WEDNESDAY, October 16, 2002

"The Genetic Factor in Breast Cancer: More Answers…More Questions?"

The most important thing to understand about genetic mutations is the difference between the abnormality and when they occur in your lifetime. Germ line mutations occur in the cells that you are born with, and don’t generally change over a lifetime.  The penetrance of the gene is affected by other genes that you have inherited and so may be different in different people with the same gene. This type of mutation represents about 10% of breast cancers. By far the majority of breast cancers are caused by somatic mutations. These are changes in genes that occur later in life by virtue of exposures during your life. Examples include duration of breast feeding, age at menarche or menopause, alcohol consumption or use of hormone replacement therapy. Exposure to toxins or having a lot of estrogen in your body can cause mutations which can result in cancer growth. These types of mutations represent the remaining 90% of breast cancers.

Our special guest for the evening is Robin Lee, geneticist at the Cancer Risk Program at UCSF. In a sense all cancers are genetic, in that they represent changes in cells that occur throughout our lives. Hereditary cancers affect the cells you were born with—the mutations are in every cell in the body. There are a handful of cancer syndromes that involve germ line mutations, which give constellations of cancer. BRCA 1 and 2 are seen in breast and ovarian cancer families. Recently genes have been found for hereditary melanoma, colon and endometrial cancers. The task of the genetic counselor is to see which families belong in the genetic high-risk group. This is important because if a person is found to belong to a high-risk family, their lifetime risk of that particular cancer is greatly elevated, maybe as high as 80%. The main tool for this research is family history. Red flags include early onset breast cancer, Ashkenazy Jewish ancestry, breast and ovarian cancer in the same family, or other cancers like pancreatic or melanoma in combination with breast cancer. After the information on a family is gathered, different models are used to see how high the risk might be. They take into account ethnicity, age at diagnosis of cancer, age at first menses, age at first child, etc. Although all these models have limitations, and may raise more questions than they answer, it is still a useful method of determining risk.

Is there follow-up surveillance for BRCA families?  After finding a mutation, a specific surveillance plan is set up. BRCA 2 mutation would require follow-up for melanoma and prostate screening at an earlier age for men. Because these screening tests have only been around since 1996, we are not yet sure of the other cancer risks. It is really hard to look for genes that increase breast cancer in heterogeneous populations. You must look for groups with a lot of inbreeding like Icelanders and French Canadians. Ashkenazy Jews have more homogeneity than other populations, so the genes could be traced through many generations. These genes are maintained because not everybody with the gene gets cancer, so even if it is in the family, any given member may have a chance of not inheriting the mutated gene. Even with an 80% risk, there are some people who will not get cancer.

What is relative risk?  This is an increased risk of getting cancer over that of the general population based on factors like alcohol use, age of first menstruation, breast-feeding, etc.  This is still much lower than those who carry the BRCA mutation.         

Do somatic mutations exacerbate the gene line mutations?  They can increase the risk of certain cancers or change the aggressiveness of the cancer. A mutation can come from either the mother’s or the father’s side. With a mutation on only one side, offspring have a 50/50 chance of inheriting. Even after inheriting the mutated gene, something has to happen in the susceptible tissue in order for cancer to develop, this is known as a “two hit theory”. In some families the penetrance (those that have cancer) is extraordinarily high.

If you are a genetic mutation carrier, what should you advise your children? Any young woman at risk should have counseling to discuss the pros and cons of testing.  A new clinical trial will give young women at risk the opportunity to have both MRI and mammography, in order to compare these two diagnostic tools . Digital mammograms don’t offer any improvement over regular mammography in the number of cancers they detect, but they do reduce the distortion.  Eventually digital will likely be the standard, but MRI is the most detailed, resulting in more false positives. Additionally, clinical breast exams should be done every six months, starting about 10 years earlier than the age (at diagnosis) of the first person diagnosed with cancer in the family. Preventive treatments like Tamoxifen and prophylactic mastectomy or oophrectomy should be considered, but can be quite emotional and controversial. 

How much does genetic testing cost? Full sequencing of both genes costs $2800 in other than Ashkenazy Jews. If a mutation is found, other members of the family only need to be tested for that site on the gene and the cost is $350. In the Jewish population, testing one of the three specific sites on the gene costs $350.

Are the BRCA cancers more aggressive?  Stage for stage there is no difference in the cancer that occurs in BRCA carriers and non-carriers. Because they tend to occur in younger women they do tend to be more aggressive, estrogen-driven cancers. BRCA gene carriers can consider reducing the incidence of cancer by having oophrectomy.  

How do you know if being a variant carrier is significant?  Variants are changes within the gene. If the change significantly affects the product, they are known as deleterious. Normal changes are those that don’t affect the gene. Some changes are seen rarely and we don’t know if they affect gene performance. They are known as variants of unknown significance. We are seeing more of these variants, but that may just be because more people are being tested. Mary Clare King who did much of the early work on the BRCA genes is looking at genes of unknown significance.

How does breast-feeding help somatic mutations?  We know that there are some modifiable risks. The duration of breast-feeding is most important because presumably the breast isn’t exposed to as much estrogen when the woman is not ovulating or having periods during breast-feeding. Clinical findings have shown that women who breast-fed for longer than nine months had significant reduction in their risk of breast cancer over women who breast fed for less than nine months, or not at all. The authors of the study concluded that increasing breast-feeding would have an impact on the incidence of breast cancer. It may be due to the type of proliferation required to make milk, or milk production may be protective on a biochemical level.

Beside Tamoxifen, what can be done to reduce the risk of recurrence or of getting a new cancer? Oophrectomy reduces risk, but not after menopause. The data shows that high risk women who had oophrectomy in their 30’s reduced their risk of recurrence by half. This is due to the reduction in estrogen caused by lack of ovulatory cycles. Ductal lavage is a procedure whereby a catheter is placed in the duct through the nipple to try to wash out cells, which might be atypical. It is interesting technology, but we don’t yet know its value. The role of aromatase inhibitors, which block the production of estrogen from testosterone, is being looked at in several trials here. In Europe, Arimidex is being given to women with the BRCA mutation who don’t yet have breast cancer for primary prevention. Another trial looked at given an aromatase inhibitor (or placebo) to women with breast cancer to prevent metastasis. The idea behind all of these trials is to extend hormone therapy beyond the five years of Tamoxifen. You are really dealing with the risk of getting a new cancer. With a BRCA mutation, this risk is significantly inflated. It is important also to be examined by your breast surgeon in addition to yearly mammograms, and definitely to be your own advocate.

How good is MRI as a screening tool?  We don’t know what the impact of MRI will be on outcomes.  It has been very hard to prove that mammography has an impact on mortality. We know that it works for some women, but in large populations, it is hard to prove on a global level. Also, mammography picks up calcifications, which usually signify DCIS. Women with DCIS almost never die of their disease, so 10-year mortality statistics will not be affected.

How do dense breast affect mammography? 10-25% of breast cancers are mammographically invisible. Women who are premenopausal or have dense breasts can miss cancers if they rely exclusively on mammography. This is why the combination of self-exam and mammography is so important.

How does the age of onset of menses affect breast cancer?  The age of onset is earlier now than it used to be, and there has been an increase in the incidence of breast cancer in the 1970s and 80s, but the early onset is thought to be related to better nutrition.

Are there any insurance problems related to genetic testing? In California, as in many other states, insurance companies cannot use genetic testing as a way to deny coverage or payment. It actually hasn’t been as big an issue as feared. Testing uses code numbers and not names, so the results are not in the medical chart, and insurance companies cannot ask for a result. Even physicians will not be given this information.

If you have the BRCA mutation what type of surveillance is recommended?  It is recommended to see a dermatologist annually; colonoscopy is recommended starting at age 50, every 5 years. Genetic testing should be done as part of a comprehensive program. Finally, check with an oncologist.

Next Forum, Wednesday, November 13^th, topic will be “Geographic Variations in Breast Cancer Incidence: Focus on the Bay Area”.