WEDNESDAY, December 13, 2000

What's New in Breast Cancer Research: Commentary on the
San Antonio Breast Cancer Symposium, 2000

The San Antonio Symposium is in it's 23^rd year and is the longest running meeting dedicated to breast cancer. There is a rich exchange of information across many disciplines including laboratory researchers, clinical investigators, behavioral scientists, epidemiologists, etc. As research in breast cancer seems to move at a glacial speed, we find small incremental steps rather than sweeping changes in cancer research.

New Findings in Clinical Investigations (new drugs):

• Hormonal therapies had seemed to hit a brick wall. We knew that they worked to lower the risk of recurrence in early stage breast cancer, and could control cancer growth in advanced breast cancer, but there didn't seem to be a clear "winner" until a new class of drugs called aromatase inhibitors. These drugs were initially developed to bring estrogen levels down in postmenopausal women. It is in these women that higher levels of estrogen have a risk for the development of new cancer or of recurrence in those that have already developed cancer. The enzyme that converts androgens to estrogens is inhibited by these drugs called aromatase inhibitors. These drugs with relatively benign side effects have been approved for patients who are no longer responding to tamoxifen. A series of studies have been done to compare these aromatase inhibitors to tamoxifen as a first line therapy. It showed a significant difference in response and duration of response. The aromatase inhibitors resulted in longer remission times for metastatic cancer, but were most effective in early stage breast cancer. The next step will be to see if using aromatase inhibitors can help lower the risk of recurrence for early stage breast cancer. One study currently open here at UCSF is comparing patients who had completed their five years on tamoxifen and given letrozole (one of the aromatase inhibitors), to patients post tamoxifen given no further therapy, to see if the risk of recurrence can be further reduced. Letrozole may also be effective for people who suffer significant side effects on tamoxifen or who locally recur while on tamoxifen although it has not yet been proven in early stage breast cancer.

• Out of 20 patients treated, preliminary results show no response to Endostatin. This is an anti-angiogenic drug which inhibits the formation of blood vessels which are necessary for tumors to grow. The great recent promise of anti-angiogenic drugs has not been realized in humans, although Judah Folkman at Harvard had had some great success in animal models. Thalidomide may have some effects in myeloma, but not in breast cancer. VEGF (vascular endothelial growth factor) is a molecule in the body that triggers the formation of blood vessels. An antibody to VEGF has been tested in trials of breast, lung and colon cancer with some fleeting success to date, about 10% of patients had transient responses. A new study will compare chemotherapy alone with chemotherapy plus VEGF antibody. The strategy of combining anti-angiogenic agents with existing therapies is likely to yield better results than we have had to date with the angiogenic drugs alone. If VEGF antibody does prove to be beneficial, we may see significant results for some people. The side effects are not too serious. Some people have developed clots and hypertension, but this was more in patients with lung than with breast cancer. These effects are to be expected because the drug affects normal blood vessels as well as those that supply the tumor.

• Growth factor receptors, like HER2/neu, are proteins that sit on the surface of cells, and are important in cell-to-cell communication. Many are important early on in embryogenesis (when the embryo is forming). When these growth factors go awry, they can sometimes lead to abnormal growth and ultimately to cancer. The HER2/neu oncogene product is present in abnormal amounts in 20 to 30% of breast tumors. By attacking the growth factor receptor with an antibody, in this case Herceptin, one can stop the abnormal process in patients whose tumors make HER2/neu. There are many small molecules along the growth factor receptor pathway that may respond in the same way as HER2/neu and pharmaceutical companies are doing research to find them. One is now in clinical trials; named Iressa it has been found to be effective in the treatment of lung cancer, but is also being looked at for breast cancer. Data so far has been from the laboratory, but seems encouraging, especially when Iressa is used in combination with Herceptin.

• One of the areas of technology that has developed over the last few years is the ability to look at multiple genes at one time. Mutations to the genes usually cause damage to the gene and end in the death of the cell. Infrequently the mutation can actually cause the end of programmed cell death, which can lead to cancer. Looking at a cancer patient's genes can give a lot of information. DNA arrays now allow us to look at tens of thousands of genes at one time and to obtain a molecular fingerprint. We can then match different individuals with the same cancer and look to see if their genetic structure is the same. This will allow us to evaluate high and low risk patients as well as more effectively predict who will respond to a given therapy. Array technology is a few years away from being used in the clinic.

Is this information being used in leukemia to make new drugs? Leukemia is genetically much less complex than other common cancers like lung, breast or colon. It is possible to develop drugs against the specific abnormal proteins which are more likely to occur in a leukemia. These drugs do not produce cures, and still must be used in combination with standard treatments like chemotherapy. In breast cancer, if you target a specific gene, most people will not respond, because there are other molecular changes driving the person's cancer. This is true with HER2/neu-targeted therapy. Developing targeted molecular approaches in breast cancer will be more complicated. UCSF has been analysing DNA for a long time. It takes many thousands of samples and complex equipment. This is presently just a research tool, not yet useful in the clinical setting.

Can estrogen receptor negative patients benefit from hormonal therapies? It probably is true that a small number of people who had their estrogen receptor levels tested ten years or more ago were misclassified. We now have better antibody tests and classify as positive anyone with staining in 10% of cells or more.

How do you know when tamoxifen is working? You don't know in early stage breast cancer as all recommendations are based on probability models of what has happened to groups of patients in clinical trials. In advanced breast cancer you follow the tumor size. Studies show that the optimal amount of time for taking tamoxifen is 5 years. After this, the risk of developing uterine cancer rises. There are two European trials that are comparing standard durations of therapy to longer durations.

If you have the BRCA 1 or 2 mutation, does tamoxifen have a large impact on the contralateral breast? The large prevention trial studying the effects of tamoxifen was stopped early due to the positive results, concluding that at least in the short term, tamoxifen did prevent breast cancer. With the BRCA genetic mutation, the risk is reduced at about the same rate (about in half). It is important to note that the sample size was quite small and so the confidence interval is quite large; the predicitive value will vary considerably.

Is prophylactic mastectomy recommended if you have BRCA 1 or 2? The risk of developing breast cancer with the inherited gene is probably 50 to 80% over one's lifetime. Prophylactic mastectomy is estimated to cut the risk of developing breast cancer 90-95%, but there will still be some breast tissue remaining. Because there is also a 20 to 30% chance of developing ovarian cancer, an oophrectomy (surgical removal of the ovaries) might be an important consideration. Genetic counselling is important for highlighting options, but no firm recommendations can be made at this time regarding prophylactic surgery.

Anything new in chemotherapy or in chemo combinations? One new combination actually lead to a small survival difference in the metastatic setting. The study compared Taxotere alone to Taxotere plus Xeloda, a regimen with greater side effects. Results indicated that the response rate was about 10% (from 40-50%) higher, the duration of the response was a little longer (2 months on average), and the survival was a few months longer as well. The question is whether the small benefits are worth the extra toxic effects. It may be more important to give the chemotherapy when the patient will get the most benefit. This is not necessarily at diagnosis if the patient is asymptomatic. Then the patient must be followed closely to determine how the patient is responding to the therapy, how are the symptoms improving, and what are the symptoms from the therapy itself. All of this must be integrated into a decision on whether to continue with a certain regimen or to change. One of the drawbacks to combination therapy is that if you become resistant to a combination, you have gone through two drugs at the same time. This is the argument for using drugs serially.

In early stage breast cancer, are the heavy doses of taxol taken every three weeks necessary, what about once a week, which is easier to tolerate? This is the same dose that is used in metastatic cancer and it is the amount that seems to work in early stage as well. We cannot yet say that weekly taxol is as effective as every three weeks. We need to get the results of some ongoing studies first. In metastatic cancer, it is probably more appropriate to begin on a weekly basis, patients tolerate it better and can stay on the drug longer. In early stage, where we are trying to prevent a recurrence, we tend to start with every three weeks since that was the regimen used on the trial that showed an advantage to adding Ttxol for early stage, node negative breast cancer.

Anything more effective than Tamoxifen? In metastatic breast cancer, the aromatase inhibitor, letrozole seems to give a higher likelihood of response, and the response lasts longer than tamoxifen in postmenopausal women. Therefore, the approach to first line hormone therapy for metastatic breast cancer is shifting to this class of drugs which also include anastrozole (Arimidex), letrozole (Femara) and examestane (Aromasin). These drugs are being used currently in the metastatic (advanced) setting; for early stage they are still investigational.

Anything new on flax seeds? On soy? On mushroom extracts? A new Canadian study suggests there may be a clinical effect because flax can change the composition of fat in the body. To date no one has done a large clinical trial on the effect of flax seed oil on breast cancer, but there is a lot in the environment and diet that can affect how cancer cells grow. Soy does have estrogenic properties, but some types of estrogen have a beneficial effect, and some have a negative effect. Soy might be protective in premenopausal women, but negative in postmenopausal women. The biological effects are probably weak. Most mushroom extracts are designed to stimulate the immune system and protect against cancer, but most studies have failed to show an improvement in breast cancer recurrence risk by immunological modulation..

Is Faslodex available? Faslodex is another hormonal therapy , a pure anti-estrogen, which binds the estrogen receptor and then destroys it. A study reported at San Antonio looked at Faslodex as second line therapy for those that progressed on tamoxifen and compared it with Arimidex. The two drugs had about the same effect, with people on Faslodex responding longer. The real value is in having another treatment option for people who progress on tamoxifen. It is not available yet but should be approved soon.

Update on Taxol? At the current time we must assume that anyone with positive nodes may derive some benefit from Taxol. The benefit may be less if the tumor is estrogen receptor (ER) positive, but we can't exclude the possibility of benefit even in these cases. If the patient is ER+ and has few positive nodes the benefits of Taxol are equivocal. If the patient is ER- and has many nodes, Taxol may actually lower the recurrence risk by as much as 5 to 10% over five years.