WEDNESDAY, FEBRUARY 10, 1999
What if I Have A Recurrence? A Revisionist Approach to the Treatment of Breast Cancer

What do we know about the biology of metastatic breast cancer, what impact have we made with therapies and where do we seem to be going in the future?
It may not always be appropriate to use the terms "early stage" and "late stage" cancer or even "metastatic". As with most things in life, there exists a spectrum. There are many healthy people walking around who may have cancer cells in their system who never develop cancer, or those with microscopic metastasis who never progress to metastatic breast cancer. When, however, metastatic breast cancer is clinically apparent, most people do have problems with it in terms of progression and symptoms. We are forced to deal with it as a separate and distinct category because it has consequences. The first thing to discuss is the incredible heterogeneity of metastatic breast cancer from one patient to another. There are two basic reasons why this is true. Everybody's tumor is different. The DNA in the tumor is unstable--amplification and loss of DNA occurs within the tumor cells. The differences in clinical behavior of the cancer (where does the cancer metastasize, how does it respond to therapy?) are driven by the genetic variability. The second cause of the heterogenity is the cancer's interaction with the body. One interaction that is well described is the angiogenic response (tumor cells need to bring in blood cells so that they can grow), another is the immune reaction of the host against the tumor cell, which is blunted or insufficient. Vaccines are being used to bolster the immune response. We are very interested in understanding these individual characteristics so that we can tailor our therapy. The current paradox is that while we understand the variability of the cancer, our therapies are essentially monolithic. In oriental medicine, where there is no knowledge of complex genetics, therapies are highly indivdualized.

What therapies are now being used and what are the impacts of these therapies?
It must be understood that the information we have is based on large population studies. It does not indicate how smaller individual subtypes may respond. If you ask the very basic question, "If I have metastatic breast cancer will chemotherapy prolong my life?" there is no good way to answer this question for everybody. No study can ethically be done comparing treatment with no treatment. Studies have been done comparing a more intensive therapy with a less intensive therapy. The results indicate that the type of therapy does not seem to affect survival.The major determinant of survival seems to be the individual characteristics of the tumor. People with very indolent cancers may live 15 or 20 years. This is typical of prostate cancer. When you look at very aggressive treatments like high dose chemotherapy and bone marrow transplant there is a small survival advantage. But there are probably subgroups within the larger population study that will have significantly different responses. This dilutes the outcome and makes it difficult to make conclusions or to outline treatment strategy. When a patient comes in with a recurrence, the treatment options might range from taking tamoxifen to having a bone marrow transplant. Both opinions may be reasonable, yet very different. The only really positive part of this is that it leaves the opportunities open. Our expanding knowledge of biochemistry and alternative therapies will come together and show us how to improve outcomes. Where there is variability,there is the opportunity for choice. Already, some biological therapies, despite their limitations, do prolong people's lives. This year there was the first randomized trial for metastatic breast cancer using a biological approach (Herceptin) that actually improved survival in some cases.

What makes tumors different?
What seems to drive tumors are the genes (DNA) themselves. Certain acquired genetic abnormalities cause cancer. This mutation occurs in a part of your body, but not in other parts, and over time, enough mutations can cause cancer. This may cause an enzyme that regulates growth to become overactive, out of control. Most cells know when to stop dividing, but cancer cells do not. Different people have different genetic changes which may impart particular characteristics. HER2/neu is an oncogene which seems to confer a certain sensitivity to some chemotherapies and a resistance to others. Herceptin is a drug that is targeted against this oncogene, and gets a response in some people. Once we find out what genetic changes are causing specific proteins, we can design a drug that targets these proteins.

Are multiple site metastases harder to control than one site metastasis ?
On average multiple sites do worse, but there is much variability. The key to survival is how responsive the tumor is to treatment and how long it can go without becoming resistant to the therapy. Some people have had liver metastases and lived for 10-15 years, going for several years on a particular therapy before becoming resistant, and then moving on to another therapy.

Should people diagnosed with metastatic cancer go immediately to aggressive treatment?
In most cases, it makes sense to start with the therapy that has the least side effects, and to move on to more aggressive therapy as the tumor becomes resistant. For someone with a large tumor, however, aggressive therapy aimed at eliminating all cancer cells is less likely to be effective as the tumor grows. The best choice is a judicious use of all therapies available to the patient, trying to get as much mileage out of what you are using as you can. A study done at Duke University found that patients who had a delayed bone marrow transplant did better and lived longer than those who had immediate aggressive treatment after progression of their disease. It is important to factor in the philosophical approaches that people have, they must feel comfortable with their decisions on a personal level, because we really do not know what the correct approach is. There are still many limitations in our ability to treat cancer. This is not, however, from lack of trying.

Is taxol considered to be an aggressive drug?
40-50% of patients will respond to taxol in the metastatic setting. A large trial comparing AC (adriamycin/cytoxan) with AC+taxol showed a small survival advantage with taxol used in the adjuvant setting. This study is preliminary, but shows that there is a point in time when intervention will improve survival and a point in time when it won't, with a continuum in between. An example is early screening mammograms which have been shown to reduce mortality from breast cancer approximately 30%. Screening for advanced disease does not seem to improve outcome. The same is true for treatment, the impact on longevity is greater in early stage disease. HER2/neu status may tell us who will do better with CMF alone, and who will gain an extra benefit from AC.

How accurate is the Biomera test?
The serum marker test is about 80% accurate. With two tests showing serially rising numbers, about 80% will have metastatic cancer. 20% are elevated for other reasons. The big question is what you do with the information. The test does not appear to improve outcome. There have been two trials, but the studies were not linked to aggressive therapy. That is the type of study you would need, screen carefully for serum markers, then give aggressive therapy to one arm and traditional to another and see if early detection made a difference based on type of treatment. The problem with doing this trial is that it is hard to get a large group to agree on standard therapy for metastatic cancer. The value of this trial would be in answering questions about the value of monitoring. If you elect to do it, serum marker testing should be done every six months to one year. It is not necessarily recommended for breast cancer.

If a cancer returns, is it because it becomes resistant to the treatment?
People that recur within a short time are probably resistant to the treatment. People that recur further out probably do so because of tumor dormancy (tumor cells that are alive and viable but not growing), not related to drug resistance. Recurrent cancers tend to look the same histologically as original cancers. It hasn't been analyzed in detail at the genetic level.

A successful treatment should work effectively on a recurrence if it is at least 3-4 years after the initial occurrence. A vaccine for cancer is unlikely to work on all cancers the way you can wipe out bacteria. The best therapies we have, lower the recurrence rate by 50% (tamoxifen, in hormone receptive cancers), chemotherapy lowers the recurrence rate by 30%.

What about hormone therapy for people who are hormone receptor positive?
Some studies show that if you are HER2/neu positive, tamoxifen works, but not as well. Some studies show no difference. Right now it may not be appropriate to use HER2/neu status to make a decision about hormone therapy. Raloxifene is a reasonable drug for osteoporosis prevention, but should not be considered a substitute for tamoxifen in breast cancer.

Is there an optimum time limit for the use of tamoxifen?
Looks like five years is the optimum time. Studies looking at five versus ten years, have shown a slightly worse outcome for patients on the drug for 10 years. This was not statistically significant. Some studies show that over time, people may become resistant to tamoxifen, that it can actually contribute to the tumor's growth. Dr. Tripathy feels that after five years--stop. There is a residual effect after stopping the drug. If you cannot take tamoxifen at all, chemotherapy is recommended. Nothing else works on ER- tumors currently, but other hormonal pathways are being explored. Targretin, a new drug in clinical trials for advanced breast cancer, binds the retinoid receptor.

What is the risk of liver metastasis if there is recurrence elsewhere?
Most of where cancer cells grow and how they grow is based more on their natural properties, the underlying biology of their cancer. It is not critical to eradicate every site of cancer to prevent its spread somewhere else, although in some situations just the presence of tumor can influence metastasis. Doing radiation in locally advanced breast cancer can lower the risk of metastasis, so part of it does have to do with local control of tumor cells. On average people with liver mets do have a more aggressive course, but it is because of the underlying biology. Sometimes hormonal therapy is used for liver mets in people that are hormone receptor positive.

Why pursue chemotherapy if the response to treatment does not affect outcome or longevity?
People who do respond to therapy tend to live longer and have a better quality of life. There is a small number of people who have such a good response that they actually have a permanent remission. It is likely that metastatic breast cancer will progress, but you can experience long periods of remission before this happens. It is the subset of people who are not having a good response from chemotherapy who need to consider if that agent is going to be of any continuing use to them.

Should people consider moving on to other chemotherapy if they progress on Herceptin?
If a patient is having a good result with Herceptin and taxol, the idea would be to stop the taxol and continue with the Herceptin to maintain the response. But, it is reasonable to try Herceptin with another drug, if there is progression with it and taxol. Cisplatin would be a reasonable choice. The statistics on which is the best combination of drugs is not yet available. For someone without progressive disease, the value of Herceptin is unknown.

Does cancer have the kind of response to Herceptin that it does to chemotherapy (develop resistance, etc.)?
Responses seem to be a little slower with Herceptin, that is the tumors don't seem to shrink as quickly. Clinically it is like chemotherapy in that most people do not respond forever, the average response time is about nine months. Even a slow growth rate might be a favorable effect of Herceptin, as long as the patient is tolerating it well.

What are the newest areas of research on breast cancer?
A very active area of research is the testing of tumors on an individual basis. Technology is developing and moving quickly forward in genome study, functional assays, apoptosis (programmed cell death). NCI is committed to developing large tissue banks, spending $100,000,000 this year. Crude individual estimates to responses to common therapies, which will allow us to make better treatment decisions, should start to become available within the next two or three years. Coming up with complex individual biological regimens is much further down the line. Opinion among oncologists is split regarding the efficacy of serum markers, in that early detection does not necessarily influence outcome. Certainly, mammograms are effective for monitoring local recurrence and new primaries.

What is the role of viruses in breast cancer?
Viruses can be best used as delivery vehicles to get genes into the cells. It is most effective in cancers where cells are accessible, i.e., bladder cancer. It is not effective in breast cancer because viruses introduced through the bloodstream will not survive long enough to affect the tumor. A new trial using patients with chest wall recurrence will begin here at UCSF in about a month. Cold virus will be injected into cells with defective p53, thus selectively invading the cancer cells. Another area of research which is not currently well studied is reversing resistance to drugs. There is currently one drug in clinical trials called PSC388 which is being used to block the protein MDR. If this could be accomplished, drugs for cancer could be made to work forever. However the mechanisms involved in studying reversed resistance are as complex as those involved in genetics research.