WEDNESDAY, DECEMBER 15, 1999
"What's New In Breast Cancer Research: Summary and Commentary on the San Antonio Meeting"

This talk will focus on those parts of the 22nd annual San Antonio meeting that are immediately relevant to breast cancer. Summaries of the meeting are available electronically at www.medscape.com, many of which were contributed by Dr. Tripathy.

Updates on the Tamoxifen Prevention Trial: Tamoxifen, used commonly for adjuvant therapy, was found to reduce the incidence of new cancers in the other breast, an observation that has led to its investigation as a prevention agent. A large clinical trial was begun in 1992 and closed early in 1998 based on the fact that tamoxifen was found to reduce the incidence of new cancers by one half. Based on this, tamoxifen has been approved. Another benefit of this study was its confirmation of the Gail model for assessing breast cancer risk. NSABP tried to use the Gail model (a model which is used to determine a woman's risk of developing breast cancer based on certain characteristics like family history, prior biopsies, age of menstruation) to determine eligibility for this trial.This model had never been evaluated prospectively in a large cohort of women to estimate their risk, and then compare that estimate to the actual number of breast cancers five years later. The Gail model proved good at both determining risk, and the effect of tamoxifen at reducing this risk. Assigning risk is population based, and it is always hard to evaluate how this affects the individual. If reducing risk by a known amount, say from 2% to 1% sounds reasonable after taking into consideration the side effects of taking tamoxifen for five years, then this treatment might be right for you. Side effects of tamoxifen had not been well tracked in previous clinical trials. In this study, the risk of uterine cancer was increased about 4 to 5 fold which translated into a 5 year risk of about 1% altogether, and this risk was mostly in older women. The risk of stroke and having a clot were also raised. Many women, especially those over 50-55 could actually have a net negative benefit if their chance of getting uterine cancer, stroke, etc. was higher than their lowered risk of getting breast cancer from tamoxifen.

The (STAR) trial of raloxifene vs. tamoxifen is generating a lot of controversy. Because raloxifene was originally studied as an osteoporosis drug for postmenopausal women, there was not enough safety data on premenopausal women to allow them to be included in the trial. We need better agents to reduce risk. Tamoxifen is only effective in lowering the risk of ER+ tumors, and the mortality benefit remains unknown. So far there is no difference in the death rate. The prevention story remains very controversial, clinical trials should continue, but people need to be made more aware of the different assessments of risk and benefit. The best time to take tamoxifen would be between the ages of 45-50 rather than 65-70, as the greater number of adverse events were in women over 60.

How does new medical information get digested by physicians in the community? Staying current in medicine is harder to do today and getting worse. Administrative responsibilities of physicians are escalating as well. Continuing Medical Education (CME) programs are required for physicians in California in order to maintain their licenses, and most physicians enroll in symposium, readings or on-line programs to fulfill their 50 hour requirement every 2 years.

Therapy for small node-negative breast cancers. There has been a large debate regarding whether hormone or chemotherapy is appropriate for women with early stage breast cancer and low risk (small node negative cancers). This is partially related to statistics. Showing a small percentage benefit requires large studies with many patients, which we usually don't have. NSABP has tried pooling their data from many trials in order to determine if there is a benefit to therapy. They claim there is, but no statistical analysis was done, so the findings at this point are questionable.

What is the latest in chemotherapy? AC (Adriamycin and Cytoxan in combination chemotherapy) is the most widely used. Its effects are somewhat dose dependent. Lowering the standard dose seems to give a worse outcome, but raising it doesn't seem to add benefit. There was a small benefit in adding Taxol in women with node positive ER-negative breast cancer. So it seems that ACx4 is probably adequate but there might be a marginal benefit from one or two more cycles. Chemotherapy increases slightly the risk of getting leukemia. In general, using chemotherapy the chance of developing leukemia is about 1/1000, with high doses of Cytoxan this chance goes up to 5/600 patients, which is pretty high. Recently, the FDA approved the use of epirubicin, a less cardiotoxic chemotherapy than Adriamycin. There has been a slight trend toward a higher risk of leukemia with this drug, but the difference is quite small.

How does Taxotere compare with Taxol? There has yet to be a direct comparative trial, but the preliminary data suggest that Taxotere may be more effective when compared to AC or Taxol. There have been some indirect inferences mostly in the metastatic setting. Adjuvant trials with Taxotere haven't matured yet. It will take a while to get data on the comparison of AC+Taxol compared to AC+Taxotere since this trial has just started. It is important to keep in mind that all studies to this point have been done at high doses of Taxotere, where side effects tend to increase. At lower doses, the results may be the same. We are planning a comparative study here at UCSF with Herceptin plus weekly Taxotere (there are less toxicities with weekly compared to the styadard every 3 week schedule) in women with metastatic cancer with HER2/neu overexpression.

What about research regarding resistance to tamoxifen after two years? A research paper from Duke University reported that resistance often develops to tamoxifen in metastatic cancer after about two years. This is true, but should not be confused with tamoxifen taken in the adjuvant setting where there is a five year optimal recommendation, especially in women over 50. The paper was actually a laboratory study that simply alluded to the fact that the average time to resistance development in the metastatic setting was about 2 years. If we can understand the mechanisms of clinical resistance we can go a long way in making our drug treatments more effective. This is especially important with hormone therapy. We would like to change the average duration of response from the current 1-3 years to 5-10 years. Targretin is a drug that can reverse tamoxifen resistance in laboratory studies and is currently in clinical trials.

What about tamoxifen in early stage breast cancer? For the sake of this discussion, early stage refers to any cancer that has not metastasized, even including those with positive nodes. Many women with small tumors and node negative cancers have a high cure rate after surgery. We can further increase the cure rate with chemotherapy and hormone therapy, but the extent to which you can do this is much smaller in someone who already has a low risk of recurring, i.e. people with small node negative tumors. The typical recurrence rate for a one centimeter node negative tumor is 10% for a ER/PR+ tumor with no intervention after surgery. Tamoxifen can lower this by about half to 5% after about five years of treatment. If treatment is only continued for one or two years, there will be an initially beneficial effect, so that one or two years is better than nothing, but the best results seem to take five years. In the metastatic setting, response is much more variable. Initially, tamoxifen was used only on postmenopausal women and was effective. This bias continued until about five or six years ago when tamoxifen was found to be equally effective in women with ER+ tumors regardless of their age. It is true that older women tend more often to have ER+ tumors. Tamoxifen has also been shown to be effective in high risk women, regardless of age, but only lowers the risk of developing ER+ tumors and has no effect on the development of ER-negative tumors. What about the use of combination therapy? The current data suggests that if your tumor is ER+, you get an independent benefit from both chemo and hormone therapy. Because tamoxifen doesn't really add any benefit to ER- tumors, only chemo is given. For metastatic cancer, the standard of care is to use one form of therapy or the other. Using agents one at a time, rather than the aggressive combination of drugs is the current thinking. You can actually maximize the time in remission by switching from one drug to another as the patient progresses. This also is more beneficial in terms of toxicity. You want to reserve combination therapy for those patients who are most symptomatic. The notion that being more aggressive will result in a higher rate of survival has not been proven, although this may be the case for inflammatory breast cancer.

What happens to the ovaries in chemotherapy? Going through menopause with chemotherapy may actually improve the outcome due to lowered estrogen. The greater the age of the woman, the greater the chance of going through menopause while on chemotherapy. Surgical removal of the ovaries in ER+ women has as good an effect as chemotherapy, but is not recommended in ER- women. Oophorectomy is not typically recommended as an alternative to chemotherapy in high risk women because people have a bias for chemotherapy, but is there an independent benefit? Several trials were reported in which patients received CAF chemotherapy (and possibly tamoxifen) and were randomized to receive Zoladex, a gonadotropin hormone which signals the pituitary to suppress the ovaries. It seems to have the same effect as oophorectomy, including the side effects, like hot flashes. The results showed some decrease in the recurrence rate and marginal improvement in the survivial, but it was not statistically significant in women already receiving tamoxifen. There may be a small independent benefit to shutting down the ovaries. Women who receive chemotherapy at a younger age do not seem to develop other problems related to early menopause, but there are not enough patients in the younger age group (30-35) to say this definitively.

Does Prozac reduce hot flashes? Hot flashes are neurogenic and the mechanism which controls them is not known. Both Prozac and the antiemetic drug Zophran work to inhibit serotonin (which works to regulate mood, nausea, and blood vessel tone). People are highly individual in their reaction to these medications. Some find that it flattens their moods and takes away their sex drive; others find it eliminates hot flashes, makes sleep easier, and has an antidepressant effect. Because symptoms may be transient, medications like these should be periodically evaluated.

EGFR and HER2/neu pathways as a paradigm in advanced breast cancer. Epidermal growth factor receptors (EGFR) and inhibitors which affect these pathways have been studied. The data has been very compelling in animal studies and early clinical trials are planned. EGFR is expressed more in normal tissue than HER2. It can be found in skin cells and salivary glands and other parts of the body. An antibody (C225) against the EGFR resulted in skin toxicity in early clinical trials. Many of these side effects were unexpected and should be viewed with caution. A word of caution regarding growth factor genes: these genes are found in the developing fetus and presumably were originally there for a reason. Developing antibodies against them may cause certain side effects. HER2 is expressed in very low levels in nasal cells of normal adults. Herceptin treated patients sometimes develop inflammation in the nasal passages. We will have to consider this as we develop cancer specific therapies.

Can we trigger cell death in cancer cells? Apoptosis or programmed cell death is a genetic program common to all cells in the body. It inhibits blood vessel formation and triggers cell death. In order to protect the organism and insure orderly growth, all cells have to mature and die a natural death. Exposure to avirus, for example, signals lymphocyte cells to divide many times and produce antibodies. Once the virus is gone, these cells must be cleared quickly and so they are programmed to do so. The exception to this is stem cells which are capable of renewal and differentiation. The classic stem cell is the one which gives rise to the red blood cell.

Genentech is developing a compound called APO1 ligand, which is a protein that stimulates death receptors in the cell. It seems that cell death can be triggered by surface receptors, which are linked to the orderly death of cells. The body doesn't recognize the killing of cancer cells in the same way it does in an injury, that is, by setting up an inflammatory reaction. Clinical trials on this compound will begin soon.

Studies are ongoing on agents that reverse hormonal resistance. Pure antiestrogens seem to inhibit the estrogen receptor in patients who have developed resistance to hormone therapy. Some of these have already been in early clinical trials. The prototype is Faslodex, which is used in women who have progressed on tamoxifen and The prototype has actually been around for a long time.

The prognostic area is being studied. This is to try to identify people who might respond to a certain therapy. We are working currently on optimizing HER2 determinations in order to best predict who might respond to Herceptin. It is difficult to standardize the assay from one laboratory to another: what one lab might call positive, another will call negative. In addition to HER2 being present or absent, it is also important to know whether the receptor is transmitting its signal to the nucleus of the cell. In order for the HER2 protein to be active, it has to bind to another receptor (EGFR) (can also bind to other proteins called HER3 and HER4). This may ultimately be a better test than just assaying for the presence of HER2.

In the future we will develop drugs that work on a particular group of tumors. It is important to classify cancers by their genetic and biochemical pathways. We then will use the drug that works on that pathway, replacing it with another drug when it no longer works. In this way we will make cancer a treatable disease. Advances are, and will most likely continue to be incremental, working on subsets of patients.