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  » Medical Topic Archive  »  Adjuvant Treatment for Cancer Breat

ADJUVANT TREATMENT FOR CANCER BREAT

Tamoxifen

Tamoxifen is a powerful drug that works against hormone-receptor-positive breast cancer.

It is effective in women of all ages and at all stages of disease, and even in women without a personal history of breast cancer but who are at increased risk for the disease.

It reduces the risk of breast cancer coming back after surgery for DCIS (ductal carcinoma in situ) and early-stage invasive disease.

It can help stop the growth of advanced (metastatic) disease.

It can decrease the risk of a new breast cancer starting. Tamoxifen also helps keep bones strong and cholesterol levels low.

Tamoxifen is taken by pill, usually once a day, for up to five years. But for women with metastatic disease, the medicine is continued as long as it is working well.

Tamoxifen should only be prescribed if the potential benefits are likely to outweigh the side effects. And while you are on any medicine, it's important to see your doctor regularly to make sure that the drug is working well for you, and to discuss other appropriate options.

Most doctors recommend that you take tamoxifen for two to three years and then switch to an aromatase inhibitor. However, you can still get a lot of benefit if you have been taking tamoxifen longer than three years and then switch. You should be checked regularly so that you and your doctor can re-evaluate the drug's potential side effects and benefits to you.

In this section you'll learn more about whether tamoxifen might be a good treatment choice for YOU. In the coming months, check out our new Hormonal Therapy section, which will include information on tamoxifen.

Side Effects of Tamoxifen

Tamoxifen's potential for unwanted side effects depends on: whether you have any personal history of blood clots or endometrial cancer, and your individual susceptibility to hot flashes associated with menopause. Although most of the side effects of tamoxifen are not life-threatening, they may still decrease your quality of life, sometimes to a considerable degree. Benefits, risks, and personal comfort all have to be factored into your personal decision.

In this section you'll learn more about: Potentially serious side effects of tamoxifen Tamoxifen side effects that aren't life-threatening (but may drive you crazy) Tamoxifen side effects that rarely happen or haven't been proven


Serious Side Effects

Blood clots (thrombosis)

The most common place for a blood clot to form is in the leg veins. These clots are dangerous because they can break loose, travel to the lung, and clog a vital blood vessel. This is called a pulmonary embolism. If you have had any history of blood clots, tamoxifen will probably not be an option for you.

The possibility of pulmonary embolism is less than 1%, meaning that it's likely to affect less than one woman in a hundred taking tamoxifen. If you are taking tamoxifen, call your doctor if you notice any new swelling, redness, discomfort, or warmth in your legs, which might be the first sign of a clot forming there.

Endometrial cancer

In post-menopausal women whose uterus has not been removed in a hysterectomy, another serious risk associated with tamoxifen treatment is cancer of the lining of the uterus (endometrial cancer).

Whether you take tamoxifen or not, if you have had breast cancer you have an increased risk of endometrial cancer. Tamoxifen makes this risk a bit higher. The longer you take tamoxifen, the higher your risk of developing a tamoxifen-related endometrial cancer. (But the risk is still low, less than 1%, even if you take tamoxifen for ten years.) If you are diagnosed with endometrial cancer within the first two years of taking tamoxifen, the cancer was most likely there before you started taking the drug.

Whether or not it is related to tamoxifen use, endometrial cancer can usually be detected in the early stages, and it is usually curable with surgery. There are usually (but not always) clear early warning signs. Unexpected vaginal bleeding is usually the first sign of trouble, and should be reported to your doctor immediately.

Related Areas:

Learn how to stay on track with tamoxifen treatment, and why it's so important to stick with it.

Professional societies of gynecologists and oncologists recommend that you see your gynecologist annually for an exam. Of course, if you have any unusual vaginal bleeding or other disturbing symptoms, you should see your doctor immediately. But a routine "Pap smear" can't detect endometrial cancer. This test only evaluates the health of the cervix. The cervix is the mouth of the uterus—NOT the inner lining (endometrium). The best way to evaluate the endometrium is via ultrasound testing or a uterine tissue sample that requires a biopsy. A biopsy is usually done in the doctor's office. It is a quick procedure that doesn't usually require any anesthesia. Experts don't recommend that you have routine endometrial ultrasounds and biopsies, though, unless you have symptoms. Discuss this issue with your doctor.

If you have had a hysterectomy (removal of the uterus) because of endometrial cancer, you may not be able to take tamoxifen to treat your breast cancer. But if you have had a hysterectomy for a benign cause, such as fibroids, endometrial hyperplasia (an overgrowth of normal endometrial cells), or endometrial polyps (fingerlike projections made up of normal cells), you don't have to worry about endometrial cancer. If you are still menstruating every month, then you have a very low risk of endometrial cancer.

Other uterine effects

If you have a history of endometriosis—a non-cancerous condition in which endometrial (uterine lining) cells grow outside the uterus in the belly cavity, on the ovaries, or on the bladder—tamoxifen can make this condition worse. Tamoxifen can also affect the uterus wall, which can lead to uneven thickening of the muscle and supportive tissues within the wall of the uterus. The result can be fibroids (ball-like overgrowths of the tissues in the wall of the uterus), or there can be bumpy irregularities in one area or throughout the uterine wall. These changes can make it difficult to assess the endometrium by ultrasound. This is because the ultrasound study may show a thickened or uneven endometrium, when the change really is in the underlying uterine wall.

In June 2002, a new warning was added to the tamoxifen label. According to this warning, women who take tamoxifen have a slightly higher risk than other women for developing uterine sarcoma. Uterine sarcoma is cancer of the muscle wall of the uterus. The risk for uterine sarcoma with tamoxifen is less than 1%.

For most women who are considered good candidates for tamoxifen, its anti–breast cancer benefits usually outweigh the risk that it could contribute to development of an endometrial cancer or uterine sarcoma.

Less Serious Side Effects

Figure out how long it takes between taking a dose of tamoxifen and having a hot flash. Then determine what time of day is the least inconvenient for you to have a hot flash, and time your medication to suit your schedule. Many women using this method choose to take their full dose (twenty milligrams) at night before going to bed.

If you're having severe hot flashes no matter what you've tried, and tamoxifen therapy is an important part of your fight against breast cancer, talk with your doctor about this plan: stop tamoxifen for a week or two, and then restart with five milligrams, and slowly increase the dose up to twenty milligrams daily. Your body may adjust better with this slowly increasing dosage.

Hot flashes

Tamoxifen blocks the effects of estrogen in many areas of your body. Natural menopause is due to the loss of estrogen production in your body, leading to similar signs and symptoms. Therefore, tamoxifen can produce menopausal side effects that include vaginal dryness, mood changes, and hot flashes. These sudden flushes can make you miserable and undermine your quality of life, but they do not endanger your life.

Most women find hot flashes to be the worst side effect from tamoxifen. About half of the women who take tamoxifen are affected by them. You may find that regular exercise helps moderate the problem. Some women adjust to the hot flashes from tamoxifen. Others grow to tolerate the problem, expecting it to decrease over time. Over a number of months it usually eases somewhat.

The menopausal symptoms brought on by tamoxifen tend to be more intense in pre-menopausal women than in older women. Tamoxifen alone does not produce permanent early menopause. If you were menstruating regularly before tamoxifen, and tamoxifen stopped or disrupted your menstrual cycles, then your cycles will probably return to your pre-treatment pattern when you stop taking the medication. But the closer you are in age to your own, natural menopause, the more likely you are to slide into menopause a little sooner if you are taking tamoxifen.

Fertility issues

If you are on tamoxifen and are pre-menopausal, you may still be fertile. If you do not want to get pregnant, you must use a barrier form of birth control (such as condoms or a diaphragm). Oral contraceptives contain estrogens, which are not known to be safe for women who have had breast cancer.

Personal Quote

Tina, 35, stayed on tamoxifen for two years, but the hot flashes and other menopausal symptoms, the fear of side effects, and the stress of feeling so out of step with other women her age finally were too much for her. "I gave it up. I want to try some alternatives, be a little kinder to my body, and enjoy my 30-something age a while longer." It's also especially important, if you are fertile, to stick to your daily dose schedule of tamoxifen. That's because if tamoxifen is taken on and off, it can actually stimulate the ovaries like a fertility drug. If you want to get pregnant, stop the tamoxifen before you start trying to conceive, because the drug should not be taken during any stage of pregnancy.

If you do get pregnant while on tamoxifen and you want to keep the pregnancy, stop the tamoxifen and don't drive yourself crazy worrying about the effect that a month or so of tamoxifen might have had on the baby. No birth defects in people are known to have been caused by tamoxifen (just in an occasional laboratory rat).

Changes of the vagina

You may notice a watery or bad-smelling discharge, dryness, irregular periods, or thinning of the vaginal wall while on tamoxifen. Just as many women note an increase in vaginal discharge as report dryness. Infrequently, intercourse may become painful, which can decrease your sexual activity or bring it to a halt. Discuss any vaginal changes with your doctor. Again, any new pattern of vaginal bleeding requires immediate medical attention to rule out cancerous change of the endometrium (lining of the uterus).

Nausea and vomiting

A problem for about 10% of women on tamoxifen, nausea and vomiting usually stops in a couple of weeks. It's uncommon for it to last more than a few months. This can be another unpleasant experience, even if it poses no danger.

Weight gain

Chemotherapy, and the steroids that are given with it, causes weight gain in many women. That weight gain may persist and continue to increase after chemotherapy, while you are on tamoxifen. Like many women, you may be certain that taking tamoxifen makes you gain weight and makes it nearly impossible to lose weight. But two of the major studies conducted in the United States and Canada by the National Surgical Adjuvant Breast and Bowel Project (NSABP, a cooperative research group) showed that women taking a placebo (a sugar pill) were just as likely to gain weight as women taking tamoxifen.

Expert Quote

"One woman after another tells me about this unending battle with weight gain: 'I put on 25 pounds, and it's real hard to get it off. It's been three years and I'm still trying!' I hear this over and over, but so far, clinical trials show that weight gain is just as common on placebo (fake pill) as it is on tamoxifen. Losing weight becomes much harder as we grow older, but it can still be done with exercise and very careful changes in your diet. Be nice to yourself; don't punish yourself—you also need tons of encouragement and willpower—and most of that has to come from you." —Marisa Weiss, M.D.

There are many possible reasons for this weight gain.

You may have gained weight during the chemotherapy before taking tamoxifen.

You may be less physically active but eating as much as (or more than) before. And you may need FEWER calories to maintain the same weight because of menopausal changes in your overall metabolism.

You may have stopped smoking and found yourself snacking more instead.

You may be struggling with a wounded self-image, and fighting depression, which can lead to overeating. If you haven't gained weight in the first six months of tamoxifen use, you're probably not going to have the problem. A few women actually LOSE weight, and some women who have gained weight do manage to lose it over time.

Mood swings and depression

You may feel moody or depressed when you take tamoxifen, but it isn't clear that those feelings are

caused by tamoxifen alone. Two of the major studies conducted in the United States and Canada by the National Surgical Adjuvant Breast and Bowel Project (NSABP, a cooperative research group), also found that depression, as these researchers measured it, was not more common in women taking tamoxifen than in women taking the placebo (sugar pill).

Expert Quote

"In my own practice, I've observed that women who have a tendency to mood swings and depression can experience more profound 'downs' while on tamoxifen. But trying to get your life back together after breast cancer can cause depression in the most well-adjusted woman." —Marisa Weiss, M.D.

Whatever the cause, depression that doesn't go away shouldn't be ignored. It should be evaluated and treated by an experienced professional. Depending on how severe a depression is, it can be treated with psychotherapy, medication, or both. You can try temporarily discontinuing or reducing your tamoxifen dosage, but this doesn't usually eliminate the depression. A short break in tamoxifen treatment may be worth trying if other anti-depression therapies are not effective and your oncologist says it's OK.

Some women on tamoxifen have reported anxiety attacks. If you experience anxiety attacks (unexplained fear, shortness of breath, tightness in the chest) that persist, you should seek medication, short-term counseling, or both.

This is a hard time in your life. Don't put up with unnecessary pain—either physical or psychological.

Seek help!
Loss of energy

Personal Quote

After taking tamoxifen for just a few months, Betsy had to talk herself into getting up off the sofa and out of the house to walk the short block to the beach. "The only other time I felt like such a cow was when I went on birth control pills. I'm determined to move myself around. I've always been someone who gets things done, and I'm not giving up on that image. If I can't shake this lethargy, I may stop taking tamoxifen." You may feel a loss of energy with tamoxifen treatment, just as you might with natural menopause. In both situations, there is less estrogen to provide the "go-go juice" of energy for some women. Actually, a whole list of things other than tamoxifen can steal your energy. Lack of exercise, weight gain, pain, hot flashes, fear, uncertainty, anxiety, and depression are all energy-robbers.

Hormonal Therapy

Keep in mind that hormonal (anti-estrogen) therapy is completely different from hormone replacement therapy (HRT), which many women take during or following menopause. HRT is not a breast cancer treatment, and once you have a breast cancer diagnosis, HRT is considered relatively unsafe.

Hormonal therapy is a very effective treatment against hormone-receptor-positive breast cancer. The main purpose of hormonal therapy (sometimes called anti-estrogen therapy") is to block the ability of the hormone estrogen to turn on and stimulate the growth of breast cancer cells. For women with

early-stage disease, the goal of hormonal therapy is to reduce the risk of the cancer coming back after surgery. For women with advanced or metastatic disease, the goal is to shrink down and get rid of as much cancer as possible.

There are six major kinds of hormonal therapy. The first two types block estrogen's ability to lock onto the estrogen receptor and turn on cell growth:

SERMs (selective estrogen receptor modulators) such as tamoxifen block the estrogen receptor.

ERDs (estrogen receptor downregulators)— Faslodex (chemical name: fulvestrant) is the only one—destroy the estrogen receptor.

The other four kinds of hormonal therapy reduce the amount of estrogen in the body:

Aromatase inhibitors, which reduce the amount of estrogen produced in post-menopausal women, include Arimidex (chemical name: anastrozole), Femara (chemical name: letrozole), and Aromasin (chemical name: exemestane).

For pre-menopausal women, there are medicines that shut down the ovaries' production of estrogen,

including Zoladex (chemical name: goserelin) and Lupron (chemical name: leuprolide).

Radiation to the ovaries can also stop their estrogen production.

Surgical removal of the ovaries dramatically lowers the amount of estrogen in the body.

The role of each of these hormonal therapies depends on a woman's stage of disease, menopausal status, overall medical condition, and personal considerations.

These medications can be given many different ways: alone, in combination, or one after the other. In January 2005, the American Society of Clinical Oncology published new guidelines for hormonal therapy for many different situations.

Hormonal therapy can be given before surgery or after surgery. It is not usually given during chemotherapy, because it works better after chemotherapy is over.

Hormonal therapy may also be recommended for women at high risk of breast cancer without a personal history of the disease.

In this section you can read about how hormonal therapies work, what the different types are, and which types might be right for YOU.

Herceptin

Herceptin (chemical name: trastuzumab) is a very effective treatment against HER2-positive breast cancer in women with stage II, III, and IV disease (medium to large cancers or cancers with lymph nodes involved or metastatic disease). It is given intravenously into the bloodstream once every one to three weeks.

Herceptin is called a targeted therapy because it targets breast cancers that make too much of the HER2/neu gene or HER2 protein. These cancers are called HER2-positive. Herceptin is also called an immune treatment because it is made of an immune system–like antibody that blocks the HER2 protein in cancer cells. Blocking the protein helps stop the growth of HER2-positive cancer cells. About one out of every four breast cancers is HER2-positive. HER2-positive breast cancers tend to be more aggressive than HER2-negative breast cancers.

Herceptin is only given to women with HER2-positive breast cancer. Herceptin is effective in women with metastatic and earlier stages of disease. It can: shrink down and get rid of cancer that has spread beyond the breast to other parts of the body, help shrink down a medium- to large-sized cancer in the breast before surgery, and reduce the risk of cancer coming back after surgery in

women with medium-sized cancer (two centimeters or larger) or if the lymph nodes are involved (no matter what size the cancer is).

Herceptin is currently approved by the U.S. Food and Drug Administration for women with metastatic disease, and is under review for women with earlier stages of disease.

In this section you'll learn more about how Herceptin works, who can benefit from it, how you take it, and what the side effects are.

The History of Herceptin

Herceptin (chemical name: trastuzumab) got its start in the 1970s, when researchers began using the new tools of molecular biology to find the genes that trigger various cancers. One scientist discovered a gene, called HER2/neu, or HER2, that directed the production of a protein that seemed to cause cancer in mice.

Then in the late 1980s, researcher Dr. Dennis Slamon showed that the aggressiveness of certain kinds of breast cancers was linked to how many copies of the HER2 gene they had. Breast cancers with the most copies of the HER2 gene spread the fastest. These tumors produced the most HER2 proteins, also called HER2 receptors. Dr. Slamon reasoned that if the HER2 receptors are associated with the aggressive spread of breast cancer, then a drug that could block the action of

those receptors might block or slow down the growth of the cancer. He convinced researchers at a

biotechnology drug company to make an antibody that could target the HER2 receptors. The antibody latches on to the HER2 receptors in breast cancer cells, and stops them from receiving signals that tell the cancer cells to grow. The antibody also alerts the immune system to selectively destroy the tumor cells that to which it binds.

Tests of this antibody showed that it was effective at stopping or slowing the spread of breast cancer for many women with metastatic tumors that made too many HER2 receptors. In 1998 these tests led the U.S. Food and Drug Administration (FDA) to approve Herceptin for the treatment of such women.

Herceptin gives women with metastatic HER2 positive breast cancer an important option for extending their lives. Ongoing research is looking at whether Herceptin may also help women with early-stage, non-metastatic breast cancer.


How Herceptin Works

Cancer cells are cells that grow in an uncontrolled fashion. Herceptin stops or slows the growth of

certain breast cancer cells by blocking the chemical

signals they need to grow.

Chromosomes inside every cell contain genes, which regulate the cell's growth, rest, and repair. The

genes do this by ordering the production of special proteins that tell the cells what to do. Each protein sets off a step in a chain of reactions, resulting in the desired cell activity—growth, rest, or repair.

Sometimes, if there's a problem with a gene or chromosome, the chain of reactions may not work

properly. For example, when there's too much of the HER2 gene, it orders an excess production of protein receptors on the surface of cancer cells, called HER2 receptors. Receptors are like ears, or antennae, on the surface of each cell that receive the signal to grow.

When HER2 receptors are turned on and get excited, they tell the cells to grow. With too many receptors, breast cancer cells pick up too many growth signals and start growing too much and too fast. One way to slow down or stop the growth of the cancer cells is to block the receptors so they don't pick up as many growth signals. That's what Herceptin does.

Herceptin is a special antibody protein medication that attaches itself to the HER2 receptors on the

cancer cells and blocks them from receiving growth signals. Herceptin can also alert the immune system to destroy the cancer cells it attaches to.

Because it doesn't usually attach to other types of proteins, Herceptin rarely affects other cells in the

body. This means that it causes few serious side effects.

How Herceptin Is Given

Herceptin + Taxol + Paraplatin Shows Promise

Past research has shown that for women with advanced HER2 positive breast cancer, the combination of Herceptin (chemical name: trastuzumab) plus the chemotherapy drug Taxol (chemical name: paclitaxel) is better than Taxol alone.

Herceptin can only be given intravenously, which means it is dripped into your body through a needle inserted into a vein. The first dose of Herceptin you get takes about 90 minutes. After that, it only takes about 30 minutes to get the other doses of Herceptin, which are usually given weekly in a doctor's office. Studies are looking at whether Herceptin can be given every three weeks instead of every week.

Unlike standard chemotherapy, which you take for a limited time, Herceptin is taken indefinitely in order to keep the breast cancer under control. Herceptin has not been used long enough to know yet if you can stop taking it after you appear to be free of breast cancer for a certain period of time. So if you have metastatic disease and start taking Herceptin, you continue to take it, unless:

Your doctor believes it is no longer effective for your situation, or Your doctor recommends that you stop the medication because of significant side effects.


Herceptin and Chemotherapy

Herceptin (chemical name: trastuzumab) and chemotherapy are two different kinds of medicines that are both very effective against stage II, III, and IV HER2-positive breast cancer. They each work in different ways, and they also work very well together or one after the other.

Herceptin is called a targeted therapy because it targets breast cancers that make too much of the

HER2/neu gene or HER2 protein. These cancers are called HER2-positive. Herceptin mainly targets

HER2-positive cancer cells and leaves most normal cells alone.

Related Areas:

Herceptin and Chemo Before Surgery Better Than Chemo Alone

Many different chemotherapy drugs can be given together with Herceptin or before or after Herceptin, including:

Taxotere (chemical name: docetaxel), Taxol (chemical name: paclitaxel), 5-fluorouracil (5-FU),

Xeloda (chemical name: capecitabine), Navelbine (chemical name: vinorelbine), Gemzar (chemical name: gemcitabine), and Cytoxan (chemical name: cyclophosphamide). Adriamycin (chemical name: doxorubicin) and epirubicin (brand name: Ellence) are given before or after Herceptin (not in combination).

Most of these medicines kill cancer cells by interfering with cancer cell growth and repair. But

because chemotherapy can also affect normal cells, it causes more side effects than Herceptin.

Herceptin and chemotherapy are very effective in women with metastatic and earlier stages of HER2-positive breast cancer. Together, they can: help reduce and get rid of cancer that has spread

beyond the breast to other parts of the body, shrink a medium to large-sized cancer in the breast

before surgery, lower the risk of cancer coming back after surgery in women with medium-sized cancers (two centimeters or greater), or if lymph nodes are involved (no matter that size the cancer is).

Herceptin and chemotherapy are used together in many different ways, depending on your stage of disease, treatments you've already had, how you respond to ongoing therapy, your overall medical condition, and personal considerations.

Will Herceptin Work for You?


If you are one of the 25% of women with metastatic breast cancer with tumors that have too many copies of the HER2 gene or too many HER2 receptors, Herceptin may work to slow down or stop the growth of the cancer.

Two tests are used to figure out if the cancer is likely to respond to Herceptin. One test measures HER2 receptor protein (IHC), and the other test counts copies of the HER2 gene (FISH):

IHC (ImmunoHistoChemistry)

IHC is the most commonly used test to see if a tumor has too much of the HER2 receptor protein on the surface of the cancer cells.

The IHC test gives a score of 0 to 3+ that indicates the amount of HER2 receptor protein in tumors. If the tumor scores 0 to 1+, it's called "HER2 negative." If it scores 2+ or 3+, it's called "HER2 positive."

Women with IHC positive scores tend to respond favorably to Herceptin. The drug is not considered effective for tumors with IHC scores of 0 or 1+.

It's important to remember that results on the IHC test may vary from lab to lab, and that some labs are more proficient at HER2 testing than others. Discuss with your doctor whether you might want to get a FISH test, especially if you have a 1+ or 2+ result from IHC. That way you can get another measure of whether the tumor might respond well to Herceptin.

The IHC test results are most reliable for fresh or frozen tissue samples. IHC tends to be an unreliable way to test tissue that's preserved in wax or other chemicals. FISH testing is the preferred way to assess preserved tissue samples.

FISH (Fluorescence In Situ Hybridization)

The FISH test looks for the HER2 gene abnormality. This test is the most accurate, but less available, way to find out if a breast tumor is likely to respond to Herceptin. The FISH test shows how many copies of the HER2 gene are in tumor cells. This gene directs cells to make the HER2 protein. The more copies of the gene, the more HER2 receptors the cells have.

With the FISH test, you get a score of either "positive" or "negative" (some hospitals call a negative test "zero"). If the tumor is "FISH positive," it will probably respond well to Herceptin.

You can find out more about these tests, and how the results are reported in your pathology report, in our section on Your Pathology Report.

So far, doctors have only tested Herceptin extensively in women with metastatic HER2 positive breast cancer. For women with non-metastatic breast cancer, Herceptin is available in clinical trials. Some doctors, however, prescribe Herceptin "off-label" for women with non-metastatic breast cancer. "Off-label" means prescribing a drug for a situation or disease that the FDA hasn't approved it for.

Herceptin Side Effects


Herceptin has some side effects, but the good news is that it doesn't cause the hair loss and nausea associated with most chemotherapy drugs.

Mild side effects

Herceptin causes flu-like symptoms in about 40% of the women who take it. These symptoms may include fever, chills, muscle aches, or nausea. These side effects generally become less severe after the first treatment. Other side effects, including low white or red blood cell counts, diarrhea, and infections, are seen in some women receiving Herceptin in combination with chemotherapy, but are rarely seen in women taking Herceptin alone.

Serious heart side effects

Less commonly, Herceptin can damage the heart's ability to pump blood effectively. Rarely (about 5% of the time), the heart damage is bad enough that women experience stroke or life-threatening congestive heart failure—a condition in which the heart can't pump effectively. Slightly more often (about 7% of the time), Herceptin causes mild heart failure.

Women who experience mild or more serious heart damage can stop taking Herceptin and start taking heart-strengthening medications. This often brings heart function back to normal.

While heart damage can be more severe when Herceptin is given along with other chemotherapy drugs known to cause heart damage, including Adriamycin (chemical name: doxorubicin) and possibly other drugs like it.

Taking Herceptin with the chemotherapy drug Taxol (chemical name: paclitaxel) does not increase your risk of severe heart damage. Studies have shown that this combination causes only slightly more mild heart damage than Herceptin alone. Women in clinical trials who are receiving Herceptin plus Taxol are being watched very closely for this effect.

Testing your heart before and during Herceptin treatment Before starting Herceptin therapy, you should have an echocardiogram or a MUGA scan to check how well your heart is functioning.

An echocardiogram uses sound waves to take detailed pictures of the heart as it pumps blood. For this quick test, you lie still for a few minutes while a device that gives off sound waves is briefly placed on your ribs, over your heart. There is no radiation exposure with this test.

A MUGA (multigated blood-pool imaging) scan takes about an hour. In this test, a tiny amount of

radioactive material is injected into a vein in your arm. This material temporarily hooks onto your red blood cells. You lie still while a special camera that can detect the radioactive material takes pictures of the blood flow through your heart as it beats. When you first start taking Herceptin, your doctor might want you to have MUGA scans or echocardiograms every few months to detect any sign of heart failure. But after you've been on Herceptin for a while, you may need a heart-monitoring test only every 6 months or so. This is because heart failure is less likely to occur the longer you take Herceptin.

If you're taking Herceptin, be sure to notify your doctor immediately, or go to the nearest emergency

room, if you develop any symptoms of heart failure. These symptoms include shortness of breath, difficulty breathing, a fast or irregular heartbeat, increased cough, and swelling of the feet or lower legs.

Serious lung side effects

According to Genentech, the company that makes Herceptin, 62 of the approximately 25,000 women who had taken Herceptin as of 2001 had a serious reaction to the medication. There were two types of serious reactions: allergic–like reactions and lung reactions. Symptoms of the allergic–like reactions included hives, wheezing, and trouble breathing because of swelling and muscle spasms of the airwas. Lung reactions included swelling of the lung, low blood pressure, or fluid buildup around the lungs (called pleural effusions).

Fifteen of the 62 women with serious reactions ultimately died of complications from these reactions. Since approximately 25,000 women have taken Herceptin, the chance of these life–threatening reactions is quite rare, much less than 1% (15 out of 25,000). In most cases (about 75%) this reaction happened within the first 24 hours of the first dose of Herceptin. The rest of the time, it usually happened within the first week of the first dose. Only occasionally did reactions occur with the second or later doses.

The reactions are more severe if you've already had lung disease, such as asthma or emphysema, or if the breast cancer has spread significantly into your lungs.

If you are currently undergoing treatment with Herceptin and have been tolerating it well, you're

very unlikely to develop these serious reactions.

Even though the severe side effects are relatively rare, your doctor should check you carefully for any heart or lung problems before starting to treat you with Herceptin. You should also be monitored closely for these serious side effects during treatment.

Systemic Treatment: The Whole Body The goal of systemic therapy is to get rid of any

cancer cells that may have spread to another part of the body. It's an "insurance policy" that may be used even if there is no direct proof that cancer has spread. If the cancer HAS spread and formed tumors elsewhere, systemic treatment can help shrink the cancer and, it is hoped, lead to remission.

Systemic treatment decisions are made based on "personality features" of the cancer. The "meaner" the cancer's personality, the higher the risk of cancer spread, and the greater the need for systemic

treatment. The milder the personality, the lower the risk of spread, and the smaller the need for systemic management.

There are four main types of systemic therapy:

Anti-angiogenesis

Hormonal (anti-estrogen) therapies are medicines usually given by pill or, less commonly, by injection under the skin. These medications either 1) reduce the amount of estrogen in your body, or 2) block estrogen's effects, in order to inhibit cancer cell growth throughout your body.

Chemotherapies are medicines given by pill or directly into the bloodstream (through a needle or port) that destroy cancer cells. Chemotherapy works by interfering with the cancer cells' ability to reproduce and function from day to day.

Immune therapy is a very new area of medicine that attempts to use or imitate the body's own system for fighting disease, to defeat the cancer. The name immune therapy comes from the immune system. The goal may be "active immunity"—to stimulate or trick the body's defenses into blocking or counteracting cancer cell activity. Vaccines fall into this category. Or the goal may be "passive immunity," which involves giving the body a fighting protein or "antibody" it lacks, so that the immune system can do its job against the cancer. The name "passive" is used because the body isn't required to do the fighting work.

Currently, only one immune therapy, Herceptin, is widely available. It is given directly into the

bloodstream (through a needle or port). Herceptin is only appropriate for women with advanced breast cancer who have a particular cancer gene, called HER2/neu, that is overactive or is being "overexpressed." Herceptin is an example of a "passive immunity" therapy. Special immune proteins (antibodies) in the medication find and stop the bad-acting proteins made by the HER2/neu cancer genes. Halting this protein action brings cancer cell growth under better control.

With more research, vaccines that work with the immune system in different ways—for a wider range of women and cancer types—will become available.

Anti-angiogenesis therapies halt the growth of new blood vessels that bring nutrients to the cancer

cells—in other words, you "starve" the tumor of things it needs to grow and survive. Currently, these treatments are available only in clinical trials, on a very limited basis.


Treating Invasive vs. Non-Invasive Cancer

Hormonal Therapy recurrence

For women with non-invasive breast cancer, hormonal (anti-estrogen) treatment may be recommended for its ability to 1) reduce the risk of a recurrence of the same cancer, and 2) reduce the risk of developing a new cancer in the same or the other breast. The most common agent prescribed in this category is tamoxifen (also called Nolvadex). Chemotherapy is never used for non-invasive breast cancer, since this type of cancer does not spread beyond the breast.

Invasive breast cancer that is not metastatic
Treatment options for breast cancer with little or no lymph node involvement

Benign breast disease increases breast cancer risk; tamoxifen helps lower it

Systemic treatment may benefit some women who have invasive breast cancer without lymph node involvement. Hormonal (anti-estrogen) therapy is usually recommended when the cancer tests positive for either estrogen or progesterone receptors ("hormone-receptor-positive" cancer). Hormonal therapy may be given alone or in addition to chemotherapy. Tamoxifen (also called Nolvadex) is the most commonly prescribed agent.

Chemotherapy may be recommended to some women with a small cancer (two centimeters or less; "stage 1" cancer). The most common choices are Adriamycin (chemical name: doxorubicin) with cyclophosphamide for four cycles (AC x 4) or cyclophosphamide, methotrexate, and fluorouracil for six cycles (CMF x 6). Other combinations of chemotherapy may be considered within or independent of a clinical trial. A more aggressive regimen may be recommended for a woman with a medium to large tumor (over three to five centimeters). The decision between these treatments

depends on the many individual "personality features" of a particular breast cancer, as well as your overall medical condition and your personal style of making decisions.

For women who have invasive breast cancer that involves lymph nodes, chemotherapy is usually

recommended as the first systemic treatment. The treatment option most commonly prescribed is

Adriamycin (chemical name: doxorubicin) with cyclophosphamide for four cycles (AC x 4), followed by four cycles of Taxol (chemical name: paclitaxel) (T x 4). Some women may choose a somewhat less aggressive approach that still offers substantial benefit.
These options include: AC x 4

Cyclophosphamide, Epirubicin (similar to Adriamycin),

fluorouracil for six cycles (CEF x 6)

Cyclophosphamide, methotrexate, and fluorouracil for

six cycles (CMF x 6).

Other chemotherapy options may be offered to women who participate in a clinical trial. Which one of all of these regimens is best for you depends on the many individual "personality features"

of a particular breast cancer. Longer or more aggressive treatment is not necessarily better. How

long you take a systemic treatment; when you switch to another; whether you take it before, after, or before AND after surgery and radiation—these decisions also depend on your individual breast cancer factors. Base your treatment decisions on your unique situation, including consideration of your overall medical condition and your personal style of making decisions.

Hormonal (anti-estrogen) therapy is also recommended when the cancer tests positive for either estrogen or progesterone receptors ("hormone-receptor-positive" cancer). It may be given alone or in addition to chemotherapy. Tamoxifen (also called Nolvadex) is the most commonly prescribed agent.

Invasive breast cancer that is metastatic

For women with metastatic disease, hormonal (anti-estrogen) therapy is usually recommended before chemotherapy for cancer that tests positive for either estrogen or progesterone receptors

("hormone-receptor-positive" cancer). Two classes of hormonal agents are usually considered separately, but sometimes in combination: aromatase inhibitors and selective estrogen receptor modulators (SERMs). Arimidex (chemical name: anastrozole), Femara (chemical name: letrozole), and Aromasin (chemical name: exemestane) are the aromatase inhibitors in current use. Tamoxifen and toremifene are the available SERMs.

If the cancer tests positive for over-expression of the HER2/neu oncogene, Herceptin is valuable, alone or in addition to other systemic therapies. One of the taxanes (Taxol [chemical name: paclitaxel] or Taxotere [chemical name: docetaxel] can be added to weekly Herceptin for significant additional benefit, usually with a reasonable level of associated side effects. Navelbine (chemical name: vinorelbine) and Herceptin is another regimen that can produce good results.

If the cancer tests negative for over-expression of the HER2/neu oncogene, weekly chemotherapy with Taxol or Taxotere is an effective option with acceptable side effects.

Chemotherapy is used first for cancer that tests negative for either estrogen or progesterone receptors ("hormone-receptor-negative" cancer), or for cancer that tests negative for overexpression of the HER2/neu oncogene. Chemotherapy is often given if hormonal or Herceptin therapy stops working.

There are many choices of chemotherapy. The same combinations of agents used for earlier-stage disease may be used here: AC, CMF, AC then T, CEF. Ther are also single agents that may be appropriate for metastatic disease: Taxol, Taxotere, Navelbine. Either Taxol or Taxotere can also be combined with Adriamycin (chemical name: doxorubicin). In addition, many new therapies are being introduced, as their efficacy is proven in clinical trials.

Which of these regimens will work best for you is a very individual equation. It depends on the many specific "personality features" of a particular breast cancer, at a specific point in time. Longer or more aggressive treatment is not necessarily better.

How long you take a systemic treatment; when you switch to another; whether you take it before, after, or before AND after surgery and radiation—these decisions also depend on your individual breast cancer factors. And your treatment decisions may well change over time. You may shift direction and try a new path. Be prepared to re-evaluate your treatment decisions periodically, with your medical team as guides. Base your decisions on your unique situation, including consideration of your overall medical condition and your personal style of making decisions.

Treatment Options for Node-Negative Disease

San Antonio Breast Cancer Symposium, December 2002,

Abstract #16

Fisher B, et al.

Until the late 1980s, women with invasive breast cancer that was node-negative—meaning no cancer cells were found in the lymph nodes—were often given only local treatment (targeted to a specific area of the body). That treatment was either mastectomy, or lumpectomy and radiation. Most of these women did well without having chemotherapy or hormonal therapy.

But some women with negative lymph nodes did have a recurrence of cancer with only local treatment. These women tended to have tumors with features that are known to be associated with an increased risk of recurrence.
These features include: medium or large size, high grade, no estrogen or progesterone receptors, and fast-growing.

New research was started in the 1980s and 1990s looking at the value of adjuvant therapy (treatment

given after surgery) for women with node-negative disease with one or more of these high-risk features. The results of these studies, presented below, showed that adjuvant therapy did offer significant benefit.

Researchers for the National Surgical Adjuvant Breast and Bowel Project conducted six studies, involving a total of over 11,600 women with negative lymph nodes. They followed the women for between 10 and 16 years. Here are the overall study results: For women with estrogen-receptor-negative tumors (tumors that do not need estrogen to grow): Chemotherapy alone is beneficial.

Chemotherapy plus tamoxifen (brand name: Nolvadex) is no more beneficial than chemotherapy alone. For women with estrogen-receptor-positive tumors (tumors that need estrogen to grow):

Tamoxifen alone is beneficial. Chemotherapy plus tamoxifen is better than chemotherapy alone.

Radiation after lumpectomy is beneficial even for women with very small tumors (one centimeter or less) The two studies covered below (abstracts #11 and #7) explore these issues further.

Hormone Receptor Status Determines Benefit from Hormonal Therapy or Chemotherapy for Women with Node-Negative Breast Cancer San Antonio Breast Cancer Symposium, December 2002,

Abstract #11 Castiglione-Gertsch, MM.

Background of the study: Between 1988 and 1999, researchers from the International Breast Cancer Study Group (IBCSG) conducted two studies to test the benefits of various chemotherapy and hormonal therapy combinations in women with node-negative invasive breast cancer.

Study design: In the first study—IBCSG Trial 8—researchers randomly assigned 1,063 pre-menopausal women with node-negative invasive breast cancer to one of three treatment groups:

Zoladex (chemical name: goserelin acetate), a drug that "shuts down" the ovaries so they stop making estrogen CMF chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil)

CMF chemotherapy followed by Zoladex In the second study—IBCSG Trial 9—researchers randomly assigned 1,669 post-menopausal women with node-negative invasive breast cancer to one of two treatment groups:

Tamoxifen

CMF chemotherapy followed by tamoxifen Results: Researchers found that the effects of

treatment differed significantly depending on the estrogen receptor status of the tumors.

For women with estrogen-receptor-negative tumors, chemotherapy alone, and chemotherapy plus hormonal therapy, were much more effective than hormonal therapy alone. The researchers did not directly compare the effects of chemotherapy alone to those of chemotherapy plus hormonal therapy for these women. But other studies have shown that for this group, chemotherapy works just as well as chemotherapy plus hormonal therapy.

For women with estrogen-receptor-positive tumors, chemotherapy plus hormonal therapy was no better than hormonal therapy alone. This was especially true for women 40 years of age or older.

Hormone receptor status made a bigger difference in predicting response to treatment for women with negative nodes compared to women with positive nodes.

Take-home message: If you've been diagnosed with node-negative breast cancer, it's very important to discuss all your treatment options with your doctor even after surgery is done, when the full pathology results are available.

Most women will do fine without chemotherapy. Some women with certain tumor characteristics may do better with chemotherapy. For example, these studies show that if you have an estrogen-receptor-negative cancer, you may get a significant benefit from chemotherapy. The studies also suggest that if you have estrogen-receptor-positive breast cancer, you may do just as well with hormonal therapy as you would with the combination of both hormonal therapy and

chemotherapy. But other studies have shown that chemotherapy may add a small benefit even for women with estrogen-receptor-positive cancer. Chemotherapy may not add much benefit above and beyond hormonal treatment, but even if it adds a little bit, you might feel it's worth taking.

The decision to take or not to take chemotherapy is not simple. Keep in mind that hormone receptor status is only one of a number of factors in making the decision.

Also, new research is looking at ways to predict which women with node-negative disease will benefit from chemotherapy and which women will do just as well without it. One study on this topic is presented below (abstract #7).

A Promising New Method to Predict Whether Women with Hormone-Receptor-Positive Disease Will Benefit from Chemotherapy San Antonio Breast Cancer Symposium, December 2002, Abstract # 7

Harbeck N., et al.

Background and importance of the study: For women with estrogen-receptor-positive cancer and more than three lymph nodes involved with cancer, hormonal therapy plus chemotherapy is usually recommended.

But most women with node-negative (no cancer found in the lymph nodes) estrogen-receptor-positive breast cancer will do fine without any recurrence after only local treatment to the breast (mastectomy or lumpectomy with radiation).

Still, some women in this group might have a problem with recurrence. What everyone is trying to figure out is: Who needs chemotherapy, and who would do just as well without it?

Studies like the one reviewed above (abstract #11) suggest that women with node-negative,

estrogen-receptor-positive cancer may not get any additional benefit from adding chemotherapy to a

treatment plan that already includes hormonal therapy (such as Zoladex or tamoxifen).

But this doesn't rule out the possibility that chemotherapy has some benefit for some women, even if

it's very small. And for many women, deciding whether or not to take chemotherapy is still very difficult: Do the benefits—no matter how small—outweigh all the side effects?

Study design and results: In this study, researchers tested a new method to see which women with

estrogen-receptor-positive cancer can benefit from chemotherapy. Some of the women had node-negative cancer, and some had node-positive cancer. The method that was tested measures levels of "invasion factors" uPA and PAI-1 in the breast tumor. These are proteins that make it easier for tumors to invade surrounding tissue and spread to other parts of the body.

The researchers checked whether women with estrogen-receptor-positive tumors and high levels of

uPA and PA-1 in their tumors would benefit from having chemotherapy in addition to hormonal therapy.

The researchers studied over 3,400 women with estrogen-receptor-positive tumors. They found that for all the women in the study, chemotherapy significantly lowered rates of recurrence IF the tumor had high levels of uPA, PAI-1, or both. For women with LOW levels of the proteins, chemotherapy did not add a significant benefit. These results applied to all the women, regardless of lymph node status.

Conclusion and take-home message: These study results suggest that a new test measuring tumor levels of uPA and PA-1 may help predict which women with estrogen-receptor-positive tumors are most likely to benefit from chemotherapy in addition to hormonal therapy. This is especially important information for women with no lymph node involvement. That's because

until now it has been very difficult to tell whether chemotherapy will add any benefit for such women beyond that of hormonal therapy.

If you have hormone-receptor-positive, node-negative breast cancer, it's important to discuss all your treatment options with your doctor. These include (1) no further treatment, (2) hormonal therapy alone, and (3) hormonal therapy plus chemotherapy.

The test in this study is brand new and only available in a few places. Your doctor will most likely use other, more standard tumor and staging factors (such as tumor size, growth rate, grade, and lymphatic invasion) to decide what treatment options are best for you.

Still, the new test may be helpful if those other factors put you into the "gray zone" and you're having trouble deciding what to do. If you find yourself in this situation, ask your doctor if you can get the tumor tested for uPA and PAI-1 levels. Make sure that you get the test done in a laboratory with experience doing this test. If the test shows that you have high levels, you may want to consider chemotherapy, even if your lymph nodes are clear. If the levels are low, you might feel more secure sticking with hormonal therapy alone.

Background and importance of the studies: "Adjuvant treatments" are the treatments you get after surgery to lower the risk of recurrence (the chance that the cancer could come back). Chemotherapy and tamoxifen are both effective in lowering the risk of recurrence for node-positive, estrogen-receptor-positive breast cancer. Chemotherapy also lowers the risk of recurrence for estrogen-receptor-negative tumors.

But there have been almost no studies on the best TIMING for these two types of treatment. In other

words, doctors aren't sure whether it's better to give chemotherapy and tamoxifen at the same time, or in sequence (one after the other). They also aren't sure whether it's better to give different chemotherapy drugs together or in sequence.

A related question is: Do tamoxifen and chemotherapy drugs interact with each other inside the body? And the next question is: How might this interaction affect the ability of these medications to reduce the risk of recurrence?

The results of three recent studies that looked at these important treatment issues were presented at the May 2002 Annual ASCO Meeting.

Chemotherapy and tamoxifen: together or in sequence?

The Southwest Oncology Group designed this study tosee whether tamoxifen alone works as well as tamoxifen plus chemotherapy, and also whether adjuvant chemotherapy and tamoxifen should be given together or in sequence (one after the other).

Study design: This study included 1,477 postmenopausal women with node-positive, estrogen-receptor-positive breast cancer. After surgery, each woman was randomly assigned to one of three groups: T = tamoxifen alone

CAF-T = Cytoxan (chemical name: cyclophosphamide), Adriamycin (chemical name: doxorubicin), and "5-FU" (chemical name: fluorouracil) followed by tamoxifen

CAFT-T = Cytoxan, Adriamycin, and 5-FU and tamoxifen, followed by additional tamoxifen

Results: After about eight and a half years of follow-up, the researchers found that:

Women taking either of the regimens with Cytoxan (CAF-T or CAFT-T) were significantly more likely to remain alive and disease-free than women who took only tamoxifen.

Women who took CAF followed by tamoxifen (CAF-T) were 18% more likely to be alive and disease-free than women who took CAF and tamoxifen at the same time (CAFT-T).


Conclusion:
These results suggest that women with node-positive, estrogen-receptor-positive disease should get both chemotherapy and hormone therapy after surgery, AND tamoxifen AFTER chemotherapy treatment is over The results of this study also suggest that tamoxifen and chemotherapy do interact in the body, somehow making each other less effective. More studies are

needed to find out exactly how they interact and why they affect each other the way they do.

Sequence of Treatment


Expert Answers:

After Surgery—What Next?

Your team of doctors will most likely recommend a particular sequence of treatment. Here is the most common "pathway":

Usually surgery is first.

If chemotherapy is going to be part of your care, it often goes second.

Radiation usually follows surgery and chemotherapy (when chemotherapy is given).

Tamoxifen or other hormonal (anti-estrogen) therapy is most commonly started after the other treatments have been given.


There are many exceptions to this sequence, however. For women with stage III or IV disease, chemotherapy may be given first to shrink large tumors and address cancer in the rest of the body, before major surgery. Some centers or clinical studies give chemotherapy and radiation together (not separately). There are also many other variations in timing and sequence.

Talk with your doctor to determine the best sequence of treatment for you.

Stages of Breast Cancer

Is it Stage II? Is it inflammatory breast cancer? Although learning where you fit in the scheme of

breast cancer stages can feel like a jail term ("So now I guess I'm stuck at stage III"), this information is a key part of figuring out how you and your doctors will approach your treatment. The purpose of the staging system is to help organize the different factors and some of the personality features of the cancer into categories, in order to: enlarge image
Tumor sizes:

3 spheres measuring 1 cm, 3cm, 5cm

best understand your prognosis (the most likely outcome of the disease)

guide treatment decisions, since clinical studies of breast cancer treatments that you and your doctor will consider are partly organized by the staging system, and

provide a common way to describe the extent of breast cancer for doctors and nurses all over the world, so that results of your treatment can be compared and understood.

This stage is used to describe non-invasive breast cancer. There is no evidence of cancer cells breaking out of the part of the breast in which it started, or of getting through to or invading neighboring normal tissue. LCIS and DCIS are examples of stage 0.

Stage I

This stage describes invasive breast cancer (cancer cells are breaking through to or invading neighboring normal tissue) in which

The tumor measures up to two centimeters, AND No lymph nodes are involved.

Stage II

This stage describes invasive breast cancer in which: The tumor measures at least two centimeters, but not more than five centimeters, OR Cancer has spread to the lymph nodes under the arm on the same side as the breast cancer. Affected lymph nodes have not yet stuck to one another or to the surrounding tissues, a sign that the cancer has not yet advanced to stage III. (The tumor in the breast can be any size.)

Stage III

Stage III is divided into subcategories known as IIIA and IIIB.

Stage IIIA

Stage IIIA describes invasive breast cancer in which: the tumor measures larger than five centimeters, OR there is significant involvement of lymph nodes. The nodes clump together or stick to one another or surrounding tissue.

Stage IIIB

This stage describes invasive breast cancer in which a tumor of any size has spread to the breast skin, chest wall, or internal mammary lymph nodes (located beneath the breast right under the ribs, inside the middle of the chest).

Stage IIIB includes inflammatory breast cancer, a very uncommon but very serious, aggressive type of breast cancer. The most distinguishing feature of inflammatory breast cancer is redness involving part or all of the breast. The redness feels warm. You may see puffiness of the breast's skin that looks like the peel of a navel orange ("peau d'orange"), or even ridges, welts, or hives. And part or all of the breast may be enlarged and hard. A lump is present only half of the time. Inflammatory breast cancer is sometimes misdiagnosed as a simple infection.

Get answers to questions about inflammatory breast cancer in our Frequently Asked Questions section.

Expert Quote

"When you're in the midst of the diagnosis and staging process, and the tumor information is coming back in bits and pieces, at many different times, it is an extremely stressful time in your life. Uncertainty really stinks! But you will feel SO much better once you know what you're dealing with, when your treatment plan has been worked out, and you start your treatment. Only then does much of that dreadful uncertainty lift, and you finally feel that you are doing something to get rid of the problem." —Marisa Weiss, M.D.

Stage IV

This stage includes invasive breast cancer in which a tumor has spread beyond the breast, underarm, and internal mammary lymph nodes, and a tumor may have spread to the supraclavicular lymph nodes (nodes located at the base of the neck, above the collarbone), lungs, liver, bone, or brain.

"Metastatic at presentation" means that the breast cancer has spread beyond the breast and nearby lymph nodes, even though this is the first diagnosis of breast cancer. The reason for this is that the primary breast cancer was not found when it was only inside the breast. Metastatic cancer is considered stage IV.

Additional staging information:

You may also hear terms such as "early" or "earlier" stage, "later" or "advanced" stage breast cancer.

Although these terms are not medically precise (they may be used differently by different doctors), here is a general idea of how they apply to the official staging system:

Early stage:
Stage 0
Stage I
Stage II

Later stage:
(stage II if there are many lymph nodes involved)
Stage III (IIIA, IIIB)

Advanced stage:
Stage IV

You may also hear the cancer described by three characteristics:
size (T stands for tumor),
node involvement (N stands for node), and
whether it has metastasized (M stands for metastasis).
The T category describes the original (primary) tumor:
TX means the tumor can't be measured or found.
T0 means there isn't any evidence of the primary tumor.
Tis means the cancer is "in situ" (the tumor has not started growing into the breast tissue).

The numbers T1-T4 describe the size and/or how much the cancer has grown into the breast tissue. The higher the T number, the larger the tumor and/or the more it may have grown into the breast tissue.

The N category describes whether or not the cancer has reached nearby lymph nodes:

NX means the nearby lymph nodes can't be measured or found.
N0 means nearby lymph nodes do not contain cancer.

The numbers N1-N3 describe the size, location, and/or the number of lymph nodes involved. The higher the N number, the more the lymph nodes are involved.

The M category tells whether there are distant metastases (whether the cancer has spread to other parts of body):

MX means metastasis can't be measured or found.
M0 means there are no distant metastases.
M1 means that distant metastases were found.

Once the pathologist knows your T, N, and M characteristics, they are combined, and an overall

"stage" of 0, I, II, III, IIIA, IIIB, or IV is assigned.

For example, a T1, N0, M0 breast cancer would mean that the primary breast tumor:

is less than two centimeters across (T1),
does not have lymph node involvement (N0), and
has not spread to distant parts of the body (M0).
This cancer would be grouped as a stage I cancer.

Tamoxifen, aromatase inhibitors and breast cancer: An interview with a Mayo Clinic specialist

Tamoxifen was the gold standard in adjuvant breast cancer therapy for more than 20 years. And there's no doubt that it provides substantial benefit to women with hormonally sensitive breast cancer. However, more information has come to light about a new class of drugs called aromatase inhibitors. This scientific evidence has established the value of aromatase inhibitors in preventing breast cancer recurrence, according to James Ingle, M.D., a cancer specialist at Mayo Clinic, Rochester, Minn.

Large clinical trials with thousands of postmenopausal women provide the basis for the use of aromatase inhibitors. These clinical trials investigate three aromatase inhibitors in various settings:

Anastrozole — used instead of tamoxifen as initial adjuvant therapy

Letrozole — taken after five years of tamoxifen therapy

Exemestane — taken after two to three years of tamoxifen for a total of five years of hormonal

therapy

Here Dr. Ingle interprets the findings from these clinical trials and addresses questions you may have about tamoxifen and aromatase inhibitors — including how they work and their effect on breast cancer.

What is tamoxifen and how does it work?

Tamoxifen (Nolvadex) is a synthetic hormone pill used to treat breast cancer. It's used:

As a treatment for women who have advanced (metastatic) hormone-sensitive breast cancer

As a preventive agent to reduce the risk of breast cancer in women at high risk of the disease

As an adjuvant treatment for women who have received a diagnosis of early-stage estrogen receptor positive breast cancer Tamoxifen belongs to a class of drugs known as selective estrogen receptor modulators. These drugs mimic the action of estrogen in your cardiovascular system and skeletal system and act as an anti-estrogen in breast tissue.

In many women with breast cancer, estrogen is thought to act as a fuel that promotes the growth of cancer cells. Tamoxifen blocks estrogen's effects on breast tissue, stopping or preventing the growth of cancer. In 1977, after many clinical trials that showed tamoxifen to be effective, the Food and Drug Administration (FDA) approved the drug for the treatment of women with metastatic breast cancer — breast cancer that has spread. In 1986, the FDA also approved the use of tamoxifen for reducing the risk of recurrence in women with early-stage breast cancer.

Adjuvant therapy: Extra treatment to keep cancer from

coming back

What are aromatase inhibitors and how do they work?

Aromatase inhibitors are drugs that reduce the levels of estrogen in your body. Anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin) are three such synthetic hormone pills approved by the FDA for treating advanced breast cancer — cancer that has spread. Of these three drugs, both anastrozole and letrozole have received FDA approval for adjuvant therapy for early-stage breast cancer. All three are very potent drugs — able to cause a marked reduction in your estrogen levels.

If you're premenopausal, your main source of estrogen is your ovaries. When you enter menopause, your ovaries stop producing estrogen, but your estrogen levels don't drop off completely. Estrogen is still present from another process in your body — the conversion of a substance from your adrenal glands into estrogen. Specifically, this substance is called androstenedione, and it circulates through your body to tissues such as muscle, fat and even breast cancers themselves, where it's converted to estrogen.

The conversion of androstenedione to estrogen takes place because of an enzyme called aromatase. Aromatase inhibitors stop the conversion of androstenedione to estrogen. Aromatase inhibitors differ from tamoxifen in that they actually reduce the amount of estrogen in your body. Tamoxifen, on the other hand, blocks estrogen's effects in your body by competing with estrogen for the estrogen receptor — the receptor to which estrogen binds in order to exert its effect.

What are the findings from the first study, which compares tamoxifen with anastrozole?

This study — known as the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial — compared tamoxifen with anastrozole as the treatment given after the removal of breast cancer. This large clinical trial evaluated five years of anastrozole use as adjuvant therapy in postmenopausal women with localized hormone receptor positive breast cancer. Investigators found that women taking anastrozole were less likely to experience a breast cancer recurrence than were the women taking tamoxifen.

The FDA has approved anastrozole as an adjuvant therapy option for postmenopausal women. The results from the ATAC trial suggest that the best treatment option for postmenopausal women with hormone receptor positive breast cancer is to bypass tamoxifen and start out immediately on five years of anastrozole as adjuvant therapy.

Regarding your choice of initial hormonal therapy, the best recommendation is to discuss with your doctor what is known about tamoxifen and anastrozole and make your own decision on which drug you wish to take.

What are the findings from the second study, which raises the question of what to do after five years of tamoxifen therapy?

A second clinical trial looked into a possible next step after tamoxifen therapy. Researchers evaluated the use of letrozole — another aromatase inhibitor — after five years of tamoxifen use in postmenopausal women who had been treated for breast cancer. Most experts believe five years of tamoxifen treatment for early breast cancer is the optimal duration — taking tamoxifen longer than five years isn't better for you, and in fact, may be harmful.

Study results showed that letrozole, when given after tamoxifen, reduced the risk of breast cancer

recurrence by almost half. Thus, letrozole provides a new extended adjuvant treatment option for women who have completed five years of tamoxifen therapy. If you've had breast cancer and you've taken tamoxifen for five years to prevent its recurrence, letrozole might be of value to you. Talk to your doctor about your options.

The decision whether or not to use letrozole will be based on a number of factors, including an estimate of your remaining risk of developing breast cancer. Potential benefits — that your risk of breast cancer recurrence may be cut almost in half — must be put into context with potential side effects, such as your risk of osteoporosis.

What are the findings from the third study, which examines switching to an aromatase inhibitor after two to three years of tamoxifen?

Results from a third clinical trial indicate that, instead of five years of tamoxifen, it may be better

to switch to an aromatase inhibitor after two to three years of tamoxifen. This trial, the Intergroup

Exemestane Study, randomized women who had already received two to three years of tamoxifen to one of two groups. Either they completed the five-year course of tamoxifen or they switched to the aromatase inhibitor exemestane to complete a total of five years of hormonal treatment.

This study demonstrated that the women who switched to exemestane had almost a one-third reduction in risk of recurrence, compared with women who remained on tamoxifen. Cancers in the opposite breast were also reduced by more than half in the women who switched to exemestane. Researchers concluded that women who elect to start tamoxifen appear to benefit from switching to

exemestane after two to three years — rather than waiting until they've completed the five-year course of tamoxifen.

The findings from all three of these studies apply only to women who are postmenopausal. Aromatase inhibitors haven't been shown to benefit women who are still having menstrual periods.

Based on this evidence, what conclusion can you draw about the use of aromatase inhibitors in early breast cancer?

A great deal of discussion has taken place regarding the role of aromatase inhibitors in early-stage breast cancer.

The American Society of Clinical Oncology (ASCO) convened an expert panel to examine all of the

available data. The ASCO panel recommends that optimal adjuvant hormone therapy for a postmenopausal woman with receptor-positive breast cancer include an aromatase inhibitor as initial therapy or after treatment with tamoxifen.

The panel further recommends that each woman and her doctor weigh the risks and benefits of all potential therapies based on individual circumstances.


What conclusion can you draw?

Consider aromatase inhibitors firmly established for use in early-stage breast cancer to reduce the risk of recurrence. Data from several other clinical trials, in addition to the three noted above, will be published soon. These data provide further evidence in support of aromatase inhibitor use for early-stage breast cancer.

What are the side effects of tamoxifen?

Common side effects of tamoxifen include hot flashes, vaginal discharge or bleeding, and menstrual

irregularities. Some women also experience hair loss or skin rashes.

Although it's uncommon — with a less than 1 percent incidence — women who take tamoxifen are at increased risk of developing blood clots in their lungs and legs. These women also have a small risk of developing two different types of uterine cancer. If you're taking tamoxifen and experience any sudden chest pain, shortness of breath, coughing up blood, pain or swelling in your legs, or vaginal bleeding, contact your doctor immediately.

What are the side effects of aromatase inhibitors?

The side effects of aromatase inhibitors are generally mild. Women in recent clinical trials reported hot flashes, joint pain and muscle aches as the most bothersome side effects.

However, a major concern with aromatase inhibitors is that they lower your body's estrogen level. This may put you at a higher risk of osteoporosis. If you're taking an aromatase inhibitor in the adjuvant setting or any other setting, be aware of the potential for osteoporosis and the need for your doctor to monitor your bone mineral density.

Lower estrogen levels in your body also affect your blood lipid levels. So some doctors are concerned that aromatase inhibitors might increase your risk of heart problems or cardiovascular disease.

Right now, researchers don't know whether the aromatase inhibitors differ with regard to their side

effects and health risks. Further study is needed to make this determination.

As with any medication, discuss your risks with your doctor. You might decide that the risks imposed by taking the medication are acceptable when compared with your risk of the disease recurring.

How long should you take aromatase inhibitors?

There's no clear guideline, as there is for tamoxifen, for how long you should take an aromatase inhibitor. One study proposed giving letrozole to women for five years — essentially years six through 10 after their initial breast cancer treatment. But so far, very few women have actually taken letrozole for five years. The duration for using anastrozole has been set at five years, but this was chosen arbitrarily. A clinical trial is currently underway to gain information on the optimal duration of therapy with aromatase inhibitors.

Can you use tamoxifen or an aromatase inhibitor to prevent breast cancer in the first place?

Tamoxifen is approved by the FDA for use in women at high risk of developing breast cancer, but there hasn't been widespread acceptance of tamoxifen because of the side effects. The three clinical trials noted above have shown a decrease in the occurrence of cancer in the opposite breast, suggesting that aromatase inhibitors may be of value in prevention. But we just don't know yet.

Currently, two clinical trials are underway examining aromatase inhibitors as a means of preventing breast cancer. One study compares taking exemestane with an inactive pill (placebo) and is being offered in the United States. The other study compares anastrozole with a placebo and is being conducted in the United Kingdom. It may be several years before results become available.

If you're considering tamoxifen to prevent breast cancer, review the potential benefits and risks with

your doctor in light of your own individual risk profile and medical history. For example, the use of

tamoxifen in a woman with a history of blood clots might pose an unacceptable level of risk of developing more blood clots.

Unless you're at high risk of breast cancer, the potential risks of tamoxifen — such as blood clots and uterine cancer — generally outweigh any potential benefits.

What can you do about prevention if you're at high risk of breast cancer?

If you're at high risk of breast cancer, weigh all your prevention options with your doctor. If you know you're at high risk, the risks associated with tamoxifen may be acceptable. Another option is close surveillance, such as having an annual mammogram and clinical breast exam by your doctor. Also consider monthly breast self-exams to familiarize yourself with normal breast changes and to monitor your breast health.

You can also check in with your doctor regarding the use of aromatase inhibitors for prevention. As

researchers learn more about these drugs from the ongoing clinical trials, recommendations may change over time.

Mammography: Screening tool for breast cancer

Breast self-examination: An option for the early detection of cancer

April 21, 2005

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