Targeting estrogen is yielding important new agents in the fight against breast cancer.

By Rabiya S. Tuma, PhD

Friedl Pantle-Fisher, MD, a 60-year-old pain management specialist in Chicago, was recently diagnosed with breast cancer. She had a lumpectomy, followed a week later by a second surgery to remove lymph nodes from under her arm. Thus far, she’s had eight out of 35 radiation treatments, but the question is what to do next. Her cancer is estrogen receptor positive, meaning the estrogen in her body can support the growth of her tumor cells, and as recently as last year that would have meant her doctor recommending five years of Nolvadex® (tamoxifen) to decrease the likelihood of her disease coming back.

But now—with the results of new clinical trial data—Dr. Pantle-Fisher and thousands like her have a choice: Tamoxifen, which blocks the activity of estrogen in the breast but partially mimics the hormone’s activity in other organs, or an aromatase inhibitor, which blocks the formation of estrogen so none is available to stimulate breast cancer cells that escape the surgery and radiation.

For Dr. Pantle-Fisher, the question of which drug to take after her second surgery came down to a series of quality-of-life issues and an important health concern. “I didn’t want this medication to take over my life,” she says. After talking to friends and family who experienced the side effects of tamoxifen, the possibility of sexual side effects was a significant issue.

The crucial factor, Dr. Pantle-Fisher says, was her existing hypercholesterolemia. That could be a bad mix with tamoxifen, which is known to increase the risk of stroke and can change a woman’s lipid (and cholesterol) profile. “The combination of all these issues made me choose Arimidex,” she says, opting for the aromatase inhibitor instead of tamoxifen.

A New Day in Long-Term Care

Results from three clinical trials have substantially changed available options for postmenopausal women with estrogen receptor-positive cancer who need long-term care to reduce their risk of breast cancer recurrence.

All three trials compare the use of an aromatase inhibitor with tamoxifen for preventing recurrence—and all three show the aromatase inhibitor is more effective than tamoxifen.

Perhaps most importantly, one of the trials shows that extending such preventive care from five years to 10 years dramatically drops a woman’s risk of recurrence when she takes tamoxifen for five years followed by five years of an aromatase inhibitor.

“Our thinking has really changed with this one study, and in a very short period of time,” says Stephen E. Jones, MD, a breast cancer specialist with US Oncology in Houston. “We know now there is something we can do to reduce the risk of late recurrence. This is the sort of study that will affect millions of women around the world.”

Estrogen Suppression in Breast Cancer Care

Physicians have known for more than a century that estrogen can stimulate the growth of some breast cancers. As early as the end of the 19th century, physicians found that by removing a woman’s ovaries, the organ that produces the majority of estrogen in premenopausal women, they could induce remission in some breast cancer patients. More recently, clinicians have used chemical inhibitors, such as tamoxifen, to suppress estrogen activity or synthesis and have achieved similar results.

The estrogen hormone is a small molecule that slips from the bloodstream into the cell and binds to another protein called the estrogen receptor, which is present in estrogen-sensitive breast cancer cells, as well as some healthy cells in the body. Once the hormone binds to the receptor, they act together to turn on specific genes that cause the cell to divide.

In healthy cells this process is tightly regulated, but in cancer cells the signal to divide goes unchecked and leads to excessive growth and tumors. Researchers have discovered three types of drugs that interrupt estrogen’s activity. Each one acts at a different step in the formation of the estrogen-receptor complex.

The best known of these estrogen-controlling drugs is tamoxifen, called a selective estrogen receptor modulator, or SERM, because it inhibits estrogen activity in some tissues and stimulates it in others. For example, tamoxifen blocks estrogen activity in the breast but increases it in the endometrial lining.
In the breast tissue, tamoxifen prevents the hormone from binding to the receptor, and the cell doesn’t start to divide.

Another drug, Faslodex® (fulvestrant), which is from a class of drugs called selective estrogen receptor downregulators (SERDs), inhibits estrogen signaling by destroying the estrogen receptor. Without the receptor, the hormone is unable to bind the DNA and fails to trigger cell signaling and proliferation. (Faslodex and another SERM, Fareston® [toremifene], are used in the treatment of metastatic breast cancer. Faslodex is not currently being used to prevent recurrence, though future trials may test its usefulness as a preventive.)

The third class of estrogen blockers, the group making headlines this year, is the aromatase inhibitors. These drugs are targeted therapies that prevent the synthesis of estrogen in tissues outside the ovaries, which are the main source of the hormone in postmenopausal women.

In postmenopausal women, estrogen is no longer produced in the ovaries but is made in the adrenal glands as well as in other tissues, such as fat, muscle and cancer cells. With no estrogen around to activate the receptor, the cells aren’t stimulated to grow.

Significantly, however, aromatase inhibitors can only be used for breast cancer control in postmenopausal women because the drugs actually increase estrogen production in the ovaries in premenopausal women. Aromatase inhibitors block non-ovarian estrogen synthesis, thus reducing the risk of breast cancer recurrence in postmenopausal women with hormone-responsive cancer. (See illustration to see where and how hormonal therapies work.)

Aromatase Inhibitors Make Headlines

For years, the gold standard of treatment for women with hormone receptor-positive breast cancer was surgery, chemotherapy and radiation, as indicated, followed by five years of tamoxifen therapy.

Five years of tamoxifen reduces a woman’s risk of breast cancer recurrence by nearly 50 percent. But that still leaves her with 50 percent of her original risk, most of which occurs during the following 10 years, says Dr. Jones. Now physicians and researchers are trying to figure out how to further reduce that remaining risk.

One simple approach was to determine whether continuing tamoxifen treatment beyond five years would further reduce a woman’s risk, but researchers found no substantial benefit. Also, because tamoxifen stimulates cell growth in the uterine lining or endometrium, prolonged use increases a woman’s risk of developing endometrial cancer. During the first five years, the benefit of lowering a woman’s breast cancer risk outweighs the risk of endometrial cancer, but beyond five years the balance tips in the other direction, which made continuing tamoxifen therapy past five years not a feasible option.

More recently, researchers have focused on the aromatase inhibitors as a possible mechanism to further reduce a woman ’s risk.

Just After Surgery

Dr. Pantle-Fisher had the option to take Arimidex® (anastrozole) because of a recent clinical trial. In that study, which is called the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, researchers tested the effectiveness of using Arimidex instead of tamoxifen immediately after a woman’s initial treatment.

In this trial, 9,366 women were randomly assigned to one of three study arms, Arimidex or tamoxifen or a combination of the two.

Betty King, 60, an elementary school principal in Frisco, Texas, had just been diagnosed with breast cancer when this study was starting. Dr. Jones, her oncologist, asked if she would like to participate since she fit the profile: A postmenopausal woman with early-stage breast cancer.

“I made the choice to be in that study,” says King. “I was so fortunate to not need radiation or chemotherapy, and we have so many females in our family. This was a way I can pay back and take part in some science.

“I took two pills every night for five years. I just found out I was on tamoxifen and a placebo.”

The trial showed that women taking Arimidex were nearly 20 percent less likely to have disease recurrence—and when their disease did creep back up, it happened after a longer period of time postsurgery—than in the women taking tamoxifen. Also, the women taking the aromatase inhibitor were less likely to develop a second cancer in their other breast.

Does it bother King that she was on tamoxifen when Arimidex was found to be more effective? “No, I don’t think it bothers me at all, because that’s what the study was trying to discover,” she says. “I’m just glad to be a part of discovering that the other medication is better.”

In the Middle of Tamoxifen

The first of the aromatase inhibitor trials showed that replacing tamoxifen with Arimidex lowers a woman’s risk if she starts taking the aromatase inhibitor right after surgery, but what if she has been taking tamoxifen for a while? To find out if switching from tamoxifen to an aromatase inhibitor in the middle of the standard five-year treatment could improve a woman’s outcome, researchers designed a separate randomized trial called the IES trial.

In the IES trial, women who had been on tamoxifen for two to three years were randomly assigned to continue the drug or take Aromasin® (exemestane) for the remainder of their five-year treatment period. With this trial design, the women still take only five years of drugs to prevent relapse, but they take two to three years of tamoxifen followed by two to three years of Aromasin.

Of the 4,742 patients who participated, 2,362 were randomly assigned to switch to Aromasin while the others stayed on tamoxifen for their five-year adjuvant therapy. Patients on Aromasin were 32 percent less likely to have a recurrence than those who stayed on tamoxifen. Again, like in the Arimidex trial, women who took Aromasin had a significant drop in their likelihood of developing breast cancer in their other breast.

These results, say the researchers on the study, are consistent with the idea that much of the benefit of tamoxifen therapy occurs in the first couple of years.
The IES trial results agree with a recent but much smaller Italian trial using Arimidex, which Dr. Jones says showed the same results with Arimidex as were seen with Aromasin, “but it was too small to change practice.” However, the IES trial involved nearly 5,000 women, and that is large enough to change practice in oncology clinics across the country.

Beverly Doss, 44, who was just married in June, is excited about her upcoming change in therapy. “I thought I was going to switch to Aromasin on this visit to the doctor, but she told me she wants me to wait until I’ve had a full two and a half years of tamoxifen.”

Doss says she read about aromatase inhibitors in CURE and was enthusiastic when her oncologist suggested they consider switching her over instead of staying on tamoxifen. “We decided to switch because of the recent studies showing it provided more reduction in risk than tamoxifen alone,” says Doss. “Also, I’ve read that tamoxifen blocks estrogen access, whereas aromatase inhibitors block synthesis, and that makes me more comfortable.”

Adding Aromatase Inhibitors to Five Years of Tamoxifen

These new trials, as exciting as they are for women like Dr. Pantle-Fisher and Doss, who are early on in their cancer treatment, still do not address the issues for women who have finished tamoxifen.

Nicholas J. Robert, MD, of US Oncology and the Inova Fairfax Hospital in Falls Church, Virginia, and others tested the possibility of extending a woman’s hormone therapy beyond the five years by adding on five years of treatment with the aromatase inhibitor Femara® (letrozole).

The researchers recruited 5,187 postmenopausal women with estrogen receptor-positive cancer who had either just completed five years of tamoxifen therapy or had done so within the past three months. The women were assigned to take either a placebo or Femara daily for five years.

In 2003, after a median of 2.4 years of follow-up time, a safety monitoring board that oversees such clinical trials stopped the trial in 2003 because the results were so dramatically in favor of Femara. The monitoring board asked the researchers to tell all of the patients whether they were taking a placebo or Femara and offer the drug to anyone on the placebo arm who
wanted it.

The decision to halt a trial so quickly is somewhat unusual, but happens when the results are already clear. In this case, 93 percent of the women on the Femara arm were disease-free at four years compared to 87 percent in the placebo arm. The rate of distant metastases was nearly half in the Femara arm (47 women) relative to the number in the placebo arm (76 women). Similarly, the rate of a new cancer in the second breast was significantly reduced with Femara.

With a longer follow-up, the researchers now find the drug also reduces the risk of death from breast cancer in women with node-positive disease by 39 percent, relative to the placebo arm. Researchers expect a similar result will be seen in women with node-negative disease, but that it will take longer to show up, says Dr. Robert.

“This is a milestone trial,” he says. “It really changes the way we think about breast cancer. We need to have prolonged treatment, and for estrogen receptor-positive cancers we can use endocrine intervention.”

King, who was on the tamoxifen arm of the Arimidex trial, must now decide if she wants to take Femara. She’s on the fence, she says. Her risk of recurrence was relatively low to start with, just 6 percent. The five years of tamoxifen reduced it to 3 percent, and if she takes Femara, it will be further reduced to 1.5 percent.

But is that worth another five years of taking pills? “I’m not sure yet. I turned 60 years old in August and I’m just not sure that I want to continue putting chemicals in my body,” says King. “Right now I feel so good that I’m just not sure whether I should do this. I get lots of exercise and I get good health reports. I’ve learned how to handle my stress better.”

Putting Results Into Practice

“These results have already changed the way we practice,” says Olufunmilayo Olopade, MD, a breast cancer researcher at the University of Chicago. She says that especially for her patients who are either older or battling other illnesses, such as diabetes, she leans toward aromatase inhibitors.

The catch is that researchers still need to figure out similarities of the three aromatase inhibitors. Can they be used interchangeably? It’s not clear yet. So for now, physicians are prescribing them in the situation for which they were tested.

Arimidex is used in women like Dr. Pantle-Fisher who are just starting their hormone therapy; Aromasin is used when women want to switch in the middle of their five years of tamoxifen; and Femara is used when a woman has already completed five years of tamoxifen but wants to further reduce her risk of recurrence.

The good news is that while doctors and researchers are working out the optimal regimen, women with estrogen receptor-positive tumors have more choices and more opportunities to reduce their risk of recurrent disease.