WEDNESDAY, APRIL 12, 2000

"Treating Metastatic Breast Cancer: A Philosophical Approach"

How we deal with recurrent or metastatic breast cancer is very important. All therapies have their limitations. There is no standard for how we approach treatment. Oncologists opinions range from doing nothing to using high dose chemotherapy. Most people with breast cancer in this country will never develop metastatic cancer because of public awareness and early diagnosis, whereas in many developing countries almost half the patients will present with metastatic cancer. Clearly early detection is important. It is difficult to determine an individual's risk when it comes to recurrence. There are few clues when someone is first diagnosed. We have some crude markers such as tumor size and lymph node involvement, and some newer markers such as micrometastases which will help us refine our estimates of risk. In large population studies, Tamoxifen can cut risk in half for ER+ tumors, but we can't know in advance who will be helped by it and who will not. Chemotherapy will lower risk by about one-third in younger people (premenopausal), but only by about 20% in women between the ages of 50 and 70 (postmenopausal). Taxol and Herceptin will tend to lower the risk further. We need to move to a better understanding of biology in order to lower risk by more than 90%. All of these numbers are probablistic, the individual will have to weigh the risks and benefits of individual therapies. Herceptin, for example can cause cardiomyopathy in some patients. Will that risk be justified by the small benefit one may derive from the treatment?

Technically the words recurrence and metastasis are not interchangeable. Recurrence means the return of cancer whereas distant metastasis means return outside the breast and lymph nodes. There can be a fine line between the recurrence of early stage breast cancer and metastasis. Some women will live a very long time with metastases and have a reasonable quality of life. Some women have metastases and, with a complete response to therapy, will never recur in their lifetimes. There is tremendous variability. Metastases are not an immediate death sentence, there is always hope. Variability in outcome poses some problems for treatment. We can talk about the best treatment choices by discussing biology and clinical outcomes. The key biological points are:

(1) You get a sense of response from a particular drug by looking at a large clinical trial, and its general side effects.

(2) The first response to a given therapy is usually the longest, so it makes sense to start with the less toxic treatment as long as the response is similar to a more toxic drug. It is rarely necessary to start off with a chemotherapy when someone has the potential to respond to a hormonal treatment. The practice has shifted from using very aggressive combinations of drugs to using single agent drugs with less side effects. The efficacy of Taxol and Adriamycin in combination is quite high, but the chance of side effects is quite high as well. Using these drugs in sequence will give less side effects and the overall response is about the same. In some cases the combination effect of Taxol and Herceptin in HER2/neu+ patients, is much better. Herceptin can be used alone as first line therapy if the patient shows continued response. This can then be followed by Taxol. Patients used to be rushed off for bone marrow transplants, but the evidence has shown that this does not prolong life and is seriously damaging to the quality of life.

The role of biological therapies. Chemotherapy still remains the best short term answer for patients who have progressed on hormone therapy. The long term limitations include cumulative side effects and drug resistance. The new model is first to try to induce a remission with chemotherapy and then maintain that remission with some of the new biologic agents (vaccines, angiogenesis inhibitors, etc.). This strategy has not yet been proven because some of the biological agents have been disappointing to this point, but new drugs are being studied. Celebrex is a pain medication which inhibits the enzyme that causes the production of messenger molecules that transmit pain, they also influence how cells communicate. In colon cancer they have been found to lower the risk of polyps turning into cancer. Another drug that falls into this category is Captopril, used to lower blood pressure, it has been shown in animal models to inhibit angiogenesis.

Define "remission" in bone metastasis. Bone is a particularly difficult area to assess. In order of importance the three most critical areas for evaluation of remission are: symptoms, objective size of a tumor or lymph node or lung nodule that can be followed and evaluated, and lastly, laboratory tests like alkaline phosphatase for bone involvement, or CEA or CA53 tumor markers. Tumor markers are the least accurate and must not be overinterpreted. Markers can transiently go up and then down in a patient who is responding (tumor flare). In 20% of patients, markers will give a discordant response. Bone scan flares can also occur in a patient who is healing. Therapies should be changed very conservatively, looking more to symptoms than to the results of laboratory tests. Chemotherapy should be used only if there is an ongoing benefit to a patient who is symptomatic. In metastatic cancer, starting treatment early does not necessarily improve outcome.

What about "pulsing" therapy? This means putting patient on and then taking them off therapy. There has not been a clinical trial comparing pulsed to continuous therapy in breast cancer, although it seems to work fairly well in lymphoma. The closest thing in breast cancer is comparing intermittent or defined time chemotherapy with chemotherapy taken for the patient's entire life. Survival is no different. It seems to be best to stop therapy after the maximum response has been achieved and then restart after the tumor progresses. In this way the patient receives the least amount of chemotherapy for the greatest effect. Some people will enjoy quite a bit of time free from progression off any therapy at all. Patients who achieve a complete response tend to have a longer disease-free interval and probably a longer survival. It is a very hard to decision to know when to stop chemotherapy.

Why is there a negative reaction (in Europe) to chemo combined with tamoxifen? Little is known about hormone and chemotherapy used together. It was thought that chemotherapy worked by dividing cells and tamoxifen tended to keep cells together, hence the use of the two together would be antagonist. Clinical studies show that combined usage neither helps nor hurts. The best practice is to use one or the other, not combined. The most common sequence would be starting with hormone therapy and then moving to chemotherapy. Resistance to tamoxifen can be induced in vitro. This happens occasionally in patients. In metastatic cancer, this resistance develops after about two years of treatment. In early stage breast cancer, five years of treatment seems to be best.

How can patients monitor symptoms before a crisis? Most experts agree that in early stage cancer there is no good way to monitor for a recurrence. Treating earlier doesn't seem to influence the outcome; what is important are the biologic characteristics of the tumor, i.e., will it respond to therapy. Routine scans are not recommended for someone who is not having symptoms. Basically one would look for the same symptoms that existed before the recurrence. This is difficult because many women suffer from symptoms which would be considered nonspecific. It is best to adopt and index of suspicion and be alert for symptoms that are typical of progression and also match the patient anatomically. This will often warrant a change of therapies.

Is it sometimes best to do nothing? There has never been a study comparing treatment to no treatment. It is not considered to be ethical because even if treatment does nothing to prolong life, it will usually relieve symptoms. The main goal of therapy should be to balance quality of life. Estimates of prolongation of life with therapy range from about 4 months to a year, but it is necessary to keep in mind that there is a great deal of variability on this issue. Due to the extreme heterogeneity of breast cancer, before making a decision it is best to see the individual's response to therapy. The stronger the response, the better the chance for longer survival. Another consideration is that aggressive cancers like brain and liver don't always mean aggressive disease.

Why do estrogen receptors go from positive to negative? About one-third of the time, estrogen receptors can revert to negative. This may be caused by mutations in the estrogen receptor (ER) gene.

Any indicators at initial diagnosis of chance of metastasis? Making the HER2/neu protein does portend a higher risk of recurrence. Grade and size of tumor, lymph node status and S phase, all can give an estimate, but are not precise. They are good for developing a probabilistic model, but not certainty.

Is there increased risk using Tamoxifen for more than 5 years? In the adjuvant setting we don't know. In one large NSABP study of 1000 women, the number of people who had a recurrence after 10 years of Tamoxifen was actually a bit higher than the group using Tamoxifen for 5 years, but it wasn't statistically significant. The higher number of cases of uterine cancer reported after 10 years of Tamoxifen use was significant. People who do not respond to Tamoxifen are more likely not to respond to Arimidex (aromatase inhibitor), but it should be considered before moving onto chemotherapy if the patient is asymptomatic and has a low burden of disease.

Any side effects from Arimidex? In general side effects are mild, but may include peripheral neuropathy, arthralgia, and more rarely, nausea and hot flashes. Tamoxifen is known to interfere with sex drive and causes vaginal dryness. Fortunately, most side effects of drugs are reversible.

What about biological therapies? When a patient is metastatic and feels that she doesn't have many options, new drugs like Clodronate (a bisphosphonate) and Mammostatin (an anti angiogenesis agent) will seem like a good idea. Sometimes the hype around a new drug is extreme and tends to ignore serious side effects. Captopril can lower blood pressure and might actually cause more harm than good.

Is it better to use Herceptin with or without other drugs? The clinical trials data on Taxol with and without Herceptin clearly shows a benefit when the drugs are combined. In the laboratory, other combinations that seem to work with Herceptin are Taxotere, the platinum drugs, and Navelbine. A new trial for those who progress on Herceptin alone will investigate Navelbine alone and in combination with Herceptin.

Is there any movement to teach doctors how to deal with terminal patients? ASCO had a workshop here in San Francisco to discuss communication between patients and their physicians. There is not much effort to retrain practicing oncologists. The concept of "patient as person" is being emphasized more now in medical school. From the 1960's through the 1980's physician training was more technical because of all the new science and technology. This was a departure from the 1930's through 1950's where the physician was a counselor. Ideally, today one wants a combination of technician, scientist and humanist. Ten percent of metastatic patients live more than 10 or 15 years, so physicians will need to deal with the individual's clinical course.

What's new in the pipeline? The most exciting are the tyrosene/cynase inhibitors, which interfere with growth factor receptors. One in particular is called Oressa, which may be a HER2/neu specific inhibitor. Clinical trials are just beginning. Another area is death receptors. Programmed cell death is a natural process all cells go through. Tumor cells make these death receptors, that when attached to a certain ligand seem to trigger cell death. This seems quite promising.