WEDNESDAY, June 13, 2001

Demystifying Genetic Risk and Hormone Influences in Breast Cancer

This is a continuation of the subject matter from last month of hormone therapyóTamoxifen in particularówith some new direction. We will discuss the role of hormones in prevention and hereditary risk, and some of the new hormone agents, how and why they work. Of course we know there is no single cause for breast cancer, no "smoking" gun as in lung cancer. Most women with breast cancer do not have a strong identifiable risk factor. The only strong factor is age. Breast cancer is very uncommon under the age of 35 or 40. Family history or estrogen replacement therapy may raise the risk, but not much. In postmenopausal women the level of estrogen in the body is mediated by the amount of fat tissue; therefore women higher in weight for their age have an increased risk of breast cancer, although they are at lower risk for osteoporosis. Preventive measures have focused on hormonal manipulation of drugs with fewer side effects in order to try to reconcile these kinds of problems. Even after diagnosis of cancer, some hormones continue to play a role in some breast cancers. A protein called the estrogen receptor (ER) binds estrogen to the cell and causes it to behave differently in some types of cells. In the case of the breast, the ER causes proliferation, which tells the cells to divide. Tamoxifen, an anti-estrogen, tells the cell to slow down. To date the drug that has the greatest impact on lowering the risk of recurrence of early stage breast cancer is hormonal therapy, greater than chemotherapy in women whose tumors are ER+.

Is there such a thing as precancerous tissue? All tissue in the body has the potential to develop cancer. Certain things can be recognized under the microscope which cause the risk of breast cancer to be higher than in the normal population. These are called precancer. One entity that is precancerous is atypical ductal hyperplasia. Cells in the milk duct divide causing greater layers or numbers of cells (hyperplasia) and the nucleus of the cell gets larger than normal (atypical). These types of cells can be found accidentally in a piece of tissue removed for biopsy. Women with atypical ductal hyperplasia are at higher risk for developing breast cancer. Ductal carcinoma in situ (DCIS) is another example of a precancer. It doesnít have the capacity to invade and to spread but may be associated with a higher risk of developing breast cancer. Sometimes the risk isnít great and doesnít require any additional therapy. Tamoxifen should be considered as a preventive for this type of person because it may lower the risk just enough to prevent cancer.

Can DCIS become invasive? DCIS is itself not invasive, but it can progress to invasive cancer. Even when it is removed, cells adjacent can become DCIS and then over time, invasive cancer, so often radiation is recommended. Cancer cells that move outside the duct are defined as invasive cancer. The types of cells in both these cases are very similar but not identical. One of the big focuses of research today is to try to identify the protein, which allows DCIS to become invasive cancer.

What is the role of estrogen (therapy) in breast cancer? High doses of the standard pharmocologic estrogen are associated with breast cancer. No one has been able to show that high doses of estrogen (HRT) taken after diagnosis and treatment of cancer, causes increase in recurrence risk.

Does soy work in the same way as estrogen? There are compounds in soy which are somewhat estrogenic. It binds the estrogen receptor, but doesnít seem to work in the same way. This is also true of Tamoxifen, which in some cases actually acts as estrogen (i.e., in the uterus). The biology of soy is too complex to make any definitive statements without further study. Epidemiological studies to date seem to indicate that soy may be a little protective in premenopausal women. It is fine to eat normal amounts of dietary soy, but extracts should be avoided.

What about the use of natural progesterone cream for the relief of menopausal symptoms? Progestin creams are probably okay, but this does not substitute for progesterone in women taking estrogen. Some studies show a higher incidence of breast cancer in women when taking estrogen and progesterone. When trying to relieve symptoms of menopause, it might be reasonable to take estrogen on a trial basis, for several months, and taper off when possible.

What did the Journal of the National Cancer Institute article show about women taking HRT? The JNCI study concluded that some breast cancer patients who had taken estrogen replacement did not have a higher risk of breast cancer, in fact it was a little lower. Although this runs counter to what we traditionally believe, the new evidence is that the hormonal environment shortly after breast cancer is most important and may become less critical after the first few years. Also there may be other factors operating on the women in the case controlled JNCI trial which are usually controlled by a randomized trial.

What is the effect if you are taking both Tamoxifen and HRT at the same time? Biologically, estrogen enters the cell and binds to the estrogen receptor, then goes into the nucleus of the cell where it binds DNA, causing the gene to be transcribed (encoding proteins, which tell cells what they are). Estrogen modulates the transcription of several genes and is present in varying amounts in different tissues. This is why its effects vary in different tissues. This is also true of Tamoxifen which works like estrogen on liver and bone, improving bone density and lowering lipids, but in breast cells it works more like an anti-estrogen. Lupron (medical oophrectomy) and the class of drugs known as aromatase inhibitors also work to remove the estrogen from the breast cells. In metastatic breast cancer it has been found that Tamoxifen plus medical oophrectomy or aromatase inhibitors plus medical oophrectomy works better than either of these drugs work alone. In metastatic studies, aromatase inhibitors may actually be better than Tamoxifen, but this has not yet been proven with early stage breast cancer.

What is the current thinking about using Tamoxifen for prevention? Tamoxifen clearly lowers the incidence of recurrence in early stage breast cancer. The number of new breast cancers that developed in the contralateral breast was significantly lower in the patients that took Tamoxifen. In 1992 a large prevention trial was started in this country taking women over the age of 65 or under 65 with risk factors and randomly assigned them to Tamoxifen for five years or placebo. The study was stopped early because they found only half the number of cancers in the Tamoxifen group. The FDA has approved it as a preventive agent. This may actually be more a case of delay rather than prevention. Perhaps the cancers are too small to be detected on mammogram, but are already established, or we might be preventing the easier to treat less aggressive cancers. There may not actually be an effect on mortality, because already, although more women are diagnosed with cancer, less are dying from the disease. So taking Tamoxifen for prevention must be an individualized decision and must balance the benefits with the side effects of uterine cancer, blood clots, etc.

Is the genetic predisposition to cancer transmitted by both parents; if the relative is older when contracting the cancer is it less likely to be genetic? Both paternal and maternal sides transmit genetic predisposition equally. The likelihood of inheriting a genetic predisposition is lower with older relatives. The genes that confer a higher likelihood of cancer, called penetrant, tend to cause cancer at a younger age. BRCA 1 and 2 are examples of these genes. People with BRCA mutations have a 60-80% lifetime risk of breast cancer and are also at higher risk for other cancers like ovarian, pancreatic and prostate. Indications of genetic risk include having many relatives with breast, colon or ovarian cancer, the cancer being bilateral, and developing at a young age.

What are down regulators? This is a new class of drugs similar to Tamoxifen, which bind the estrogen receptor. Instead of going to the nucleus of the cell, disintegrates, creating an unstable protein and eliminating the estrogen receptor. Faslodex, the prototype, may be used when the patient is resistant to Tamoxifen. It is in the late stages of clinical trials and may be approved soon.

What about the Canadian study on Tamoxifen and flaxseed? This was a small study that compared Tamoxifen with and without flaxseed in metastatic women and found a slightly higher response in the Tamoxifen plus flaxseed group. Flaxseed has some compounds called lignands, which affect the cell membrane and may slow down cancer cell growth. Although these studies are very preliminary, flaxseed oil is probably safe, but high in fat (3 tablespoons at 100 calories/Tbsp.).

Have aromatase inhibitors been tried for prevention? The concern in using aromatase inhibitors for prevention long term is that they lower the amount of estrogen in the body. Women with the lowest amounts of estrogen have a higher risk of osteoporosis. So far the data on metastatic breast cancer at two years does not show an increase in osteoporosis, but we need to see the data at five years.

Is there a difference between aromatase inhibitors and their effect on the adrenal glands? The new generation aromatase inhibitors are very specific for the enzyme aromatase and so donít affect the adrenal gland, just the conversion of androgen to estrogen. Three are approved in the United States: Aromasin, Arimidex and Femara. All are very potent and equally good. All but Aromasin have been approved for first line therapy.

How long is the treatment and how long does it take to work? In the metastatic setting patients are treated as long as they donít progress. In the adjuvant setting, we use Tamoxifen for five years in metastatic patients. The effect on the cellular level is instantaneous, but clinically it may take some time for the tumor to actually shrink. In very sensitive cases, you may see a reaction within a week, in others not for a month or two. The response may not be immediate shrinkage but softening of the tumor or in bone, a flare in which the pain actually becomes worse before it gets better. Cells can develop a mechanism of resistance whereby the hormonal therapy ceases to work. The time over which this can happen is extremely variable from person to person. Median time to disease progression in most clinical trials thus far is one and a half to two years, but this can be as long as five or ten years.

In early stage breast cancer, how much benefit do you get from adding chemotherapy to Tamoxifen? Some of this is age dependent. In women under the age of 50, you can lower the risk by 1/3. If you look at a large population, 20% of women will recur with no further treatment, which can be lowered to 12% with Tamoxifen. Chemotherapy will lower that to 8%. In women between the ages of 50 and 70, adding chemotherapy to Tamoxifen will reduce your risk to about 10%. None of the trials have been large enough to look at the benefit in women over the age of 70. Risk reduction is also very dependent on stage.

Is age an important variable even without family history? The younger you are when you develop breast cancer, the greater the likelihood that it is inherited even without the BRCA 1 and 2 mutations. Also important is oneís ethnic background. Different genes tend to be more prevalent in certain ethnic groups, i.e., BRCA 1 and 2 is found more often in Ashkenazi Jews. Your background should be factored into the decision to consider genetic testing. Guidelines indicate that testing should be considered if your baseline risk is over 10%. A caution: Because we really donít know what to do with the results, the benefits of genetic testing are unclear. The detriments can be many: emotionally, legally and ethically.

Does the protection from Tamoxifen end when you stop taking the drug? There is a residual effect up to year 10 for recurrence, which ends between years 10 and 15. Protection from death from breast cancer is preserved out to year 15.