WEDNESDAY, January 9, 2002

"Further Updates from the San Antonio Breast Cancer Symposium, 2001"

Are musculoskeletal problems common with Femara? Femara, one of three aromatase inhibitors approved for metastatic breast cancer, provides most of the body’s estrogen in the postmenopausal woman by stimulating androgens to make estrogen through the enzyme aromatase. Inhibiting this enzyme drops the already low level of estrogen in the body to almost nothing. That change makes a big difference to any tissue that responds to estrogen. In this case the tissue of interest is microscopic breast cancer cells. Of the three drugs, Femara and Aromasin seem to be a little more potent than Arimidex. About 5% of women who take these drugs will develop a musculoskeletal syndrome of joint and muscle pain, which are usually not severe nor dangerous. In rare cases the drugs may cause nausea and vomiting or hot flashes.

In looking at hormone treatment, many women start out premenopausal but can be pushed into perimenopause. Yes, any disturbance to the menstrual cycle that causes a change in the hormone profile, by chemotherapy or hormone therapy, can push a woman into perimenopause or even menopause. We do not know if an aromatase inhibitor would work in this situation, as it has only been proven to have an effect on the postmenopausal woman.

If you are currently on Tamoxifen should you consider switching to an aromatase inhibitor, or should you complete your 5 years of Tamoxifen and then start Arimidex? Is Arimidex effective in BRCA-2 positive patients? For people who are already on Tamoxifen it is a dilemma, but we feel that they should stay with Tamoxifen at least until we have more information. Even newly diagnosed postmenopausal patients are being asked to consider very carefully before deciding on the aromatase inhibitors because there has been only a slight reduction in recurrence and no difference in mortality as yet. We do not yet have information on long-term side effects. If the risk is high (as with positive nodes), side effects may not be as important a consideration relative to the benefits, and a patient might be more inclined to use Arimidex. To summarize, patients on Tamoxifen should probably continue their treatment for five years and then consider Arimidex. It would be important to stay current and see where the field is from time to time. With patients who have BRCA-1 or –2 genetic mutations which confer a predisposition to breast and ovarian cancer, therapy considerations are the same as for those without the predisposition. Stage for stage the outcome is about the same and the response to treatment is about the same. It it really more about the hormone receptors.

Does the effect of the therapy end when you finish taking the drug? At the end of 5 years of hormonal therapy, there is still a protective effect. There are fewer recurrences in years 6,7,and 8 for patients who have taken hormone therapy than for those who have not. Studies of Tamoxifen use for 5 years versus 10 years have not shown an added benefit for 10 years of treatment. We might consider longer treatment regimens when we can be sure of safety (bone density, heart disease, uterine cancer, etc.).

What is new with Raloxifene and the STAR trial? Raloxifene is an anti-estrogen like Tamoxifen but without the increased risk of uterine cancer. The original trial studied Raloxifene for osteoporosis and it was only secondarily noticed that women developed less breast cancer. The ongoing study compares postmenopausal women with high risk but without breast cancer on these two drugs.

Is there new information on the value of mammography? Recently some Danish researchers re-analyzed 7 large mammography trials and determined that mammography did not save lives. The original studies looked at deaths due to breast cancer while this new analysis looked at all causes of death, thus the benefits of mammography were not easily determined from the data, as the sample size would have to be much larger for this to show significance. Obviously this new conclusion has caused concern. If we go by the way the trials were originally designed, it is fairly clear that mammography does improve mortality. Without question, we know that mammography leads to earlier stage diagnosis, so the size of the cancer and the number of positive nodes are both lower. We are not sure whether it affects the death rate, but the proportion of people who are dying of breast cancer has definitely gone down from 1998-2001. Possible reasons that the studies seem flawed are that the technology is changing at such a rapid rate, and follow-up to abnormal mammograms is different today than in the past. Treatments now include MRI and stereotactic biopsies.

When cancer progresses do you move to another drug (aromatase inhibitor) in the same class or to another type of drug? Changing from one drug to another in the same class doesn’t usually work. Most of the literature deals with moving from one type of aromatase inhibitor to another. There are two kinds: reversible (Arimidex and Letrozole) and irreversible (Exemestane), and they work in different ways. Exemestane inhibits the conversion of androgen to estrogen by bonding more tightly to the enzyme Aromatase than either Arimidex or Letrozole and ultimately destroying the enzyme. Although they have different mechanisms, they are equally effective. Resistance may occur when the enzyme changes and no longer binds to the reversible aromatase inhibitor. If you become resistant to one type you may still be sensitive to the other type. When progression of disease is slower, it is reasonable to go to another drug in the same class, but when progression is fast, it is necessary to use the drug with the best chance of arresting the disease and that is usually another hormone therapy, Tamoxifen or Megase. The only other option is to move on to something entirely different, like chemotherapy or Herceptin if you are HER2/neu+.

What are the options for treatment for patients who are ER and PR negative? For patients who make neither estrogen or progesterone receptor, the options are either chemotherapy or Herceptin, an antibody to the growth factor receptor HER2/neu for patients who are positive.

What about the controversy of using either four cycles of AC alone or in combination with a taxane for Stage II, ER-/PR- women? A study of 3000 node positive women compared 3 months of (AC x 4) with 6months of (AC x 4) followed by (Taxol x 4). Overall the recurrence after 5 years was 7% less in the Taxol group, suggesting that adding the taxane was superior. The difference however was essentially 0% in patients who were ER+ and 9-10% in patients who were ER-. We are uncertain as to why this should be the case.

Are there any tests that can be done in advance of treatment to determine side effects? Known as in vitro drug sensitivity assays, they involve taking cells from the patient at surgery and exposing them to chemotherapy to see if they grow. These tests have become quite popular, but in vitro sensitivity may not correlate with how patients actually do.

What is tumor fever? Patients with advanced metastatic cancer can sometimes have fevers. The tumor cells make cytokines, proteins which can cause fever. The only good treatment is to treat the cancer itself.

A recent study in Holland studied insulin levels. They found that women with higher insulin levels have an increased risk of breast cancer and a higher risk of recurrence. Insulin levels vary widely during the course of the day. Carbohydrates stimulate insulin. Breast cancer cells have many growth factor receptors including insulin-like growth factor receptors. It is not known whether this insulin growth factor receptor is stimulated in the same way as other growth factor receptors like Herceptin. When relationships like breast cancer and insulin are reported, it is necessary to ask whether this is cause and effect. It may be that women with higher insulin levels also have higher estrogen levels. This is an hypothesis that needs more study. Case controlled studies suffer from bias, so the best level of proof is to fund a good scientific controlled study with patients following various diets to see if there are differences in breast cancer. There have been studies in Germany using insulin potentiation therapy where the insulin levels are brought down (or intentionally raised) and then gradually increased (or decreased) to see the effect on cancer cells. This method seems to give transient results, much like with hyperthermia, and to some extent chemotherapy.

Is ACx4 enough for women with positive nodes and ER+ cancers? About 10 years ago, a large study showed that 3 months of AC was roughly equivalent to the older therapy of 6 months of CMF. Several other studies showed that CAF and CEF were somewhat better (relative difference of 10-20%) than CMF. In theses cases the A (Adriamycin) and the E (Epirubicin) are substituted for the M (Methatrexate). The heart risk for all of these regimens is the same, about .5 to 1%. The addition of taxotere to AC makes a very toxic combination with a lot of side effects.

Anything new on sentinel lymph nodes? In earlier times, when pathologists were doing complete lymph node dissections, they merely cut each node in half and looked at one edge. Now that pathologists are doing sentinel node biopsies, where they look at the first node to which the cancer cells drain, they can take the time to do multiple sections of the node analyzing this single (or sometimes two) node to determine whether cancer has spread. With the help of cytokeratin staining even micrometastasis can be seen. Sentinel lymph node dissections have been found to be predictive 95-97% of the time. The group at John Wayne Cancer Center in Los Angeles has presented the results of 600 cases of micrometastases which are positive only with immunohystic chemical staining (IHC). These patients had outcome risks that were essentially the same as patients who had totally negative nodes. All the cooperative groups that do clinical trials in this country have agreed that if the sentinel node is only positive with cytokeratin staining that should be considered a negative node.

What if the sentinel node is positive? The practice is to go ahead with a regular lymph node dissection because the possibility of finding additional positive nodes is higher. It is important to know the nodal status because it helps us get information on the benefit of therapy. The greater the number of positive nodes, the greater the benefits of therapy. If a person is willing to do chemotherapy based solely on the positive sentinel node, there might be no need to do the more invasive dissection, because it would not affect treatment. It might also save some women from the debilitating effects of lymphedema.

Can cancers change from ER+ to ER-? About one-third of the time, when patients have been on hormone therapy and they have a recurrence, the estrogen receptor goes from positive to negative. Sometimes, although the tumor is still ER+, it has altered somewhat so that it doesn’t bind estrogen in the same way. If ER- changes to ER+, chances are that the initial assay was not sensitive, because the change is not likely to go that way.

What is the nature of surveillance with metastatic cancer? This is very much dependent on the type of cancer. With lung and liver metastasis, patients who are on hormonal therapy should have scans done every 2-3 months, unless the metastasis is limited to a single area of bone, in which case the interval can be lengthened to 6 or even 12 months. The frequency of the scans should be individualized and take into consideration how long the patient has been stable. Most important is to catch a progression in time. With recurrence, catching it early is not as important as the aggressiveness of the cancer, because treatment is usually not initiated until symptoms appear or the patient exhibits a pattern of growth that might indicate symptoms might appear soon. With a single site of metastatic recurrence, it is good to treat early with local treatment; with multiple sites this is not done.

Can drugs be used again once they have been used to treat a cancer? Yes, if the recurrence is a long time after the initial treatment, they can be used again. If the recurrence happens a short time after its use, the patient is probably resistant, or not sensitive, to it.

Should I be afraid of the radiation from numerous CAT scans? Radiation from a CAT scan is not insignificant—about 3-4 times that of a chest X-ray, but much lower than therapeutic radiation. It is really a matter of relative risk. If you are a healthy person, don’t expose yourself to the risk. If you are someone with cancer for which a scan will give you valuable treatment information, go ahead. (FYI: a CAT scan exposes you to .1rads, while a course of therapeutic radiation is about 5000rads.)

What do you know about Tarceva? Tarceva (OSI-774) and Iressa are drugs against the epidermal growth factor receptor (EGFR). Growth factor receptors sit on the surface of cells and bind to a ligand, which activates different molecules that sends a signal to the nucleus that tell the cell to grow. Drugs have been designed to interfere with this process, keeping the signal from getting to the nucleus of the cell. Herceptin works in a very similar way. Breast cancer cells express EGFR in very low levels, so it is unclear whether these drugs will work in breast cancer. Tarceva and Iressa studies are ongoing, but the preliminary reports show no dramatic responses.