WEDNESDAY, NOVEMBER 14, 2001

"When is Breast Cancer Inherited: What Can be Done About It?"

The field of genetic risk in breast cancer has been quite controversial of late, with many ethical, clinical and legal dilemmas. The risk is hard to assess, but needs to be demystified. Special guests for tonight’s meeting are Beth Crawford, genetic counselor at the Breast Care Center and Robin Lee, genetic counselor who is also involved in physician and community outreach regarding the Cancer Risk Program.

It has been known for many years that cancers can occur in clusters in families. Back in the 1970’s when the role of genes was first beginning to be acknowledged, a mathematician named Alfred Knutsen postulated that because we have two copies of every gene, inherited susceptibility to cancer must be due to the loss of good copies of genes from both parents. He first studied retinoblastoma, a childhood malignant tumor of they eye. In some rare cases, children displayed the disease immediately after birth. Another cluster more commonly occurred later in childhood. Knutsen believed that later onset retinoblastoma was a result of inheriting one bad gene and developing the second bad gene as a result of aging and cell division. The disease displayed at birth required inheriting one bad gene from each parent—a much rarer occurrence. In 1987 a researcher called Wen Ha Lee cloned the retinoblastoma gene and proved Knutsen’s theory. Mary Claire King, a postdoctoral fellow at UCSF in the early 1970’s began studying families where breast cancer was very prevalent. She identified polymorphic proteins-- proteins that differ from one person to another, like blood types—to determine which gene might be responsible for breast cancer. By tracking which genes went with which family member, she was able to isolate the chromosome that had the breast cancer gene, isolating it to chromosome 17Q. The gene itself was finally isolated in 1994 and named BRCA1. It is known that there is a clear risk of developing breast and ovarian cancer if you carry this gene. Once the gene has been located, we are left with many questions: what should we do with this information, what does it mean for surveillance, what about preventive surgery or agents like tamoxifen, who should get tested and when, and what are the legal and ethical implications? Clearly, many of these questions have yet to be answered, but we have a need to collect information and add to our database so that improved information can be given back to the population at risk.

One of my identical twin daughters and I are cancer patients. What is the risk for her twin sister? Two key factors in identifying high risk in affected families are age at onset and type of cancer. Ashkenazi Jewish background is also important. Breast cancer in a premenopausal mother and daughter may indicate that a hereditary process is going on, but the great majority of breast cancers do not have hereditary factors. It is only in 5 to 10% of cases where there is an identified predisposition gene. Monozygotic twins share the same DNA, so the risks would be similar. We are all exposed to different environmental events over a lifetime, some of which may be triggers or may cause some of the mutations that cause cancer. It would be important to know if there are other family members with cancer. It is usual to take a three generation family history. The more appropriate question might be what is the risk of carrying the gene.

Can this history be gotten from a gynecologist? A big part of the cancer risk program is to get information out to primary care providers. They are certainly in the best position to ascertain level of risk with general guidelines as to who to refer to the genetic counselor.

How did researchers discover the link to the Jewish population? Blood tests were originally done looking for Tay-Sachs disease, prevalent in the Jewish population. DNA banks were thus available and were used to determine BRCA1 information. It was found that 1 in 40 Eastern European Jews would carry one of the three common mutations found in the Jewish population. We know now that there are other founder mutations. One in Iceland explains all of the male breast cancer and 40% of all the hereditary female breast cancer found in Iceland.

Is the treatment regimen any different for cancers caused by hereditary mutation? The risk of dying from cancer caused by the BRCA-1 and -2 mutations are the same as if you didn’t have the mutation. Recommendations for chemotherapy and hormone therapy are the same. What is different is how to handle the cancer locally. With hereditary mutations, the risk in the other breast is much higher, 50% over a lifetime. Close surveillance or consideration of prophylactic surgery is recommended. Risk of local recurrence in the same breast may not be the same; breast-conserving surgery may not be indicated.

What is a polymorphism and how does it relate to cancer? In genetic testing a result can be positive, negative or a variant of unknown significance, in which the code from the individual is compared to the known code and shows a small change in the DNA. This change may not disturb the protein that is made as part of the cell cycle. These variants do not stay "unknown". They will either end up as a positive indicator of disease or become a polymorphism common in less that 2% of the population, which don’t cause cancer or significant mutation. The real benefit of genetic testing is to be able to inform family members if they do have or don’t have a mutation. If they do, at least they can know what is causing the cancer in the family.

Aside from surgery, what preventive methods do you recommend if the test is positive? Yearly bilateral screening MRI for breast surveillance is now in clinical trials. A recent JNCI article following up on this trial reported that 13 early cancers have been identified in BRCA-1 and -2 mutation carriers, 7 of which did not show up on mammogram. Another clinical trial features ductal lavage, looking at fluid in the ducts of the breast for atypical cells. Known mutation carriers might also consider tamoxifen.

What about surveillance for ovarian cancer? We recommend ovarian surveillance. With a positive test, we recommend oophrectomy (removal of the ovaries) after 35 or when childbearing is over. This may seem extreme, but surveillance only picks up about 50% of ovarian cancers, and as many as 15% of patients with known mutation have ovarian cancer at the time of a prophylactic oophrectomy.

I am premenopausal, BRCA-1 positive, with an ER negative cancer. Will chemically stopping my period help? About 50% of women who are BRCA positive will present with their cancer premenopausally. It would be important to consider oophrectomy. Chemically stopping your period will not help the risk of ovarian cancer. It would only have an impact on breast cancer risk if the tumor were ER+/PR+.

Is the value of tamoxifen affected in BRCA positive women? As far as lowering the risk of recurrence of the original cancer, tamoxifen is recommended if the tumor is ER+ or PR+ regardless of the BRCA status. We know from the tamoxifen prevention studies that the entire high risk population does benefit. About half the number of cancers are diagnosed. We don’t know if it is affecting mortality. About 80% of women with BRCA-1 are estrogen receptor negative, so it may not be helpful in prevention with this population. About 80% of BRCA-2 cancers are ER+, so it could be helpful, but numbers are too small to make definitive statements.

Have any other preventive agents been shown effective? None have been proven at this point. The only agent shown to lower the risk of breast cancer at all is tamoxifen. People are interested in many dietary components like antioxidants, but they haven’t been tested clinically. Because testing requires many patients and lots of money, researchers have been looking at surrogate markers. A new clinical trial will look at soy as a preventive agent. The markers will be breast density and ductal lavage to see if small changes can be picked up.

What about new preventive agents? If it works, the next agents we will hear about in breast cancer are the Cox2 (cyclooxygenase) inhibitors. They have been shown to inhibit inflammation, and currently are being used as pain relievers. Vioxx and Celebrex are the trade names. These drugs are already known to lower the risk of colon cancer in people that have polyps. There is very early evidence that they may change the biology of breast cancer cells, but it has not yet been tested clinically. It will probably be at least three years before we know if they are an effective treatment because drugs for treatment take a long time to study and develop.

How does one know the correct dosage of dietary supplements? There are no real guidelines. The best advice is to try and get them from dietary sources. Whole grains, cruciferous vegetables and fatty fish should be the building blocks of the diet. Some of the recommended doses are so huge that eating to get them is impossible. The daily dosage recommended for flaxseed oil is 500 calories.

Have there been any large studies on dietary supplements? The one studied the most is soy. The effect is so small that it is still being debated vigorously, but there may be a slight benefit to premenopausal women. There is some evidence that green tea may be beneficial in stomach cancer, but no evidence yet in breast cancer. Population studies on food are very easily confounded, e.g., women who use soy may also consume less alcohol, eat less meat, etc. It is hard to know what is causing the change. Prospective, randomized trials are the best, but they are hard to do, expensive, and take a great deal of time.

Is there much difference in chemical oophrectomy and surgically removing the ovaries? The lifetime risk of developing ovarian cancer is between 20 and 40%. When the ovaries and the fallopian tubes are removed, the risk is reduced by at least 50%. One study shows that it may be reduced by as much as 80-90%. During the development of the fetus, ovarian cells migrate; thus there are ovarian cells in other parts of the peritoneum, so risk reduction can never be 100%. Different surgical procedures are recommended for ovarian surgery due to genetic mutation. An oncological gynecologist should be consulted. Gynecologists are very clear that the procedure should be done at 35 or after childbearing is over.

I have just had a recurrence of cancer in the same breast. I am not planning to have chemotherapy, but it has been recommended that I have my ovaries removed. Is this new? The recommendation may not have as much to do with having a risk of ovarian cancer, as with removing estrogen to prevent a recurrence of your breast cancer. If your tumor is either ER+ or PR+ it may have impact. Our primary recommendation for premenopausal women with ER+/PR+ tumors is tamoxifen for 5 years. If you are taking tamoxifen at the time of the recurrence, it is generally stopped and a new hormonal agent or oophrectomy is used. For postmenopausal women with ER+/PR+ tumors, a drug called aromatase inhibitor is used as a medical oophrectomy.

Why not do a complete hysterectomy at the time of menopause? Sometimes people do choose this option, especially if they are taking tamoxifen and are concerned about the risk of uterine cancer. The only real downside of having the hysterectomy is that it is a larger surgery.

What surveillance is recommended for ovarian cancer? Vaginal ultrasound every six months is recommended if you are at high risk. It doesn’t always detect ovarian cancer at the earliest stages, but it is better than doing nothing.

Is the possibility of inheriting BRCA-1 and -2 from the father the same as from the mother? How about from both sides? The paternal side is just as important as you get half of your genetic material from your father. Often it is neglected because you may be less likely to see a clear link coming from the father’s side of the family. Inheriting risk from both sides is rather uncommon, but can be seen in some Ashkenazi Jewish families. There doesn’t seem to be an additive affect, or earlier onset.

If you are 19 years old with a BRCA+ mother, should you be tested? It is not recommended at that age because nothing can be recommended or changed relative to a young woman’s medical care if she is positive. It could be harmful or disturbing for a young person to get this information and not be able to put it into a context. Testing is recommended at a time when it might make a difference, but surveillance should be started at around 25.

If you have been tested (negative) for BRCA-1 and -2, but a variant showed up, does this require follow-up testing? Variants of unknown significant are treated as positive until we get other information. Some polymorphisms do not need a high level of surveillance while others may be a case of not having found the cancer in the family. It is important to keep in touch with the genetic counselor because research findings can change, and family history can change.

How widely available is genetic testing and who should be tested? Usually the general guideline is if there is a likelihood of 10% or higher of finding a BRCA mutation, it is reasonable to offer testing. Although any physician can order a test, it probably should be the genetic counselor that recommends the test. One of the reasons for this is that the test is quite expensive: $2700 to do a full sequence. After identification, it is $200-300 to look for a specific mutation within a family. Some insurance companies are beginning to pay, but many people are not sure they want their insurance companies to have this information. Most people without insurance can’t afford the test. Only Myriad Laboratories in Utah holds the patent on genetic testing. This is good and bad. Small volume in many labs would not make it cost effective or accurate, but competition would be valuable to bring the cost down.

How much does genetic counseling cost? You can come to a free class that is given here at the Breast Care Center once a month. An individual first session is an intake and education session that lasts 90 minutes and costs $88. Second visits gather information on family history, procures medical records, track down death certificates when necessary to pinpoint diagnoses, and end with recommendations about what can be done. The cost is $148. The third session gives the results of tests and costs $111.

When should one seek a second opinion with metastatic cancer? Probably it is a good idea when changing chemotherapy regimens and when looking for appropriate clinical trials.

Q. Dr. Tripathy, A recent Danish study reported that scientific data do not support the benefits of screening mammography for breast cancer. How does this reconcile with U.S. recommendations that women over the age of 40 should have annual screening mammograms?

A. This comes from a recent article in The Lancet, written by people who took a very critical look at the 7 randomized trials that have been published over the last 30 years regarding screening mammography vs. no screening. In general what the original trials reported is that the risk of dying of breast cancer is about 30% lower with screening mammography; this lead to the general screening recommendations. The group in Denmark reanalyzed all the data in a much stricter way. Instead of just looking at deaths from breast cancer, they looked at all causes of mortality. This dilutes the effect and requires a much larger sample size to make predictions. But the trials were designed to look at deaths from breast cancer, so they should not be expected to show all other causes of death. The best evidence we have is that screening mammograms are useful. The question of whether they lower mortality and how much is still subject to controversy, but cancers are clearly identified at an earlier stage with no nodal involvement with screening mammography. 30% of cancers are diagnosed mammographically (not palpable). We can look forward to making the mammography more interpretable with digital mammography and computer assisted reading.