WEDNESDAY, February 12, 2003

"New Directions in Hormone Treatments: What's New, What Works, What are the Risks? "

We have known for some time that hormones are important to the development of breast cancer. About 60% of breast cancers are hormone receptor positive. Younger women have a lower percentage of hormone receptor positive cancers. As women get older, the percentage of breast cancers that are hormone receptor positive increases. The estrogen receptor is different biologically than the receptor that guides HER2/neu or the growth factor receptors like EGFR. In the latter case, the receptor is located on the outside of the cell, where it sends a message to the nucleus, telling it to grow. We have developed novel therapies like Herceptin that hook onto to this receptor and interrupt the message. The estrogen receptor is a nuclear receptor that works in a different way. Estrogen is in the cytoplasm of the cell, where it binds to a gene and tells it to grow, making other genes and other proteins that drive cancer growth. Estrogen growth also helps to increase progesterone receptors.

There are several areas in which we are interested in the use of agents that could block the estrogen receptor. One of the biggest areas is prevention, especially for women who are at high risk of developing cancer. Another area is in pre-invasive cancer, DCIS, which has not invaded the lymph nodes. Lastly is the treatment of established cancer.

The first class of drugs that people understood were important in hormone sensitive cancers were actually the hormones themselves: estrogen and progestins. In the early days, very high doses of estrogen were believed to block activity through the estrogen receptor. There are some problems with this therapy in that high doses of estrogen can stimulate cancer growth and cause side effects. High doses of progestins like megase have been used.

The class of drugs called SERMS (selective estrogen receptor modulators) was initially called anti-estrogens because they were thought to block the ability to bind to the receptor. We have come to understand that the SERMS have both pro- and anti-estrogen activity. They seem to work differently depending on the type of cell. At the breast cancer cell level they work to block cancer growth. In the uterus or bone cell, they act more like estrogen, improving bone mineral density and building up the lining of the uterus, causing dysfunctional bleed or ovarian cysts. Blood clots also can occur with this class of drug. Tamoxifen is the drug with which we now have the most experience—35 years. We have a better idea of the side effects from this drug than from any other, even from chemotherapy agents. Another SERM on the market for the treatment of osteoporosis and breast cancer prevention is raloxifen. It doesn’t stimulate the lining of the uterus, but is also not very potent at blocking the breast cancer cell. Novel SERMS are being studied, but the toxicities must be carefully assessed before being used in clinical trials. We know that tamoxifen is very effective in the adjuvant setting. It is largely the reason we are seeing a reduction in recurrence and death from early stage breast cancer. Ten years of administration of the drug is actually not better—maybe worse—than five years. It may be that exposure over a prolonged period of time actually drives cancer cell growth.

Aromatase inhibitors are the next class of drugs. The aromatase enzyme blocks the production of estrogen. Three new third generation drugs include the non-steroidal (letrozole and anastrazole), and the steroidal (examestane). The steroidal looks more like a steroid, the non-steroidal look less like a steroid.   All three of these drugs result in 90% reduction in the aromatase enzyme.

Pure estrogen receptor antagonists are the next generation of drugs and may be the best way to deal with estrogen, by blocking it completely. When the drug is removed, estrogen returns. The drug most recently approved is fulvestrant, given by an intramuscular injection once a month. There is some controversy about this dosage, as it takes up to six months to achieve the optimal dose. As this is a drug approved for metastatic cancer, the time period is excessive. It is no better than tamoxifen for first line therapy. New combinations like Iressa and hormone agents, presented at the recent San Antonio Symposium, may work to overcome the resistance that can develop to single drug therapy.

Prevention: The ongoing STAR trial, comparing raloxifen and tamoxifen is going to close to accrual soon. More people are interested in aromatase inhibitors. New studies compare aromatase inhibitors (AI) in postmenopausal women who are BRCA+. Some are looking at the side effects of AIs that include joint pain, hot flashes, increased osteoporosis, and fractures. These effects generally resolve over time. The osteoporosis is the most concerning, but oral bisphosphonates seem to delay the progression. Increased doses of aromatase inhibitors like aromasin seem to inhibit bone loss. This is because it acts like testosterone. In the pre-invasive area, a study compared women with DCIS who had lumpectomy and radiation followed by tamoxifen to those having placebo. It   showed that all the response was in women who had hormone receptors (were ER or PR positive). So in the prevention setting, tamoxifen should only be given to women who are hormone receptor positive. This means ER+, PR+, or both. Better assays today will allow much better screening of women to find if they are hormone receptor positive.

Treatment: It has been estimated that there are between 20,000 and 30,000 postmenopausal (at diagnosis) women enrolled in adjuvant clinical trials worldwide. There will be a lot of information from these trials starting in 2004. These studies are looking at: aromatase inhibitor versus tamoxifen for 5 years, sequential therapy (2 years of tamoxifen followed by 3 years of AI or the reverse), and preventing late recurrences after 5 years of tamoxifen by extending treatment (5 years of AI). Most information should come from the first two types of studies.

Why does it take so long to get results? Women are doing better, and for longer periods of time, especially with tamoxifen. Because there are fewer events (recurrences), it takes a longer time to get answers.

Is there anything new on the ATAC trial? We know that anastrazole is at least equivalent to tamoxifen in postmenopausal women with early stage breast cancer. At this point there is only recurrence data—no survival data, so we cannot assume that the drug is better, but it is certainly an alternative to tamoxifen if side effects are a problem. We have to be cautious and look carefully at our patients. These aromatase inhibitors may be particularly effective in prevention. Another result of the ATAC trial is that there is no difference to date for women who received chemotherapy between the aromatase inhibitor and tamoxifen. In the metastatic setting, AIs have a better response rate than tamoxifen, and survival is identical. This may be because other drugs will work after first line therapy fails. AIs are better than megase as second line therapy, and faslodex is good for third line therapy.

Is anything being developed for ER- women? It doesn’t appear that these hormone agents are effective in hormone negative cancers. We need to look for the receptor in these cancers that is driving cancer growth and resistance. There may be a growth factor that is turned on that turns off the estrogen receptor. This research is still in the laboratory. Aromatase inhibitors might be effective to prevent the development of a distant cancer, but because the risk of a new cancer is much less than a recurrence of an existing cancer, it might not be worth the side effects.

If a patient has taken tamoxifen for five years and then develops a recurrence, can you retreat with tamoxifen? It would not be as effective as an aromatase inhibitor.

Is anyone going straight from 5 years of tamoxifen to Arimidex? There are many patients and physicians who are interested in extending treatment after tamoxifen who might go right on to an aromatase inhibitor. That choice should be made with a clear understanding of the risks. Because we don’t yet have the data, you might do more harm than good. At this point AI after tamoxifen should only be attempted as part of a clinical trial.

What about tamoxifen for premenopausal women? Up until the 1995 Oxford Overview Analysis, a collection of randomized clinical trials, it wasn’t thought that tamoxifen was beneficial for women with functioning ovaries (estrogen). But it seems that tamoxifen is just as effective in reducing recurrence in premenopausal women. It might be somewhat controversial in women under 35, where ovarian suppression might be preferred.

Would steroidal AI increase osteoporosis risks? We don’t really know because there is no data. It may be dose related. There is increased bone mineral density loss in women who take Arimidex, but this may just be due to the lack of estrogen.

What is the effect of tamoxifen on the liver? Tamoxifen doesn’t always affect the liver. For most people the liver function tests remain stable. Nor is there a change in the lipid profile. Lipid levels may change in a negative direction with AI, but levels are less important than ratios.

Can AI be used serially? They can be used in sequence with good responses. In women who are responding, this can delay the time to chemotherapy and to progression.

How long does tamoxifen remain in the system after use? The effect of tamoxifen goes away quickly. If one is concerned about osteoporosis, most drugs, with the exception of raloxifen, can be taken simultaneously with tamoxifen. The best oral drugs currently are Fosamax and Actinel. The intravenous bisphosphonates, Iridia and Zometa, are FDA approved for treating metastatic cancer to bone. Although it has not yet been approved for osteoporosis, administration twice a year has shown some increase in bone density.

How long should you be on tamoxifen before you are checked for symptoms?  Tamoxifen helps to stimulate bone mineral growth, so a baseline bone mineral density is important to look at the hip and the spine. The issue of blood clots is not something you can screen for. People with more advanced cancer have a higher rate of clots, as do women getting chemotherapy for breast cancer. With no family history of clots, the risks with tamoxifen are extremely low, especially in younger women.

Can birth control pills help to prevent cancer? There is no data that the use of birth control pills increases risk. Oral contraceptives control the cycling of the ovaries, so that women who took birth control pills for 5 years or more have a lower rate of ovarian cancer.

What can hormones do to treat HER2/neu positive breast cancer? About 40% of HER2+ breast cancer is also hormone receptor positive. Tamoxifen may not be as effective in these cases. Aromatase inhibitors may work better for these cancers.

Should patients on AI be checked routinely? After a baseline bone density, patients with bone loss should be checked annually; with good BMD, every two years. Other symptoms that may require attention include vaginal dryness, loss of libido, hot flashes and diminished cognition. Lipid levels should be checked.

Are there effective treatments for hot flashes? Some women have found black cohosh to be beneficial. One study has shown that Effexor, an antidepressant, is better than placebo, but it may have significant side effects. Weight gain associated with Effexor has averaged only 5 to 6 pounds, but it may relate more to other issues like menopause. Other treatments include acupuncture and herbal remedies.

How long after starting an AI should you begin to see changes in tumor markers? At least three months. There is no value in checking tumor markers with early stage breast cancer. Tumor markers may be present years and years before an actual recurrence. It does not change survival strategies to know they are there in an asymptomatic patient. In the metastatic setting, it may be the only way to follow the progression of the disease, or make it possible to do fewer x-rays.  It is most important not to change treatment with a change in a tumor marker in the absence of symptoms.

Next month: “Advances in Diagnosis and Management of Breast Cancer: MRI”, featuring UCSF radiologist Nola Hylton, PhD. and Laura Esserman, M.D., Director, Carol Franc Buck Breast Care Center at UCSF.  Wednesday, March 12^th, 6:00-7:30.