WEDNESDAY, JUNE 12, 2002

"The Anatomy of a Treatment Decision: Clinical and Research Issues"

Over the last few years we have talked about the many different elements that get factored into the treatment decision: chemotherapy and hormone therapy, individual characteristics like family risk and environmental exposure, complementary and alternative medicine, and the importance of the mind/body interactions. Today we want to express a message of hope. We know much more about cancer today. The information acquired over the last few years has really been exponential. New treatments may not always be dramatic, but they continue to offer an advantage over what was there before. In the next 10 years, 25-30 new drugs will be approved. Cancer treatment will continue to be individualized, because we know that at a molecular level breast cancer is very individual. Hormone receptors like estrogen and HER2/neu have been used in the last 5-10 years. Current research is studying 10,000 genes at a time on gene chips which will really begin to tailor treatment options for patients as we begin to realize that no two tumors are the same. The second message today is one of empowerment. Patients can help themselves by taking ownership of the new data, opening a dialogue and questioning their physicians.

Why are patients sent to psychiatrists for pain and fatigue post breast therapy? It may be that complaints don’t get properly addressed due to ignorance on the part of the physician. Pain and fatigue are very common side effects of treatment, which are being recognized more and more. This is a matter of education. It is necessary to raise awareness of these problems individually and collectively through advocacy and question your physician. Side effects may be underreported because physicians don’t ask their patients about them. We need to collectively look at these issues which have not been well studied. The question is how to capture this information on all patients or at least on a broad cross section of patients. The barriers to this type of capture are great—witness the reluctance of most people to participate in clinical trials.

When studying a specific research issue, is it helpful to include other types of cancer? Under ideal circumstances you want to look at one particular regimen. Too many variables make it hard to evaluate age, depression, and other health problems.

What are the cognitive effects of radiation? We know that white blood count and fatigue are affected by radiation but there are physical changes like breast tenderness. The amount of radiation and the sites of radiation are significant.

Is it possible for you to find out about allergies to certain cancer regimens before starting the treatment? We know about the significant side effects of a new drug when it comes out. For example, we know the percentage of people who have reactions to Taxol, but not who is allergic because less than one percent of people are. A new field called pharmacogenomics deals with patient-specific side effects and polymorphisms (variants which don’t cause disease but make one person different from another).

If a patient had drug-induced lupus 10 years ago, are they at risk for complications with radiation? If the disease activity is not there at the time of the treatment, there is no danger in radiation. Here at UCSF the radiologists are nervous about radiating anyone who has ever had a diagnosis of lupus, but this is not true at Stanford. It would be important to develop a computerized database of systematic side effects in order to answer the question. There is some effort at NCI to do this, but individual practices don’t have the budget to do this.

How do you advise patients to make treatment decisions when there is not clear cut clinical information, when do you advise a second opinion? There are two main issues: the situation and the person. The situation can be discussed by offering the pros and cons of the various treatment options. The other aspect is how does the person make decisions (aggressive vs. conservative treatment) because we all react differently to the same circumstances. The collaborative care program here really delves into how the individual makes decisions. Outside the university, many specialties are very monolithic in decision-making. Breast cancer seems to be much more about individualized care, but it should be applied to all medical decision-making. Society needs to educate itself because there is less interaction time with physicians now due to managed care.

Is it possible for new medications to be taken at home rather than at the infusion center? The older chemotherapy drugs can’t be absorbed well by the stomach or are so caustic that they can’t be in contact with the skin. Many of the new wave of drugs (called small molecule drugs) are oral. Subcutaneous administration of Herceptin is being considered. There is also the social dynamic of the infusion center, which has its pros and cons. It is a conduit for social interaction, but can be depressing.

Are samples of tumor and slides stored for future use should new therapies be discovered? This is important in order to study new biomarkers. States have different laws regarding how long they have to keep the tissue blocks. In California and New York, it is ten years. As new biologic therapies multiply, the law will probably change so that the block is kept indefinitely. It is advisable to contact the hospital to see if they will release the block to you for diagnostic purposes.

How about doing assays to see what the most appropriate chemotherapy is? You can generate in vitro sensitivity curves against a specific tumor, but in practice it doesn’t work very well, as different labs will yield different results on the same tumor. It is more accurate to look at multigene arrays and match them up to sensitivity. Even without new therapies, we could vastly increase the value of our current treatments by matching up these assays with existing treatment options at the optimum time to individualize therapy.

Can ER/PR status change over time? There are often changes in the genetic structure from the primary cancer to the recurrence. About 20-30% of the time, especially on hormone therapy the estrogen receptor will revert from positive to negative. It almost never reverts from negative to positive. Whenever possible, it is advisable to get a biopsy on recurrence.

How much estrogen receptor do you need to respond to hormone therapy? Experts in the field say that weak staining in only 5% of the cells can be enough to respond to hormone therapy. Mixed receptors like ER+/PR- or ER-/PR+ still have a chance of responding to hormone therapy. We treat premenopausal patients with Tamoxifen, Xoladex or Lupron. With postmenopausal patients, aromatase inhibitors tend to be more effective than Tamoxifen.

How much do assays cost? Assays usually cost a few hundred dollars. The Oncotech Labs (http://www.oncotech.com) and Weisenthal Labs (http://weisenthal.org) are two examples of labs that charge for this service.

Are there any studies on novel causes or prevention of breast cancer? Few cancers have a strong causal effect (like smoking and lung cancer). In breast cancer, strong causal factors are few and far between. Family history is a strong factor, with 60-80% of women with BRCA 1 and 2 mutations getting breast cancer in their lifetime, but this only accounts for about 10% of breast cancers. The cause of breast cancer probably has to do with hormonal relationships; there is a slight positive correlation between taking birth control pills or hormone replacement therapy for more than ten years and breast cancer. There is a reduction in risk for women who have had their ovaries removed (especially before the age of 35). Women with higher postmenopausal estrogen levels have a higher risk of breast cancer. The amount of estrogen that a woman experiences today is much greater than earlier in history. Girls start their periods earlier and have more periods by delaying childbirth. The number of periods a woman had 500 years ago is equal to the number girls have today by the age of 14. But cancer, like estrogen, is a part of normal physiology, part of the aging process. It is seen in any cell that divides. This may be why it is harder to find the "smoking gun". Clearly, breast cancer is a more common disease now than it was 100 years ago. Bizarrely, healthier societies seem to have a higher incidence of breast cancer.

Is it possible that breast cancer is contagious? There are usually patterns that are seen with contagious situations, clustering of cases that identify an epidemic. These have not been seen with breast cancer in humans. In mice and rats, there is a mammary tumor virus that causes breast cancer. Researchers have identified this retrovirus in some Chinese women.

Is the traditional way of categorizing tumors changing? Genes and proteins make a cell do what it does. By looking at genes and proteins we will evolve a much more functional classification of cancers.

How do you classify perimenopausal women relative to making treatment decisions? With aromatase inhibitors, we measure estrogen levels because it won’t work with women who make any estrogen. With Tamoxifen and chemotherapy it doesn’t matter.

Is there a distinction between lobular and ductal carcinoma? Stage for stage, the survival and outcomes are the same, responsiveness to hormone and chemotherapy is about the same. Lobular cancers tend to be ER+/PR+ and HER2/neu (neg), so the treatment would be based more on these biomarkers.

Is radiation recommended in postmenopausal cancer? In early stage it is recommended after breast conserving surgery. In women over the age of 65-70, their risk of a local recurrence with or without radiation is very low. If the tumor is small and they have good margins, they can probably do without radiation. It is still recommended for metastatic disease.

Can you give estrogen to women who have had breast cancer during menopause? Because we have always avoided giving women estrogen after breast cancer, there is very little data on this. Now because women can really have improved quality of life with hormone replacement therapy, a small body of experience suggests that it may not matter. Two small prospective studies and one large case control study compared women with breast cancer who did or didn’t receive estrogen replacement. The recurrence rates didn’t seem very different. Unconjugated estrogens like Estrace may be preferred to conjugated estrogens like Premarin. Phytoestrogens (plant source of estrogen, found in soy) may not be harmful, but the research is preliminary. (See chapter on soy in Breast Cancer Beyond Convention, by D. Tripathy, M. Tagliaferri, and I. Cohen, editors.)