January 14, 1998
"Blue Genes: Determining Inherited Breast Cancer Risk: What Next?"

Familial (or genetic) association of breast cancer has been known for centuries. Fear of developing cancer from family members actually lead to looking for microorganisms that caused cancer. Cancer patients were sometimes sent to leper colonies because of fears that the disease could be transmitted to other members and then be passed on to their children. The first scientific work did not begin until the 1970's when people started applying biology to study the familial relationship to cancer. Scientists began to excise and clone DNA to look for mutations. Before this a researcher here at UCSF, Mary Claire King began studying the location of genes on a chromosome according to its linkage to its neighbors. Cancer should clump with other information on the chromosome if it is genetically related. At that time one could only look at polymorphic proteins, those in which you could trace the maternal and paternal copies, and it was very laborious work. This all changed in the late 70's, researchers could look at the genetic structure of large families and narrow down the part of the chromosome associated with breast cancer. In 1989 Dr. King was able to show clear linkage to chromosome 17Q. In 1994, using the process of positional cloning (identifying a gene by location alone),a mutated gene-- BRCA1 was finally located which showed clear genetic susceptibility to cancer in some families. About a year later BRCA2 was located on chromosome 13. Although these studies were done on families with significant amounts of breast cancer, research has now moved to study other populations. Up to 1% of Ashkenazi Jews from Eastern Europe have been shown to display the BRCA1 gene. The larger question is what is the meaning of mutation, and what does it have to do with risk? What are the interactions of the gene and the environment? How can we use this information to develop better therapies or prevention, especially in people who have been identifed as being at higher risk for disease? There are also many ethical dilemmas attached to these findings, such as discrimination against patients who have been shown to display these genes.

Dr. Tripathy introduced two genetic counselors from UCSF, Beth Crawford and Peggy Conrad, who developed the Cancer Risk Program here. They have been involved with genetic testing of patients and are familiar with the problems associated with these tests.

Questions and Answers:

There has been a prevention trial (closed now) using tamoxifen for people with increased family risk for breast cancer, but this did not involve genes. Currently there are no trials for BRCA 1 patients. Most BRCA 1 tumors are estrogen receptor negative, so hormonal therapy may no be helpful. There is soon to be a nationwide registry for patients that undergo genetic testing, with information about mutations and treatment strategies.

HER2/neu is an acquired genetic abnormality, it is not amplified in normal tissue. No one knows why these genes become amplified, but it is a common feature of cancer. Many tumor suppressor genes have been discovered this way. Genomic instability develops early in cancer cells; leads to an inability to correct mistakes in the DNA. HER2/neu is generally amplified, but not mutated in human cancers. Someone who is ER+ is probably a little less likely to carry BRCA1.

Some people indicated that they were less likely to undergo genetic testing after getting information about the process: high cost, no research, what will actually be done with the information that is accrued? Beth and Peggy said that their counseling tries to give the patient an idea of their chance of carrying the mutation, so that they can make a decision about whether they want to go ahead with the testing. They are offered risk assessment to get more information about the type of tumors they might develop, if there is a hereditary pattern, and what type of surveillance might be recommended. Weekly education sessions are offered and open to the public where people can get more information about familial vs. sporadic cancers. If the patient already has breast cancer, they will counsel about other cancers you are likely to contract, such as ovarian, and screening and surveillance practices that they might want to employ. Currently, they cannot pinpoint specific mutations, as there are 400 associated with BRCA1 and 200 associated with BRCA2. Some mutations are more common and have specific types of tumors associated with them. Our database is too small currently to have much information so far, but it is another reason why pooling databases is so important for future research. One thing that is known is that stage for stage, people with BRCA1 don't seem to do any worse that people with sporadic cancers, in fact they may do a little better. Also it's important to note that only 5-10% of cancers are thought to be inherited cancers, although in families with strong cancer history, the hereditary factor is still unknown. The balance of cancer is sporadic and usually occurs at a later age.

If you knew that you were positive for BRCA1, the likelihood that you would develop cancer over your lifetime ranges from 55-85%, with about 30% of these cancers occurring before the age of 50. Early intervention and monitoring with mammography should be considered.

Currently genetic testing is not done if there is a negative family history. It is most likely that the test would yield a negative result and any positive result would have to be suspect (false positive reading). Most cancer risk programs have criteria for genetic testing so that the result can be more precise. It is very important to realize that carrier for the mutated gene can come as easily from the paternal as the maternal side. Although the risk for breast cancer is not the same for men as for women, men who are carriers of the BRCA1 gene do have a slightly increased risk of developing colon and prostate cancer. And the male carriers of BRCA2 may have an increased risk of breast cancer, very uncommon in men. In establishing a family history, it is very important to look at linkage. What is reported as abdominal cancer could well be ovarian, which is highly linked to breast cancer.

Unlike ovarian cancer which is usually diagnosed in Stage 3 or 4, endometrial cancer is usually caught at Stage 1. Tamoxifen and roloxafene have been quite effective in reducing breast cancer, 80% less in a recent trial. Oral contraceptives have been shown to reduce some ovarian cancers 40-50% in some cases, but tend to increase breast cancers. It is a difficult decision to make, but it may buy younger women some time to complete their childbearing, before considering oophrectomy (removing ovaries).

What about women with breast cancer having elective oophrectomy? In premenopausal women, chemotherapy has become a much more common treatment. It allows for more maneuverability, can be combined with other drug therapies, etc. Newer therapies often become the standard, and people have a difficult time going back to older therapies, but Dr. Tripathy thinks that the therapies may be equal in ER+ women. The one study he cited which compared oophrectomy to chemotherapy showed about equal effects. One serious drawback to oophyrectomy is the side effects: abrupt withdrawal of estrogen can cause severe hot flashes, severe vaginal dryness, severe loss of libido, restlessness, night sweats. All of these things make the oncology community very reluctant to recommend this procedure. Although chemotherapy may cause some of the same problems if it shuts down the ovaries (and this in fact may be a large part of what chemo does), it does it in a more gradual way. In post menopausal women it does not seem to be effective to remove the ovaries. Premenopausal women who are HER2/neu+ and ER+, may not respond well to hormone therapy. Oophrectomy would probably not be as effective if you are HER2/neu+ and ER+ as it would be if you were negative.

Oophrectomy does not confer 100% protection from ovarian cancer. During embryogenesis, cells migrate and our organs are not as differentiated as we would like to think. Thus, there can be ovarian cells in the peritoneal area, and in males about 10% of testicular cancer can be found outside the gonadal area. After breast cancer, women can develop peritoneal cancer. Prophylactic surgery is not 100% effective, but about 80% effective, based on the Mayo Clinic study. Some of the problem here may have been that subcutaneous breast tissue has been left behind during the mastectomy allowing cells to regenerate.

Breast transplants are not likely, but transplantation of tissue is certainly possible. The sheep cloned in Scotland was cloned from a mammary cell. Live tissue could be developed from cloned material and used by the patient after being formed by the plastic surgeon. This would certainly cut down on rejection.

Many political/legal issues regarding genetic testing. Insurance companies can discriminate based on family history as well as testing. Currently there is considerable state and federal legislation being developed to protect people. This should be of great concern to all of us because in addition to depriving people of the right to get testing which will allow them to make decisions of great importance to them, it is stifling the advancement of science. Currently all shared databases are going to be removed of patient identifiers, but it is hard to guarantee confidentiality, because someone must enter data. Portability in group policies and protection against raising rates are protected by federal legislation. Many bills are in front of Congress currently to protect against pre-existing condition exclusion and genetic testing prejudice, but the laws haven't been challenged yet, so beware. This is a very murky area that raises more questions than it answers.