the tumor itself is tested, and if the cancer cells have estrogen or progesterone receptors (proteins to which estrogen will bind) the test is considered positive.  ER/PR positive cancers tend to have better outcomes.
VEGF (vascular endothelial growth factor)
Positive results noted as an "over-expression"
VEGF is a chemical signal produced by cells that stimulates the growth of new blood vessels.  Although it is vital for tissue repair after an injury, it can also supply the blood for the cancer to grow.  This test is not unique to breast cancer, as it is seen in all cancer metastasis.
HER-2 (Human Epidermal growth factor Receptor Type 2)
Results:  Positive (over-expression)/Negative
The HER2 protein is involved with the pathways leading to cell growth and differentiation. Healthy breast cells have two copies of the HER-2 gene. If breast cells have more than this, the duplicates can start to overproduce the HER2 protein.

About one of every four breast cancers is HER-2 positive.

Breast Cancer Staging
          In order to gauge the extent of disease in an individual, one of two types of lymph node biopsies are normally performed.
 
           The first is an axillary node dissection.  This is often done during the same operation as a lumpectomy or mastectomy and involves removing 6 to 30 lymph nodes to be tested for breast cancer cells, after the surgery. The most common side effect of an axillary node dissection is lymphedema of the arm, which may affect up to 10% of patients.  

          The second is a sentinel node biopsy.  This procedure makes lymphedema less likely.  The sentinel lymph node is the first lymph node to receive lymphatic drainage from a tumor, therefore this would be the first metastatic site.  A radioactive substance and/or blue dye is injected near the tumor. The substance or dye flows through the lymph ducts to the lymph nodes. The first lymph node(s) to receive the substance or dye is/are removed. A pathologist studies the tissue for cancer cells and if no cancer cells are found, it may not be necessary to remove more lymph nodes. After the sentinel lymph node biopsy, the surgeon removes the tumor (1).

Staging Definitions
Stage 0 Carcinoma in situ (DCIS or LCIS)
Stage I Tumor size is less than or equal to 2 cm
Stage II Tumor size between 2-5 cm with or without axillary lymph node involvement on same side of breast
Stage III Tumor size greater than 5 cm with lymph node involvement on same side of breast
Stage IV (metastatic cancer)  Any size tumor w/non-regional metastasis.  Most commonly in lymph nodes, lung, liver, bone, or brain.
 
Breast Cancer Grade
          The nuclear/histological grade is based on the degree of tumor cell differentiation, of which a tumor can be graded 1, 2 or 3.  Well-differentiated tumor cells are slow growing and carry a better prognosis (grade 1) whereas poorly differentiated tumors are less organized and tend to be faster growing (grade 3).
 
TNM System
          In addition to the numerical system listed above, some doctors also use the TNM system to stage breast tumors.  The T refers to the size of the tumor, and a number will be placed after the T to denote it's extent (0-4).  The N refers to lymph nodes, and there is also a number following the N denoting how much lymph involvement there is (0-3).  The M refers to metastasis to other parts of the body, followed by a number describing to what extent (0-1).  If there is an X after a T, N, or M, it means there is no cancer found in those areas (a TX would mean the tumor can't be measured or found).
 
          For example, "T1 NO MO" means the tumor is less than 2 cm across, and there is no lymph node or metastasis involved.

        To download free breast cancer staging charts using TNM, you can visit the American Joint Committee on Cancer's website at: www.cancerstaging.org





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Breast Cancer Treatment
          Though treatment strategies vary widely depending on the stage of disease, the most common course of treatment for a breast cancer patient is surgery, chemotherapy and radiation, and in ER/PR positive cases, hormone therapy.  

          Surgery, either lumpectomy or mastectomy, is the most common treatment strategy for most types of breast cancer.  For women with a confined tumor  (the surrounding breast tissue is clear of cancer, referred to as having negative margins of resection), breast conserving, involving a lumpectomy and radiation is standard of care.  For women whose tumors are not confined, treatment may be a radical mastectomy.  
 
          A radical mastectomy includes the removal of the entire breast, all underarm lymph nodes and chest wall muscles underneath the breast.  A modified radical mastectomy allows for the conservation of more tissue, so it is used more frequently.  Radical mastectomy, rarely done today, is recommended only when cancer has spread to the chest muscles under the breast.

          Radiation is used as an adjunct to surgery.  It is almost always given after a lumpectomy, and sometimes after a mastectomy and axillary node dissection.  Radiation is not used as a stand-alone treatment.  For most types of breast cancer, radiation after surgery significantly decreases the possibility of cancer recurrence in that breast while allowing for conservation of the breast.  However, recent studies have found that for women over 70, lumpectomy and tamoxifen plus radiation did not increase life span compared with lumpectomy and tamoxifen alone (13).  

          The standard form of radiation used is a high energy photon beam (generated by a linear accelerator) which works by preferentially damaging the DNA of dividing cells.  Tumor cells in general are dividing more frequently than the surrounding normal cells, so tumor cells are more susceptible to radiation damage.  The treatment also damages the DNA of healthy cells in the vicinity of the tumor, but these cells have more sophisticated repair mechanisms and are therefore considered better equipped to survive the damage.  The effects and side-effects of radiation can continue to evolve for up to nine months or longer after treatment is given.  

          Treatment is typically 5 days a week for 6-8 weeks.  Just as the benefits of radiation are gradual, the onset of side effects is gradual as well which include (but are not limited to):  dryness, soreness, discoloration, and blistering of skin, fever, nausea/vomit, fatigue, swelling of the breast from fluid retention, scar tissue development, loss of sensation and sensitivity of breast area, pain in chest wall area and dry cough.  Most patients tolerate treatment well, however it is expected that patients will develop some sort of skin reaction due to treatment.  The two areas most likely to become irritated are the fold underneath the breast and in the axilla of the arm on the treated side.




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Breast Cancer Treatment Continued        
 
          Chemotherapy works by interfering with rapidly dividing cells.  The cells in the blood, mouth, intestinal tract, nose, nails, vagina, and hair are also undergoing constant, rapid division.  This results in some damage to those cells as well, resulting in the common toxicities of myelosuppression (lowering of blood counts or depression of the immune system) and GI distress. Infections like sinus and yeast infections may become more prominent during chemotherapy.  Side effects include (but are not limited to):  Nausea, vomiting, diarrhea, hair loss, fatigue, anemia, infections, anorexia, mouth sores, taste and smell changes, cessation of menses and onset of menopause, infertility, memory loss, peripheral neuropathy.

          Chemotherapy drugs are used to treat invasive breast cancer or to try to prevent recurrence and metastasis of high-risk breast cancers.  There are about 13 types of chemotherapy used in breast cancer treatment and they are used in combinations, because the response rate seems to be higher than single chemotherapeutic agents (Merck).

          There are three main types of chemotherapy.  The first group consists of drugs that include alkylating agents that damage the proteins that control growth in the genes of the tumor cell. These mainly include cyclophosphamide.  The second are anti-metabolites, such as 5-Fluorouracil, that act as false building blocks in a cancer cell's genes, causing it to die as it prepares to divide.  The third group consists of anti-tumor antibiotics that are potent inhibitors of gene replication like doxorubicin (Adriamycin) and are used for patients with more advanced disease that are not ER positive (1).

The standard drugs are:
• cyclophosphamide (Cytoxan) - the C in a chemo regimen
• methotrexate - the M in a chemo regimen
• 5-fluorouracil (also known as 5-FU) - the F in a chemo regimen
• doxorubicin (Adriamycin) - the A in a chemo regimen
• epirubicin (Ellence) - the E in a chemo regimen
• paclitaxel (Taxol) or docetaxel (Taxotere) - the T in a chemo regimen.

Common chemo regimens are:  CAF, CMF, CEF, FAC, AC and TC.

          Chemotherapy treatment is typically several days in a row reoccurring periodically as a cycle.  On average a patient will receive between three and six cycles of chemotherapy, so they will be on “chemo” for 3-6 months.  Chemotherapy can be administered intravenously or orally.
 
          Adjuvant chemotherapy is given to the patient after the primary treatment has been given (usually surgery) to safeguard the surgery's effectiveness.  Neoadjuvant chemotherapy is given to the patient before surgery, in an attempt to shrink the tumor before the operation.

         Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells.  Herceptin (trastuzumab) is among the first of such approaches to cancer therapy.  It uses antibodies made in the laboratory, from a single type of immune system cell, to treat cancer throughout the whole body.  It works only against breast cancers that are HER-2 positive. Herceptin blocks the chemical signals these cells need to grow, slowing or stopping their growth.   Herceptin is given via intravenous infusion (IV) on a weekly basis.



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Hormone/Endocrine Therapy 
          Hormone therapy is used as a systemic therapy for people with hormone receptor positive cancer.

Selective Estrogen Receptor Modulators (SERMs)
          Tamoxifen (nolvadex) is a drug known as a selective estrogen receptor modulator (SERM) and is used to prevent estrogen from binding to the receptor sites on the breast cells.  This can slow down or stop the growth of cancers that need estrogen to grow. It can also reduce the risk of a new breast cancer or delay the return of breast cancer and control its spread.  These drugs are used in women who are pre-menopausal. 

          Drugs in this class are used for a maximum of five years, as longer than this does not seem to produce any clinical advantage.  In fact, prolonged use of SERM’s has been associated with uterine/endometrial cancer and more breast cancer recurrences (14).  

Aromatase Inhibitors Arimidex (anastrozole), Femara (letrozole), Aromisin (exemestane)
          Like SERM’s, aromatase inhibitors are given to women whose breast cancer is ER positive.  Unlike SERM’s, aromatase inhibitors are a different type of anti-estrogenic drug.  They work by blocking the final step in estrogen production, not by blocking ovarian estrogen production completely.  They are given to post-menopausal women, due to the fact that aromatase inhibitors can cause ovarian cysts in pre-menopausal women by increasing gonadotropin levels. Length of treatment is not recommended for more than 5 years, due to the fact that aromatase inhibitors induce the loss of bone mass thereby leading to the risk of fractures.

Ovarian ablation
          Ovarian ablation is the blocking of estrogen production by either the removal of the ovaries surgically or via drugs.  Drugs that block estrogen production by the ovaries are known as luteinizing hormone-releasing-hormone (LHRH) analogs, and one such common example is Lupron (leuprolide).  Removing ovarian function will put a woman into menopause replete with menopausal symptoms like hot flashes and night sweats.



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Treatment for Breast Cancer Metastasis
          Breast cancer metastasis is most often seen in the lungs, liver, bone, brain and lymph nodes. Treatment for metastasis increases median survival by 3 to 6 months though there is tremendous variability.  For example, patients with disease that has spread only to bone tend to survive longer.  In order to formulate a treatment plan for breast cancer metastasis, a doctor will consider the type of cancer, how long the disease-free period was before the cancer metastasized, and what therapies were previously given (Merck).  

          Often systemic and non-systemic treatment therapies are combined like chemotherapy plus hormone therapy or herceptin plus chemotherapy.  In addition, drugs are added to target the areas or tissue the cancer has spread to.  For example, in the case of metastasis to bone, which causes bone disintegration, biphosphonates like Zomeda (zoledronic acid) are often used.  

          Radiation therapy alone is sometimes used in the case of a single metastatic site such as the bone.  Radiation therapy is the most effective treatment for brain metastases (Merck).  

     Experimental research using mice gives hope to brain metastasis patients. 
Metastatic brain tumors occur ten times more often than primary brain tumors, and due to the blood/brain barrier, chemical agents have typically been ineffective.  Treatment involves using immunotherapy and gene therapy combined.  Let's hope the treatment will move to human clinical trials soon.1

          A challenge to any drug treatment is that resistance to the drugs is acquired, making treatment difficult.  A challenge to cancer treatment in general is that the cancer itself is adaptive, it changes its behavior over time.  For this reason, several types of cancer fighting agents are often used in biomedicine.

Conclusion
          Breast cancer is not going away - in fact the rates of breast cancer have risen and keep rising.  Being able to understand diagnosis and treatment from a biomedical perspective will better enable the practitioner of Chinese medicine to implement their treatments accordingly.  For guidance on using Chinese medicine as an adjunctive therapy for breast cancer patients, please refer to Breast Cancer Part 2:  Etiology, Pattern Differentiation, and Adjunctive Therapies from a Chinese Medical Perspective.


1  UCLA Jonnson Comprehensive Cancer Center.  "New Treatment Strategy for Breast Cancer Spread to Brain."  Available at:  http://www.cancer.ucla.edu/index.aspx?recordid=662&page=644

 
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Appendix A:  Sample patient blood work 
 
Patient A:  Breast Cancer Stage IV  
Type DIC with metastasis to bone (pelvis) and liver, ER/PR +
Tumor markers CA 15.3 = 429;  CA 125 = 90;  CEA 19
Other pertinent blood work ordered Albumin = 3.5, AST = 62;  Fibrinogen = 654
Current Rx's Zomeda, Arimidex
Commentary In addition to the standard tumor markers, this patient’s liver enzymes were being monitored due to her liver metastasis.   
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
Patient B:  Breast                Cancer                   Stage 1V  
Type DIC w/ metastasis to parietal/temporal bone and liver.  Previous treatment mastectomy, chemotherapy and radiation
Tumor markers CA 15.3 (308), CA 27.29 (152), CEA (13)
Other pertinent blood work ordered CRP (7.3), AbsNeutr (83), Hbg (10/31), h/h (9/27), Neutro(82) Lymph (1)
Current Rx Taxotere, Avastin, Zomeda
Commentary This patient was not hormone receptor positive, and was  receiving chemotherapy treatment (Taxotere) to control the bone metastasis as well as biphosphonates (Zomeda) to stop further bone disintegration.  Her red and white blood cell counts were being monitored due to frequent infections from the chemo.  Avastin was prescribed to stop the blood supply to the metastasis site.
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
Patient C: Breast Cancer Stage II   
Type                                             DIC, ER/PR +.  Previous treatment mastectomy, chemotherapy, radiation, Arimidex (one year)
Tumor markers Ca 27.29 = 23, CEA 1.9
Other pertienent blood work ordered estradiol (20), progesterone (551)
Current RX Celexa, Iodoral, medrol
Commentary This woman was responding to treatment as evidenced by her CA 27.29 and CEA tumor markers being within normal range.  She was on the anti-depressant Celexa (anti-depressants are commonly prescribed to cancer patients). Her naturopathic doctor had her on Iodoral, a form of iodine, used for estrogen positive cancers (iodine treatment is not generally an allopathic approach). Medrol is a synthetic corticosteriod, used to treat inflammation and in some instances, cancer.  Normal estradiol levels for post-menopausal women are between 10 and 32 pg/ml. Normal progesterone levels are 0.2-25.9 pg/ml.


Appendix B
These are the common drugs used in the treatment of breast cancer and breast cancer metastasis.  The brand name of the drug is followed by its generic name in parenthesis.
 
Drug Name Class Use Administration
Adriamyacin (doxorubicin)
Anthracycline Antibiotic Chemotherapy IV
Arimidex (anastrozole)
Aromatase inhibitor
Estrogen blocker for post-menopausal women
Oral
Aromosin (exemestane)
Aromatase inhibitor
Estrogen blocker for post-menopausal women
Oral
Avastin (bevacizumab)
Antiangiogenic agent 
Stops the formation of new blood vessels to the tumor
IV
Cytoxan  (cyclophosphamide)
Alkylating agent Chemotherapy IV or oral
Ellence (pirubicin)
Anthracycline antibiotic Chemotherapy IV
Femara (letrozole)
Aromatase inhibitor Estrogen blocker for post-menopausal women
Oral
Adrucil, Carac, Efudex and Fluoroplex5-fluorouracil (also known as 5-FU)
Antimetabolite
Chemotherapy
IV
Herceptin (trastuzumab)
Monoclonal antibody
Targeted therapy, for HER 2/neu cancers only
IV
Lupron (leuprolide)
Luteinizing hormone-releasing-hormone (LHRH) analogs
Stops ovarian manufacture of estrogen (will put someone into a chemical menopause) Intramuscular implant
Trexall (methotrexate)
Antimetabolite
Chemotherapy
Oral or by injection
Tamoxifen (nolvadex)
SERM Prevents estrogen from binding to receptor sites on breast cells for pre-menopausal women
Oral
Taxol (paclitaxel)
Anti-neoplastic alkaloid
Chemotherapy
IV
Taxotere (docetaxel) Anti-neoplastic taxane
Chemotherapy
IV
Zoladez (goselerin) Luteinizing hormone-releasing-hormone (LHRH) analogs
Stops ovarian manufacture of estrogen (will put someone into a chemical menopause.)
Subcutaneous implant
Zomeda (zoledronic acid)
Biphosphinate Stops reabsorption of bone (for bone metastasis) IV
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




References

(1)
 American Cancer Society,  "What are the risk factors for breast cancer?" available online at http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-risk-factors (last visited May 2, 2011).

(2) National Cancer Institute, "BRCA1 and BRCA2: Cancer Risk and Genetic Testing", available online at:  http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA (last visited May 3, 2011).

(3) Lahans, T.  (2007).  Integrating Conventional and Chinese Medicine in Cancer Care.  Philadelphia:  Elsevier Ltd.

(4) Rachel Ann Clark, Suzanne Snedeker, Carol Devine, "Fact Sheet #9:  Estrogen & Breast Cancer Risk:  The Relationship,"  March 1998, available online at   http://envirocancer.cornell.edu/FactSheet/General/fs9.estrogen.cfm (last visited April 28, 2011).

(5)  Russo, J., Moral, R., Balogh, g, Mailo, D, Russo, I.,  "The protective role of pregnancy in breast cancer," 2005, available online at http://www.ncbi.nlm.nih.gov/pubmed/15987443 (last visited May 9, 2011).

(6)  Ross, R., Paganini-Hill, A., Wan, P., Pike, M.  "Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin," 1999, available online at http://jnci.oxfordjournals.org/content/92/4/328.full (last visited May 9, 2011).

(7)  Green Brody, J., Movsich, K., Humblet, O., Attfield, K., Beehler, G., Rudel, R, "Environmental pollutants and breast cancer: epidimiologic studies," June, 2007, available online at http://www.ncbi.nlm.nih.gov/pubmed/17503436 (last visited May 9, 2011).
 
(8)  Rachel Ann Clark, Suzanne Snedeker, Carol Devine, "Fact Sheet #10:  Estrogen & Breast Cancer Risk:  What Factors Might Affect a Woman's Exposure to Estrogen?" July 2002, available online at:  http://envirocancer.cornell.edu/factsheet/General/fs10.estrogen.pdf (last visited May 5, 2011).
 
(9) Cui, Y, Miller AB, Rohan TC, "Cigarette smoking and breast cancer risk:  update of a prospective cohort study," 2006, available online at www.ncbi.nlm,nih.gov/pubmed/16773435 (last visited May 9, 2011).
 
(10) Carol Ann Clifford et al, "Diet and Cancer Risk," available online at http://rex.nci.nih.gov/NCI_Pub_Interface/raterisk/risks73.html (last visited May 2, 2011).
 
(11) Dean Ornish, et al, "Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention," June 16, 2008, available online at http://pnas.org/content/105/24/8369.full.pdf+html?sid=b9a5803d-db40-4256-9be7-7ec01c1f1c40 (last visited May 9, 2011).
 
(12) Kösters JP, Gøtzsche PC, "Regular self-examination or clinical examination for early detection of breast cancer," April 2003, available online at http://www2.cochrane.org/reviews/en/ab003373.html (last visited May 3, 2011).

(13) Hughes NS, et al, "Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer," 2010, available online at http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=50014 (last visited May 9, 2011).

(14) National Cancer Institute, Understanding Cancer Series:  Estrogen Receptors/SERMS at Slide 20 available online at: http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors/page20 (last visited May 3, 2011).

Special thanks to Dr. Joshua Lawson of the University of California at San Diego, and Dr. Walter Kim of the Issels Medical Center in Santa Barbara, Ca. for reviewing this course.  


 

 
 
 
 
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