Hormone Therapy

Since 2004, the American Society of Clinical Oncology (ASCO) has recommended that postmenopausal women with hormone-sensitive tumors be treated with an aromatase inhibitor (AI). (Before that the standard of care was tamoxifen.) Tamoxifen is the standard of care for premenopausal women. This change was a response to findings from several clinical trials, most significantly ATAC (Anastrozole, Tamoxifen, Alone or in Combination).

Currently three AIs are approved for use by the U.S. Food and Drug Administration (FDA): anastrozole (brand name Arimidex), letrozole (brand name Femara), and exemestane (brand name Aromasin). These drugs reduce estrogen by blocking the aromatase enzyme and keeping it from converting androgens into estrogen. Tamoxifen blocks estrogen by attaching itself to the estrogen receptor on breast cells. Both pre- and postmenopausal women can use tamoxifen as hormonal therapy. But only postmenopausal women can use an aromatase inhibitor. That's because postmenopausal women get most of their estrogen from the conversion of androgens into estrogen by the aromatase enzyme, while premenopausal women get most of their estrogen directly from their ovaries, which the AIs don't block.

The ATAC trial put Arimidex and tamoxifen head-to-head. The trial included 9,366 postmenopausal women with early breast cancer from 21 countries. The women were initially divided into three treatment groups. One-third took Arimidex, one-third took tamoxifen, and one-third took Arimidex and tamoxifen. (Nearly three years into the study, the researchers stopped the combination arm when it was found to be no more effective than tamoxifen alone.)

The study found that after five years of treatment, women in the Arimidex group had fewer recurrences and a longer time before recurrence occurred than did women in the tamoxifen group. Specifically, 575 women in the Arimidex group had a recurrence compared with 651 women in the tamoxifen group. Arimidex also reduced the risk of a woman developing contralateral breast cancer (cancer in the opposite breast), with 35 of the women on Arimidex developing contralateral cancer compared with 59 of the women on tamoxifen.

But the ATAC trial showed the AIs are not problem-free. Women on AIs have a higher risk of developing fractures and bone and joint pain. For this reason, women who are at high risk for osteoporosis or who already have osteoporosis should avoid the aromatase inhibitors and take tamoxifen, which actually increases bone density.

One other thing to consider: There is evidence that there are benefits to starting on tamoxifen for two or three years and then switching to an aromatase inhibitor for the remainder of the five years of hormonal therapy. Starting on tamoxifen and then switching to an AI may not only reduce the recurrence but may also be a way to minimize the side effects of both drugs. However, if your tumor is HER2-positive, starting on or switching to tamoxifen is not recommended. There is some evidence to suggest women who are both HER2-positive and estrogen receptor (ER)-positive may have tumors that respond better to an aromatase inhibitor.

Tamoxifen has been used for breast cancer treatment and prevention for decades. So, we know a lot about its risks and benefits. Perhaps the best overview of risks comes from the Breast Cancer Prevention Trial. This study found that women taking tamoxifen had more than twice the chance of developing uterine cancer compared with women who took a placebo. But while that sounds ominous, the numbers aren't really that big. Specifically, the study found that 36 of the 6,600 women taking tamoxifen and 15 of the 6,600 women taking the placebo developed endometrial cancer. In other words, the women taking tamoxifen had a 1.52 in 1,000 chance of developing uterine cancer and for the women on the placebo the risk was one in 1,000. (The risk was higher in women over the age of 50.) The percentage sounds like a large increase, but, the true numbers are small. Still it is a risk that must be taken into account. Tamoxifen also slightly increases a woman's risk of developing a pulmonary embolism (blood clot in the lung), a deep vein thrombosis (blood clot in a major vein), and stroke.

If you have invasive breast cancer these risks may be worthwhile. If you are high risk and taking tamoxifen for breast cancer prevention, they may not be, depending on your risk.

Adjuvant! is a decision tool designed to help health professionals and women with early breast cancer discuss the risks and benefits of adjuvant (after surgery) treatment. After you input information about your diagnosis, Adjuvant! will determine what absolute benefit you can expect from hormone therapy. You may want to use this tool to get a better sense of the benefit you will get from hormone therapy.

Some experts recommend endometrial biopsies and uterine ultrasounds for all women on tamoxifen. This may be a bit much, but annual gynecologic exams are important. Some gynecologists prescribe progesterone or progestin-containing IUDs for women on tamoxifen although there is no data on the safety of progesterone in women with breast cancer or the efficacy of this treatment. Most importantly, you should be aware that uterine cancer presents with vaginal bleeding. Therefore any woman on tamoxifen who has vaginal bleeding should see her doctor immediately.

This is a very important question—and no one yet knows the answer.

There are currently three aromatase inhibitors (AIs) approved by the FDA: anastrozole (Arimidex), letrozole (Femara), and exemestane ( Aromasin). The first AI clinical trials in postmenopausal women which tested the drug against tamoxifen. At that time, the standard of care for women was to stay on tamoxifen for five years. So, the trials tested five years of tamoxifen against five years of an AI. Then, in 2013, we got findings from the ATLAS (Adjuvant Tamoxifen Longer Against Shorter) trial which found 10 years of tamoxifen provided more benefit than five.

Those findings raised the question of whether 10 years of an AI should also be the standard of care. Clinical trials are exploring that question, but the answer is not yet clear. Should postmenopausal women go back on tamoxifen for five years after finishing their AI? Maybe. An AI keeps testosterone from being converted into estrogen, so it decreases estrogen throughout the body. But tamoxifen works in a different way. It blocks the estrogen receptor on cancer cells, but acts like an estrogen in the bone, liver and uterus. So, it would be easier to stay on longer.

What about other risks and benefits? Tamoxifen decreases cholesterol, and improves bone density, which is good for both pre- and postmenopausal women. The biggest risk is uterine cancer. It's not a huge risk, but it's real.

What should you do? Right now, the best any of us can do is make an educated decision based on what we know. Some doctors are not having any of their patients stay on an AI longer than five years. Others believe there may be some small benefit to all women continuing on an AI for more than five years, and that the benefit may be even larger for women who had positive nodes or an aggressive tumor. However, the long-term downsides of prolonged suppression of estrogen levels that occur with an AI are unclear, and worries about osteoporosis and potential heart problems due to estrogen-deprivation remain. This means it comes down to every woman talking to her doctor about her risk for recurrence, her quality of life, and the potential (but unknown) benefits/risks of staying on an AI for longer than five years.

Note to Premenopausal Women:

Aromatase inhibitors can only be used by women who are postmenopausal. If you are premenopausal, you cannot take an AI unless you are also taking a drug, like Lupron, that will put you into temporary menopause.

Some women have tumors that are strongly ER-positive, others have tumors that are only 15-20% positive. Studies have found that both types of tumors can respond to hormone treatments, like tamoxifen or an aromatase inhibitor. Some studies have found that women with ER-positive and PR-negative tumors have a slightly worse prognosis than women with ER-positive and PR-positive tumors, but no one really understands why. This is why chemotherapy may be more helpful for women with PR-negative tumors.

You should also talk to your doctor about having your tumor tested with the Oncotype DX test. This test can help assess your recurrence risk, and thus help you and your oncologist decide if you should have chemotherapy as well as hormone therapy.

Hormone therapy is still recommended for women with early-stage breast cancer who have had mastectomies because it can help prevent a distant recurrence (metastatic disease). Even when a woman is node-negative, it’s still possible for there to be cells that have escaped and that are floating around, and the hormone therapy will deal with them.

What you are describing is called neoadjuvant therapy. Neoadjuvant means "before surgery," and both chemotherapy and hormone therapy can be used as neoadjuvant treatment. When chemotherapy or hormone therapy is used after surgery, it is called adjuvant treatment.

Neoadjuvant treatment is typically used to decrease the size of a large tumor before surgery. By shrinking the tumor, a woman who would otherwise require a mastectomy may instead be able to have a lumpectomy. Chemotherapy has been studied more in the neoadjuvant setting than hormone therapy has. But it certainly makes sense to use hormone therapy, since the goal is to shrink the tumor, and hormone therapy can do that without the side effects that accompany chemotherapy. Many clinical trials are also now giving treatments in the neoadjuvant setting.

Neoadjuvant hormone therapy is only an option for women whose tumors are estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive. Typically, a woman will take hormone therapy for three or four months prior to surgery. After her hormone therapy is completed she will have a mammogram or ultrasound or both to determine what effect the hormone therapy is having. If the hormone therapy does make the tumor smaller, a lumpectomy can be performed rather than a mastectomy. It can be exciting to see that the hormone therapy has been effective, the tumor has responded, and a lumpectomy can be performed. But it is also important to keep in mind that treating the tumor with hormone therapy or chemotherapy prior to removing it surgically has not been found to improve a woman's chance of surviving from breast cancer.

The question you need to consider before starting neoadjuvant hormonal therapy is whether you would prefer to have a lumpectomy followed by radiation, or a mastectomy. If you want to try to give yourself the option of having a lumpectomy, then you should try the hormone therapy. If it is okay with you to proceed directly to a mastectomy, then there may not be a reason to take the hormone therapy before surgery. The other advantage of neoadjuvant therapy is that you can see if the tumor is responding to the particular therapy. If it does not shrink, that may mean that you should try a different drug. If you decide to have the neoadjuvant hormone therapy, you and your doctor can determine which one is best for you.

Pregnancy makes most oncologists very nervous because of the increase in hormones. A few small studies have looked at women who have become pregnant after a breast cancer diagnosis. These studies found that women who got pregnant had about the same risk of recurrence as did women who were the same age and had the same tumor type bu tdid not get pregnant. Even so, most doctors recommend that a woman wait at least two years after finishing treatment to become pregnant. There's no real science behind this recommendation. It's just that many doctors believe that the most aggressive tumors would probably reoccur during this time period.

A study published in August 2015 in the Journal of the National Cancer Institute found that fertility concerns lead many young women to not take or to stop taking tamoxifen. (This is a good article about the study’s findings and implications.) No one knows the exact risks of postponing tamoxifen, and there is no data on what impact tamoxifen has if it’s not taken for five years in a row. However, there is a clinical trial now underway that is investigating if tamoxifen remains effective if women stop taking it to have a baby and then goes back on it. This trial was started because of the number of women who have asked the same question you are asking.

You and your oncologist need to have a very open conversation about your hopes for a baby and your treatment needs. You should find out from your oncologist what your risk of recurrence is if you don't take tamoxifen and then what it would be if you did. That information could help you make your decision. If you were just diagnosed, you should speak with a fertility specialist to find out what options you have--such as freezing eggs and embryos--prior to starting treatment. Livestrong Fertility (formerly Fertile Hope) is an excellent resource.

The one thing you don't want to do is start taking tamoxifen and then just see if you become pregnant. Tamoxifen can cause birth defects, and any woman who is on this drug must use an effective form of birth control.

The decision to take tamoxifen for ductal carcinoma in situ (DCIS) is a difficult one for many women, as the benefits from taking it are small and have to be weighed against the risks associated with the drug as well as any side effects you may experience.

Tamoxifen began to be routinely offered to women for DCIS in 1999, after researchers reported the results of a study that looked at the benefit of adding tamoxifen to DCIS treatment. The study randomized 1,804 women with DCIS to tamoxifen or a placebo for five years. All of the women had already had surgery and radiation. (Their tumors were not tested for estrogen receptors, as the study was started before the importance of this was realized.)

After following the women for five years, the researchers found that:

• Forty women in the placebo group and 23 in the tamoxifen group developed subsequent invasive cancers in the treated breast. This meant that, statistically, tamoxifen reduced the chance of developing invasive cancer from 4.2%to 2.1%.
• There were 47 noninvasive recurrences (more DCIS) in the placebo group and 40 in the tamoxifen group. This meant that, statistically, tamoxifen lowered the rate of noninvasive recurrences from 5.1% to 3.9%.
• Thirty-six cancers (noninvasive and invasive combined) developed in the opposite breast in the placebo group while 18 developed in the tamoxifen group. This meant that, statistically, tamoxifen lowered the rate of developing cancer in the opposite breast from 3.45% to two percent.
• There were seven recurrences in the placebo group and three recurrences in the tamoxifen group in the nodes, chest wall, or elsewhere in the body (metastases). Although the recurrence rate was less than half as great in the tamoxifen group, the numbers are too small to be statistically significant.
• There were six deaths from breast cancer (a very rare event for DCIS) in the placebo group, including twofrom cancers in the same breast as the original DCIS. In comparison, there were four deaths in the tamoxifen group, including three that were attributed to cancers in the treated breast.
• Overall, tamoxifen reduced the risk of a recurrence, a second cancer in the opposite breast, or metastasis from 13.4% to 8.2%.

Side effects included two cases of phlebitis (inflammation of a vein) in the placebo group and nine in the tamoxifen group, with one nonfatal pulmonary embolism (obstruction of a blood vessel in the lungs, usually due to a blood clot) in the placebo group and two in the tamoxifen group. In addition, there were 36 cases of uterine cancer in the tamoxifen group and 15 in the placebo group, although there were no uterine cancer deaths. There was also about a 10% higher incidence of hot flashes, fluid retention, and vaginal discharge in the tamoxifen group than the placebo group.

Choosing whether to take tamoxifen to treat DCIS is obviously a complex issue. The advantages are small, but then so are the risks. Each woman will probably evaluate these risks and benefits differently. The only right choice is the choice that you feel is right for you.

Aromatase inhibitors are hormone therapies that are used to treat women with hormone sensitive tumors. (ER+ and/or PR+) Aromatase inhibitors work by blocking the aromatase enzyme, which converts androgens into estrogen. A woman must be postmenopausal to benefit from an aromatase inhibitor. That's because postmenopausal women get most of their estrogen from the conversion of androgens into estrogen by the aromatase enzyme. In contrast, premenopausal women get most of their estrogen directly from their ovaries (and aromatase inhibitors aren't able to block this estrogen).

Currently three aromatase inhibitors are approved for use by the U.S. Food and Drug Administration (FDA): anastrozole (Arimidex), letrozole ( Femara), and exemestane (Aromasin). These drugs are the standard of care for postmenopausal women, while tamoxifen remains the standard of care for premenopausal women. For a premenopausal (still menstruating post chemotherapy) woman to take an aromatase inhibitor, she must have her ovaries removed (oophorectomy) or take a drug that will suppress ovarian functioning and decrease estrogen levels, putting her into menopause. The drugs most commonly used for this purpose are goserelin (Zoladex), leuprolide (Lupron), and triptorelin (Trelstar).

In 2003, The International Breast Cancer Study Group (IBCSG) launched two large randomized phase III trials, called TEXT and SOFT, to look at whether it was better for premenopausal women to take tamoxifen or the AI exemestane (Aromasin). These trials also looked at if using tamoxifen along with ovarian suppression was better than tamoxifen alone. The findings from these studies, announced in 2014, suggested that exemestane along with ovarian suppression was more effective than tamoxifen along with ovarian suppression in preventing recurrence. However, at this point in time, no difference was seen in overall survival. The women in the study will need to be followed longer to get that information. But the study also showed that some premenopausal women with hormone-sensitive tumors have an excellent prognosis with tamoxifen alone. So, it goes back to you, as an individual, and your specific tumor. If your doctor feels that you are at higher than average risk for recurrence (in general, this includes women 35 and younger and women who needed chemotherapy in addition to hormone therapy) ovarian suppression and exemestane (Aromasin) should be an option you discuss with your doctor.

If you are not at higher risk of recurrence, you will want to think about the side effects of ovarian suppression. These drugs (or having your ovaries removed) puts you into immediate menopause and you are likely to experience many of the side effects that go with it, such as hot flashes, night sweats, and vaginal dryness. You can learn more about how to manage these symptoms here.

Another thing to consider if you are premenopausal is that, depending on your age, it is possible that while you are on tamoxifen, you may become menopausal. At that point, it will be important for you to talk with your doctor about whether you should switch from tamoxifen to an aromatase inhibitor.

If you do decide to use an AI as adjuvant therapy, you should have your bone density monitored during your treatment. Some oncologists recommend that premenopausal women try to decrease their risk of bone loss by also taking a bisphosphonate, a drug used to treat osteoporosis. You should speak with your oncologist about this as well. Whether you take tamoxifen or an AI, you should to try to maintain your bone health by doing weight-bearing exercises. You also need make sure that you get adequate amounts of vitamin D and calcium in your diet, taking supplements if necessary.

It would be easy to assume that because both tamoxifen and raloxifene (brand name Evista) are approved as treatments to reduce breast cancer risk in high-risk women, that raloxifene could be used as a breast cancer treatment too. But that's not the case. Raloxifene has never been approved for use as a drug to treat breast cancer.

The FDA approved raloxifene for use as osteoporosis prevention in 1997 and then as an osteoporosis treatment in 1999. When it began to look like raloxifene reduced breast cancer risk in postmenopausal women with osteoporosis, researchers decided to test raloxifene in the prevention setting. This resulted in the STAR trial, which tested raloxifene against tamoxifen as breast cancer prevention in postmenopausal women. Also, even though tamoxifen is not approved to treat osteoporosis, it is actually just as good as raloxifene is at preventing bone fractures.

Tamoxifen may cause some menopausal side effects, but it won't put you into menopause. The drugs used in chemotherapy work by killing cells and they often do enough damage to the ovaries to shut them down. We call this chemical menopause, or "chemopause." Tamoxifen doesn't do that, even though it may make you feel as though you are going through menopause. Instead, it works by blocking the effects of estrogen in the breast and certain other tissues, including the regions of the brain that control body temperature and possibly some aspects of memory and reasoning. It also may overstimulate the growth of the endometrium, or uterine lining, which is why it can increase a woman's risk of uterine cancer.

Your ovaries continue to produce estrogen, and eggs during tamoxifen treatment. In fact, tamoxifen was first used as a fertility treatment to induce ovulation. Although you can get pregnant while you're taking tamoxifen, it isn't advised because tamoxifen can cause birth defects. You should use birth control during tamoxifen treatment and for at least two months afterward, until the drug is out of your system.

Bone and joint pain are two of the most common side effects associated with aromatase inhibitors: anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin). You should talk to your doctor about the side effects you are experiencing and how they are affecting your quality of life. Tamoxifen remains an excellent choice for hormone therapy, unless you are HER2-positive. We encourage you to talk to your doctor about switching to tamoxifen, or switching back if you were already on it. You should also talk to your doctor about how long you will be on hormone therapy. The standard of care for tamoxifen is 10 years, but you may only need to stay on an AI for five years.

You have had quite a reaction to tamoxifen and quality of life is something that has to be considered as you think about treatment for your cancer, especially given the severity of the side effects you describe. (Many women have side effects from tamoxifen, but what you are describing is pretty unusual.)

If you are postmenopausal, you may want to consider switching to an aromatase inhibitor. If you are premenopausal, you may want to consider switching to toremifene (Fareston), which is a cousin to tamoxifen and is a reasonable thing to take if tamoxifen can't be tolerated. Although toremifene has not been tested head-to-head against tamoxifen, it has been studied in women whose cancer has metastasized (spread to other parts of the body). In that setting, toremifene has been found to have about the same benefit as tamoxifen and to have similar side effects.

If you decide to stay on tamoxifen, you may want to stop taking it for two weeks and then restart gradually by first taking five mg, then going up to 10 mg, then 15mg, and then 20mg to see if that makes the drug easier for you to tolerate. If you develop the same symptoms even with the slow progression onto tamoxifen, then you will need to weigh the benefit you might be getting from the tamoxifen against the impact the drug is having on your quality of life.

You may also want to discuss with your oncologist whether you should also be taking venlafaxine (Effexor), an antidepressant that when given at low doses can help reduce hot flashes from tamoxifen. To make a fully informed decision about whether to stay on any hormone therapy, you will need to talk to your oncologist about what your risk of recurrence is, and how much hormone therapy will reduce that risk.