Chicago Center for Jewish Genetics Disorders - Health Professionals

Breast and Ovarian Cancer

What Are the Different Stages of Breast Cancer?

Each breast cancer stage describes the pathology (tissue characteristics) of the tumor and the progression of the disease according to tumor size, lymph node involvement, and whether or not metastasis (spread to other tissues) has occurred.

The stages are:

Stage 0: A non-invasive tumor is present only in the lining of a lobule (milk producing gland) or a duct but not in the surrounding fatty tissue. This is called a ductal carcinoma in situ (cancer of the duct) and if it is found on a breast biopsy, a woman has a 25% chance of developing breast cancer within the next 25 years.
Stage I: An invasive tumor less than 2 cm is present only in breast tissue
Stage II: There are three different possibilities in this stage =>
- A tumor smaller than 2 cm but with lymph node involvement is present
- A tumor 2 to 5 cm in size with or without lymph node involvement is present
- A tumor greater than 5 cm without lymph node involvement is present
Stage III: A tumor larger than 5 cm with lymph node involvement OR any sized tumor with a lumping together of the lymph nodes or metastasis to adjoining tissues such as the skin or chest wall.
Stage IV: Cancer has already metastasized to other tissues in the body, most commonly the bones, lungs, liver, or brain

Common Genetic Variants and Breast Cancer Risk

Recent research has been exploring the concept of common genetic variants that might act as low-penetrance risk factors for various forms of cancer. The theory is that these factors may be much more common in the general population than high risk cancer-predisposing mutations, such as BRCA1 and BRCA2, and may have a larger effect on overall population risk. Some of the genetic variants that are being investigated are:

Heterozygosity for ATM gene mutations: The ATM gene is involved in DNA repair and when an individual is homozygous for ATM gene mutations (neither copy of the gene is functional), this causes a disease called Ataxia-Telangiectasia (AT). AT is a progressive movement disorder characterized by telangiectasia of the conjunctiva (causing the white part of the eyes to turn red) and an increased sensitivity to ionizing radiation. Females heterozygous for ATM mutations do not have AT because they still have one fully functional copy of the ATM gene but they do however have a 2 to 5 times increased risk for breast cancer according to some studies. Overall these women have not been found to develop breast cancer at an earlier age, but are more likely to develop it in their lifetimes beyond the general population risk.
N-acetlytransferase 2 (NAT2), Glutathione transferase (GST) polymorphisms, and smokers: NAT-2 and GST are proteins that metabolize tobacco smoke products into carcinogenic compounds. In certain studies, specific polymorphisms (variations) in either of the genes encoding for these proteins have been associated with a slight increased breast cancer risk in smokers. However, other studies have not upheld these findings and more research needs to be done.
Polymorphism in the CYP17 gene: The CYP17 gene encodes for the 17-alpha hydroxylase protein, which is required for cortisol and estrogen synthesis. A specific polymorphism (variation) in this gene is called A1. A1 has been associated with late menarche and a reduced risk of advanced post menopausal breast cancer when it was found on both copies of the gene (A1/A1). The A1 polymorphism might be quite common in the general population and thus may have a minor protective effect for many women.

Management of Breast Cancer

Once breast cancer has been diagnosed, five major types of treatment are commonly used. The therapy or combination of therapies that is undertaken depends upon the location, size, and staging of the tumor and the overall health of the patient. The different treatments are:

Surgery: Surgery is used to remove existing tumors. It may also be done to prophylactically remove tissue that is at high risk to become cancerous.

Radiation: This treatment consists of large doses of high-energy beams or particles that destroy cancer cells in a specifically targeted area.

Chemotherapy: This therapy involves the use of anticancer drugs that kill cancer cells and/or control their growth. The drugs are administered such that they enter the bloodstream and travel throughout the body and this is often used when metastasis has occurred.

Biotherapy: This treatment involves administering drugs which stimulate the body’s own defense system (immune system) to fight cancer by blocking the growth of cancer cells. For example, 30% of breast cancer cells produce excess amounts of protein receptors called human epidermal growth factor-2 (HER-2) receptors. This overexpression of HER-2 receptors increases cell growth, which can result in more aggressive tumor cells. Herceptin ® (trastuzamab) is a monoclonal antibody that binds to the HER-2 protein receptor located on the surface of breast cancer cells, blocks the action of this receptor, and therefore slows or stops the growth of that cell.

Hormonal therapy: Hormonal therapy blocks the body’s naturally occurring hormones that are known to stimulate the growth of cancerous cells. Examples of this type of therapy are anti-estrogen drugs, which are covered in more depth in The Role of Estrogen and Breast and Ovarian Cancer. Sometimes, surgery is necessary to remove the source of the body’s naturally occurring hormone. For example, female hormones are produced by the ovaries, and their surgical removal (called an oophorectomy) blocks this production.

Please note that the only monitoring technique that has been proven to be beneficial for individuals with a genetic susceptibility to breast or ovarian cancer is routine mammography screening. Yearly mammograms are recommended to women of average risk beginning at the age of 40 to 50 years. At this time, additional experimental approaches to surveillance of breast cancer are currently being evaluated, but are not part of standard recommendations.

Risk Models for Breast and Ovarian Cancer

Risk models are mathematical formulas that use various factors and information to calculate a theoretical risk. In the case of breast cancer risk models, data such as family history of cancer, type of cancer, and age of diagnosis are entered for an individual, and a theoretical risk is then given for their likelihood to develop breast cancer within a specific time period or over their lifetime. Models also exist to predict the likelihood of a BRCA1 or BRCA2 mutation being present in an individual. There are several different breast and ovarian cancer risk models that have been developed. A review of three of the most common models, including what risk factors they use and their strengths and their weakness, are presented here.

Claus Model: The Claus model was developed from the information gathered from the Cancer and Steroid Hormone Study (Claus et al, Am J Hum Genet 1991; 48:232-42). This model makes that assumption that the inherited risk in an individual is due to an autosomal dominant gene mutation with high penetrance, such as is seen for BRCA1 and BRCA2. The risk estimate that is calculated is based upon a woman’s current age, the number of her 1st and 2nd degree relatives that have been diagnosed with breast cancer, and their respective ages of diagnosis. The risk is given as the likelihood of developing cancer over a woman’s lifetime or in 10 year intervals. This model is considered to be a good tool for estimating breast cancer risk based upon a family history of breast cancer. However, it does not take into account any of the other factors known to increase breast cancer risk such as atypical hyperplasia found on breast biopsies or hormonal history. It also only allows the calculation of risk for women who have at least one female relative with breast cancer. For extensive family histories of breast and ovarian cancer, the BRCAPRO model would be more appropriate.

Gail Model: The Gail model is based upon the Breast Cancer Detection Demonstration Project (Gail et al, J Nat Cancer Inst, 1989 Dec 20;81(24):1879-86) which identified major predictors of risk such as: current age, age at menarche, age of 1st live birth, number of previous breast biopsies, presence of atypical hyperplasia on breast biopsy, and the number of 1st degree relatives (mother or sisters) with breast cancer. It estimates the risk of developing invasive breast cancer over the next five years of the woman’s life or over the course of the her lifetime. It is considered the best current model for a woman without a strong family history of breast cancer and for those who adhere to regular mammography screening. However, it does not take into account 2nd degree relatives such as paternal relatives with breast cancer or the ages of onset of the cases of breast cancer. It also does not take into account any cases of ovarian cancer in a family. It overestimates the risk for women with mothers or sisters diagnosed with breast cancer after the age of 50 years and for premenopausal women who do not receive annual mammograms. It is considered an underestimate of women who have had 2nd degree relatives with breast cancer before the age of 50 or ovarian cancer at any age.

BRCAPRO: BRCAPRO is a model that calculates the probability that a particular family member carries a germ-line mutation in the BRCA1 or BRCA2 gene (Parmigiani et al, Am J Hum Genet 1998;62:145-158). The model has been validated and takes into account ethnicity (specifically whether an individual is of Ashkenazi Jewish descent or not), the individual’s personal cancer history, and their 1st and 2nd degree relatives’ medical history. An advantage of this model is the ability to add information about both affected and unaffected 1st and 2nd degree individuals in the calculation, and to use ages of cancer onset and ages of unaffected individuals. Many medical sites do BRCAPRO analysis before testing and have a calculated 10% cut-off risk of having either a BRCA1 or BRCA2 mutation before proceeding to genetic testing.

Decisions to have testing are not driven exclusively by the risk number, but by medical decision making factors, and the impact of testing on the well-being of their relatives. Please read the ASCO guidelines for more information regarding updated guidelines for cancer genetic testing from the American Society of Clinical Oncology, 2003. To access the original article: ASCO, 2003, J Clin Oncol 21(12): 2397-2406.

When providing risk assessment, it is important to give patients figures for the probability of carrying a mutation AND for the risk to develop breast cancer. In order to do so, one must incorporate the use of all models in order to balance the advantages and disadvantages of each model. Furthermore, it is crucial to choose the relative in the family history who will best capture all cases of cancer to determine risk figures and then to provide estimates of risk to your patient based on their relation to that relative. Because risk assessment is complex and technically difficult, expert opinion and clinical judgment are important to provide accurate information to patients, especially in families with pancreatic cancer and male breast cancer. Geneticists and genetic counselors are knowledgeable in these models and should be the medical professionals performing this risk estimation as part of a genetic counseling session. For more information and to find a genetic counselor in your area, please visit www.nsgc.org/resourcelink.asp, www.cancer.gov, www.nci.nih.gov/cancerinfo/prevention-genetics-causes/breast.

Reviewed by Wendy Rubinstein, MD, PhD, FACMG, Assistant Professor, Feinberg School of Medicine, Northwestern University; Medical Director, ENH Center for Medical Genetics and Gershon Locker, MD, Head, Division of Hematology and Oncology, Evanston Northwestern Healthcare