Breast Cancer Treatment: Weighing the Hormonal Options

Last Editorial Review: 1/31/2005

Tamoxifen has been the standard in hormonal breast cancer treatment for decades. But newer treatments are challenging tamoxifen's superiority.

WebMD Feature

Reviewed By Michael Smith

To Kathryn Anderson, the hormonal treatment tamoxifen offered a new lease on life. A survivor of breast cancer, she had been through two surgeries, radiation therapy, and chemotherapy when her doctors put her on tamoxifen.

Anderson is not alone. In the 25-plus years since tamoxifen became a mainstay of breast cancer therapy, the pill has saved thousands of lives. But now, newer hormonal agents known as aromatase inhibitors are contesting the superiority of tamoxifen and competing for attention.

One of the biggest concerns with tamoxifen is that it stops working after five years, doctors say. Yet one-third of cancers that recur come back between five and 10 years later.

Anderson says that after her five years of tamoxifen therapy ended she always feared a recurrence, feeling that her safety net had gone away.

Until now. A study published in 2004 in The New England Journal of Medicine showed that taking the aromatase inhibitor Aromasin after two to three years of tamoxifen reduced breast cancer recurrence by 32%.

And in 2003, another study in the same journal showed that women could cut their risk of recurrence by nearly half by taking the aromatase inhibitor Femara after they completed about five years on tamoxifen.

And another recent study showed that postmenopausal women who switch to another aromatase inhibitor, Arimidex, after two or three years of tamoxifen therapy had fewer recurrences of cancer than those who continued to take tamoxifen for the full recommended five years.

Aromasin Helps Prevent Cancer Recurrence

The Aromasin study, performed by R. Charles Coombes, MD, PhD, showed that when postmenopausal women took Aromasin for two to three years following two to three years of treatment with tamoxifen, the risk of breast cancer recurrence dropped by 32% compared with women who continued to take tamoxifen.

It's a revolutionary finding, says Paul E. Goss, MD, PhD, director of breast cancer prevention at Toronto's Princess Margaret Hospital and professor of medicine at the University of Toronto. Goss was lead researcher on the Femara study that showed it cut breast cancer recurrence nearly in half after five years of tamoxifen.

"The extent of risk reduction surprised us," Coombes tells WebMD. "It indicates a fair number of people become resistant to tamoxifen two to three years after they start taking it."

Several smaller trials showed that Aromasin may also be effective for the treatment of hormone-responsive metastatic breast cancer. In one study, 122 women who had received no prior hormone therapy were randomly assigned to get tamoxifen or Aromasin. Disease stabilized for at least six months in 57% of those on Aromasin vs. 42% on tamoxifen.

And in a study of 105 women who had previously been on aromatase inhibitors, about one-fourth appeared to benefit from the newer drug.

Aromasin appears to be useful for in women whose breast cancers failed to respond to aromatase inhibitors like Arimidex or Femara, says co-investigator David Cameron, MD, a medical oncologist at Western General Hospital in Edinburgh, Scotland.

Three in Five Breast Cancers Fueled by Estrogen

Breast cancer is the second biggest cancer killer of women in the industrialized world, taking the lives of about 40,000 women each year in the U.S. alone. More than 211,000 new cases will be diagnosed.

About three in five of these women have tumors that are fueled by the hormone estrogen, making hormone therapy to stop this growth a cornerstone of regimens to prevent recurrences and improve survival.

While tamoxifen prevents estrogen from acting on tumors, aromatase inhibitors actually block an enzyme the body uses to make estrogen, thereby slashing the body's production of estrogen altogether.

The new studies suggest that this different mechanism of action to decrease estrogen levels may mean that aromatase inhibitors may shrink tumors better and longer with fewer side effects, doctors say.

Femara Study Halted Early

Goss says the drug was so effective that an international committee decided to disclose the results early in order to offer the drug to all women in the trial.

The international trial pitted Femara against placebo in nearly 5,200 women following five years of tamoxifen therapy. Four years after the start of the study, cancer came back in 13% of the women on placebo but only in 7% of those on Femara.

Anderson, who as a patient of Goss was invited to participate in the study, tells WebMD that the day the trial was stopped early was "very exciting. I found out I had been on Femara for the last two years, indicating to me that my chances of recurrence had been cut in half."

Arimidex Beats Out Tamoxifen

In the Arimidex trial, women who switched to the aromatase inhibitor fared better than if they stayed on standard tamoxifen.

The study followed 448 postmenopausal women who had been taking tamoxifen for at least two years following breast cancer surgery. The women were randomly assigned to continue taking tamoxifen or switch to Arimidex for five years.

By three years later, cancer was 64% less likely to recur in the group of women who switched to Arimidex, the study showed.

Other Hormonal News

Those were not the only studies on the new hormonal treatments in 2003.

Yet another trial showed that women who took Arimidex instead of tamoxifen were slightly less likely to see their cancer recur after four years compared with those who took tamoxifen.

And in another study of nearly 300 women, those who took Arimidex were significantly more likely to become candidates for breast-conserving surgery than those who took standard tamoxifen, says Ian Smith, MD, of Royal Marsden Hospital in London.

And in the one trial that pitted Femara against Arimidex, those on Femara were slightly less likely to respond. But there was no difference in the amount of time it took for the cancer to grow.

Finally, the largest study ever to evaluate a hormonal therapy for women with advanced breast cancer showed that those on Femara stayed free of disease longer than those on tamoxifen.

A Gentler, Milder Drug?

As for side effects, the old standby drug tamoxifen is associated with a higher risk of uterine cancer than the newer aromatase inhibitors. But some studies have shown that women taking aromatase inhibitors are more prone to bone fractures than those taking tamoxifen.

But in general, side effects from aromatase inhibitors are mild, Goss says. Studies on the various aromatase inhibitors have shown that the drugs are generally tolerated about as well as placebo and any side effects appear to be mild. But one side effect in particular, increased bone loss, does concern doctors, but it has not been seen to be a problem in the short term.

Another Hormonal Treatment

Still another type of hormonal therapy is Faslodex. Unlike the other drugs, which are given daily in the form of a pill, Faslodex is given as a monthly injection into the muscle.

The trials so far show only that Falsodex is effective for the treatment of metastatic breast cancer, not for newly diagnosed women undergoing surgery.

One study reported reported in December 2003 showed that Faslodex is about as effective as Arimidex in the treatment of postmenopausal women with advanced breast cancer (large cancers that have spread outside of the breast) whose disease continues to spread after treatment with tamoxifen. Investigator John E. Pippen, MD, of Baylor-Sammons Cancer Center in Dallas, says the findings should give more hope to women with advanced breast cancer, buttressing the fact they have options when other hormonal therapies fail.

Robert W. Carlson, MD, a professor of medicine (oncology) at Stanford University School of Medicine, says that ongoing studies are looking at Faslodex in the treatment of early breast cancer.

So What Should Women Be Doing?

There is no doubt that tamoxifen still has a major place in the prevention and treatment of breast cancer. For starters, aromatase inhibitors only work for postmenopausal women, Carlson points out.

So far, the main role of the aromatase inhibitors appears to be in treating postmenopausal women following breast cancer surgery, he says. But whether they should be on tamoxifen or an aromatase inhibitor following surgery is still an open question.

"Switching from tamoxifen to [aromatase inhibitors] does appear to be an effective strategy," he tells WebMD. "But there is still uncertainty about the optimal time for the switch and long-term side effects."

There are trials pitting the various agents against one another, trying to find the optimal duration of treatment and looking at the anti-aromatase agents for prevention and in the presurgical setting that will give more answers, he says.

"There are over 25 years of experience with tamoxifen in various settings. Aromatase inhibitors are still relative newcomers."

Life After Tamoxifen

As for women who already received the full benefit of five years of tamoxifen therapy, Goss says that Femara or Aromasin treatment may be a good option. "Until now, there was no other treatment option for women after five years of tamoxifen therapy," he says.

"The message here is if a woman has been on tamoxifen coming up on two to three years, she should talk to her specialist about switching to an aromatase inhibitor," Coombes says.

Patients like Anderson say the most important thing to do is talk to your oncologist. With all the data so rapidly coming out, even a primary care doctor might not be up to date on all the findings.

Putting together all the data, Lawrence Wickerham, MD, associate chairman of the National Surgical Adjuvant Breast and Bowel Project in Pittsburgh, tells WebMD, "The bottom line is, women now have a choice."

Originally published Dec. 18, 2003.

Medically updated March 10, 2004.

SOURCES: Coombes, R.C. The New England Journal of Medicine, March 11, 2004; vol 350: pp 1081-1092. R. Charles Coombes, MD, PhD, head, department of cancer medicine and section of cancer cell biology, Imperial College, London. San Antonio Breast Cancer Symposium, San Antonio, Dec. 3-6, 2003. Kathryn Anderson, breast cancer patient. Francesco Boccardo, MD, University of Genoa; Italian National Cancer Research Institute. Robert W. Carlson, MD, professor of medicine (oncology), Stanford University School of Medicine. David Cameron, MD, medical oncologist, Western General Hospital, Edinburgh, Scotland. Paul Goss, MD, director of breast cancer prevention, Princess Margaret Hospital, Toronto. Lawrence Wickerham, MD, associate chairman, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh.

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