WEDNESDAY, May 9, 2001

The Latest on Tamoxifen and Other Hormone Therapies

Tamoxifen is a very intriguing drug and certainly one of the most effective drugs we now have. A little history of biology may help to explain how it works. As humans evolved from single to multi cell organisms, cells had to differentiate into bones, nerves, brain, etc. and to migrate to the appropriate place in the body to form an organized animal. In adulthood all cells need to maintain their function, and be timed properly to secrete enzymes, to divide and even to die. These functions are mediated by signals that one cell gives to another in the form of receptors and ligands, molecules that fit together like a lock and key. The ligand is a hormone that needs to hook up with its receptor in order for the cell to do its work properly. It causes the male and female sex organs to develop differently. It is involved in the development of breast and uterine tissue, as well as being present in liver and bone. An example of this is the estrogen receptor (ER) system, which is involved in organ development in both men and women. Estrogen is the ligand, or circulating part, the receptor is the part that is fixed on the cell. When these two components combine, the resulting compound migrates to the nucleus of the cell where it binds DNA, causing gene expression. Estrogen can have different effects on different cells. Tamoxifen also binds the estrogen receptor. It acts to block the effect of the receptor and acts as an anti-estrogen in some cases. In others, like in the uterus, it can act like estrogen and cause an increase in uterine cancer.

Many of the new hormone therapies do not work in the same way that Tamoxifen does. Some simply lower the amount of estrogen rather than binding the estrogen receptor. Tamoxifen has long been identified as a drug that could affect the hormone sensitive tissues, like the ovaries. In fact, it was originally developed as a fertility drug. It was noted that breast cancer cells that made the estrogen receptor had their growth inhibited by Tamoxifen. The first studies done on advanced breast cancer in the late ë60s and early ë70s led to a temporary shrinkage of the cancer, and to the idea of using it in earlier stage breast cancer, after women had had surgery to lower the risk of recurrence. The most recent finding indicate that in ER+ patients, Tamoxifen has been shown to lower the risk of recurrence by half when used for a five year period. It is important to bear in mind that these are population statistics; it does not work on everyone. It was also noted that Tamoxifen reduced the incidence of new cancers in the contralateral breast by half, generating a lot of interest in using Tamoxifen as a prevention agent. A large trial in the early ë90s did in fact show that the number of cancers that develop in high-risk women could also be cut in half. It is not yet known if this improves mortality, or if the Tamoxifen just slows down the growth of a cancer that is already established.

The field of hormone therapy in general is still very active. Recently a new class of drugs called aromatase inhibitors has been shown to be superior to Tamoxifen when used in metastatic breast cancer. There is much interest in using these drugs in the place of Tamoxifen in early stage breast cancer and many studies are ongoing.

How was five years determined to be the best duration for taking Tamoxifen? This is for early stage and for prevention. The original studies were for one year and showed approximately a 15-20% reduction in risk. After two years the reduction was about 30% and after five years the maximum reduction of 50% was reached. It is necessary to understand that this is relative risk, not absolute risk. If the initial risk of recurrence is low, say 10%, Tamoxifen would lower that risk by half to 5%; if the initial risk of recurrence is high, say 40%, Tamoxifen would lower that risk to 20%. A few trials looked at five vs. ten years of therapy and actually showed a slightly higher recurrence rate after ten years. Longer time frames seem to induce a resistance to Tamoxifen. In the metastatic setting, Tamoxifen is given as long as the patient shows no sign of progression.

Why not measure estrogen levels on women on Tamoxifen? In young women who are still cycling, the pituitary gland stimulates the ovaries to cycle. Because Tamoxifen is an anti-estrogen, it can change the signal to the ovaries to accentuate the cycling, eventually causing estrogen levels to go up. The question is, is the beneficial effect of the Tamoxifen countering the rising levels. Some physicians are reluctant to use the drug in women under the age of 40 unless they also shut down the ovaries while on the drug. Dr. Tripathy doesnít measure the estrogen levels because he knows they will go up, but doesnít really know what to do with this information.

What is the relative value of Tamoxifen vs. Arimidex? After menopause, the main source of estrogen is converted androgen. Arimidex, one of the new aromatase inhibitors, works by inhibiting a substance called aromatase, which converts androgens made by the adrenal glands into estrogens. Inhibiting this conversion further lower the amount of estrogen in the body. This works in postmenopausal women when Tamoxifen is no longer effective. It has a better side effect profile: less hot flashes, uterine cancer, and blood clots. Studies done to compare Tamoxifen to Arimidex show that the aromatase inhibitors are a little more effective as a first line therapy for metastatic cancer in post menopausal women. Studies are currently looking at efficacy in early stage breast cancer after five years of Tamoxifen. One cautionary note: women in the lowest 20% relative to estrogen levels have increased risk of osteoporosis and decreased risk of breast cancer. In the highest 20%, the reverse is true. Therefore prolonged use of aromatase inhibitors may result in increased rates of osteoporosis.

Any clinical trials comparing ER+, HER2/neu+ and metastatic (defined as cancer spread outside the breast and nodes)? There has been one large study comparing Letrozole, another aromatase inhibitor, to Tamoxifen in ER+, HER2+ women. Tamoxifen was not as effective as in HER2(neg) women. Letrozole was equally effective in both HER+ and HER2 (neg) groups. HER2/neu might be more of an indicator to consider using an aromatase inhibitor.

What about vision problems with Tamoxifen? The main side effect is an increase in cataracts in women over 70. In the largest prevention study with 13,000 women, no significant changes were found in vision or retinal abnormalities. It is sometimes hard to determine which side effects are attributable to a drug and which are not. Finally, it is necessary to have a sense of what the numbers are, and not be deterred from taking a drug by a rare side effect not likely to occur.

Does hormone therapy offer any benefit to a patient who is ER (neg)? There seems to be no benefit if the patient is both ER and PR (neg), but there can be a benefit if the hormone receptors are mixed.

What is the effect of Tamoxifen on fibroid tumors? Tamoxifen affects the lining of the uterus, not the benign growths under the lining of the uterus (fibroids). Fibroids can cause increased bleeding and increases in the size of the uterus. These problems can sometimes be made worse with Tamoxifen. Increased bleeding on Tamoxifen should be evaluated because bleeding is often the first sign of uterine cancer. It is advisable to have a uterine biopsy whenever this symptom is present. Bleeding caused by the hormonal therapy is usually not dangerous. Screening ultrasound of the uterus is not effective because it can lead to many false positives, which lead to more biopsies. Only 1/100 patients develop uterine cancer and about 1/1000 actually die of it.

Any data on liver metastases and aromatase inhibitors? All hormonal therapies, both Tamoxifen and aromatase inhibitors have the same likelihood of response regardless of the organ system (bone, liver, and lung). In general, people who are hormone receptor positive and metastatic should start off with hormone therapyóthere is no advantage to starting with chemotherapy except for people with visceral crisis (large involvement of either lung or liver), where a small amount of progression might put those organs in jeopardy of dysfunction.

Have there been studies comparing surgical oophrectomy to medical oophrectomy? There are now medical ways to shut the ovaries down, rather than surgical removal of the ovaries. Drugs like Zolodex mimic the pituitary hormone called gonatropin, signaling the ovaries to stop cycling. Estrogen levels and effectiveness are about the same in both types of procedures. Recent evidence seems to suggest that oophrectomy combined with Tamoxifen may increase the effect or likelihood of response in premenopausal women.

How long does Tamoxifen stay in the body, how long do the effects of the drug remain with you? It is out of the blood in about two or three weeks, although it may adhere to fat tissue for as long as six months. Women should not become pregnant for at least six months because of this. The effects of Tamoxifen on the uterus should disappear after two to three months, however the risk of uterine cancer persists for another year or two.

Any reason to avoid alcohol when on Tamoxifen? No, but it should be used with moderation.

When do you expect to see results of the effectiveness of Tamoxifen out further than five years? In about two more years we might begin to see some data from the earliest trials investigating more than five years of Tamoxifen. If the effect is very small it may take longer; if the effect is large, it may be within two or three years. The additional therapy should be effective even if there is a few years break in treatment.

How is dosage determined? The initial trials were with 30-40 mg. of Tamoxifen. No one has ever gone below 20 mg., which is the accepted dose now. When side effects are very prominent, five or ten mg. are better than nothing.

Do phytoestrogens like black cohosh or soy interfere with Tamoxifen? These extracts from plants do have estrogenic activity, but it is not necessarily bad. A soy vs. Tamoxifen prevention study will begin soon. Women at high risk for breast cancer will take either soy or Tamoxifen, and then look at mammographic density of the breast (which is felt to be a surrogate marker for risk) to see if there is an effect on density from either treatment. Currently there is not enough information to determine the value of phytoestrogen, but if taken they should be from natural sources rather than extracts. Flaxseed can also be potentially beneficial.

Are some cancer cell mutations in BRCA1 resistant to Taxol and Taxotere? These studies are in very early stages, so there is no confirmatory data. There is very little information as to how women with BRCA1 and 2 mutations do after treatment, but the data suggests that the outcomes of these women are not really different stage for stage from other breast cancer patients.

Why isnít Zolodex recommended more frequently for early stage cancers? There is now good evidence that two or three years of Zolodex, an injectable drug that shuts down the ovaries, is as effective as chemotherapy for premenopausal women with ER+ tumors. One of the reasons it is not recommended as often is that the standard of care for women with ER+ cancers has been Tamoxifen and chemotherapy. Oophrectomy may be as good as Tamoxifen, but it is doubtful whether it is as good as Tamoxifen plus chemotherapy. There is also a bias in this country against the use of oophrectomy and toward the use of chemotherapy. Oophrectomy is a good option for someone with node positive breast cancer that wishes to avoid chemotherapy altogether, but it has many side effects, especially in younger women.

What are the differences between aromatase inhibitors like Arimidex and Femara? Is five years the recommended duration? What about the long term effects (osteoporosis)? Three aromatase inhibitors are now available in this country: Arimidex, Aromasin, and Letrozole, with Letrozole being the most potent but not necessarily the most effective. The duration for taking the drug is fairly arbitrary, but five years is being recommended. The only time aromatase inhibitors are used in the adjuvant setting is when the patient cannot take Tamoxifen due to blood clot or uterine cancer. As far as long term side effects, all women should be on 1200 to 1500 IU of calcium carbonate and 400 to 800 IU of vitamin D daily, depending on age. The vitamin D is necessary to help the absorption of the calcium. If the bone mineral density is significantly below average for age, a bisphosphonate like Fosamax, is recommended. In a small percentage of women peripheral arthralgias (pain in the joints) have been reported.

Does Tamoxifen cause memory loss or Alzheimerís type symptoms? In the prevention trial, no difference was found between the people on Tamoxifen and placebo, but no detailed level of testing has been done. A subtle suggestion in the literature is that women on estrogen have a lower likelihood of getting Alzheimerís disease. There are many side effects that can be influenced by Tamoxifen such as vaginal discharge, and hot flashes, which can lead to sleep disruption and insomnia. Arthritis and arthralgias have also been reported; the only treatment is discontinuing the drug.

How and when is Tamoxifen best tolerated? Timing really doesnít matter, but if you are having trouble sleeping take it during the day. The amount absorbed by food doesnít seem to matter either. To be extra sure: orange juice and lemonade should be avoided for one hour before taking the drug.

What about hormone replacement therapy plus Tamoxifen? Taking both together may increase the risk of recurrence. There has never been a randomized study comparing women on Tamoxifen with and without HRT, so we really donít know the answer. Taking HRT after diagnosis is very controversial, and being on HRT for a long time is clearly a risk factor for breast cancer.

Do you recommend calcium for women with bone metastasis? People with bone mets are at higher risk for developing hypercalcemia, and taking calcium would make that risk even higher, but with the development of bisphosphonates like Iridia, it is pretty safe, and everyone should try to protect themselves from osteoporosis.

What is the preventive care for uterine cancer for women on Tamoxifen? In premenopausal women under the age of 50, the risk is very low. Women over the age of 50 to 60 are at risk. There is no good surveillance that helps. Some recommend annual ultrasound and biopsies, but it has not been shown to make any difference in outcome. Most physicians recommend no particular screening if you are asymptomatic, but with vaginal bleeding, a uterine biopsy is recommended.

What about Tamoxifen during radiation? This has never been formally studied, but it is used here after radiation. One hypothetical reason, which has not been proven, is that Tamoxifen might make cells less sensitive to radiation. Another reason is that it is harder to explore side effects when too many treatments are being done at the same time.

Is it advisable to take medication like aspirin to prevent strokes while on Tamoxifen, as it may tend to cause blood clots? There are two kinds of clots that can develop on Tamoxifen: venous clots, which are the more common, are not affected by aspirin; and strokes, which are affected by aspirin. Aspirin should only be used by those who are predisposed to strokes.