Tamoxifen: 25-year success story looking for a sequel

The silver anniversary of the introduction of the breast cancer treatment prompted a look at the hormonal therapy's track record.

By Susan J. Landers, amednews staff. June 16, 2003.

Washington -- When tamoxifen was first introduced, it was a pioneering drug and, like many of the women who took the medication, it has been a survivor.

"When tamoxifen came into widespread clinical use in the late 1970s, it was really at that time what we could consider a wonder drug," said Len Lichtenfeld, MD, American Cancer Society's deputy chief medical officer.

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In the 25 years since, it has played an important role in cancer therapy, not only as a weapon in physicians' breast cancer arsenal, but also by expanding the range of options available to women and by focusing attention on other possible treatments that build on its success.

Before tamoxifen made its debut, it was chemotherapy that was expected to save the day in breast cancer treatment, noted Craig Jordan, PhD, DSc, director of Northwestern University's breast cancer research program.

Chemotherapy was elbowed aside to make room for another category of breast cancer treatment when tamoxifen's importance as an anti-estrogen became apparent. The discovery prompted a "revolution in targeted therapy," said Dr. Jordan during a May 28 teleconference. The conference was hosted by Vital Options, a nonprofit cancer organization and funded by AstraZeneca Pharmaceuticals, which manufactures the drug, under the brand name Nolvadex.

"Long-term therapy with tamoxifen has resulted in 400,000 [more] women being alive today," said Dr. Jordan, who was involved in the earliest stages of the drug's development.

Tamoxifen is a member of a class of drugs known as selective estrogen receptor modulators. It is used as a treatment for patients with advanced breast cancer, as an adjuvant therapy after primary treatment for early-stage breast cancer and as a preventive for women at high risk of developing breast cancer.

But even after 25 years, its uses are not entirely without issue.

Fran Visco, president of the National Breast Cancer Coalition, agrees that tamoxifen has been a significant breast cancer advance, but she does not think it's the "be all and end all."

Tamoxifen therapy isn't covered by Medicare.

She particularly questions its role in prevention. "I've had women call the office and ask if they should give tamoxifen to their 18-year-old daughter so she won't get breast cancer," Visco said. "I think it really has been overhyped."

Tamoxifen is also not without risks. Among them are increased risk of endometrial cancer, stroke and venous thromboembolic disease. Women taking tamoxifen also may be at higher risk of developing cataracts.

The fact that tamoxifen is available in pill form has pros and cons, Visco said. On the plus side, pills are easy to take, but on the minus side, tamoxifen isn't covered by Medicare. Because breast cancer is a disease of older women, the importance of Medicare coverage, accompanied by the likelihood that other insurers will then provide coverage, can't be overlooked.

Tamoxifen has been well-studied over the years, and many of those clinical trials were conducted by the National Surgical Adjuvant Breast and Bowel Project, a clinical trial cooperative group of 200 treatment centers that has existed for 40 years.

Testing a successor

The results of the many trials helped reveal that breast cancer was more than just a mass in the breast, said Lawrence Wickerham, MD, associate chair of the breast and bowel project. Dr. Wickerham also spoke at the May 28 teleconference.

"Breast cancer was shown to be a systemic disease that could affect the entire body and as such require treatment for the entire body," he said. Numerous trials have shown that treatment in addition to surgery could improve long-term survival.

The additional treatment was initially chemotherapy but is now likely to be hormonal therapy or a combination of the two, Dr. Wickerham said. And the adjuvant therapies are also now more targeted to individual patients, especially when it comes to hormonal therapy.

The success of tamoxifen has spurred a search for its successor, possibly one with fewer side effects. Among the candidates is a class of medications known as aromatase inhibitors, which have attracted much attention in recent years.

The breast and bowel project has launched a 5-year study of 19,000 participants to compare one of the newer agents, raloxifene, with tamoxifen. The Study of Tamoxifen and Raloxifene, or STAR, has already enrolled 16,000 women who are at high risk for breast cancer and will test the potential of raloxifene to reduce that risk.

Another trial recently launched by the project will evaluate the effectiveness of anastrazole, marketed as Arimidex by AstraZeneca, compared with tamoxifen in preventing a recurrence of breast cancer in women with primary ductal carcinoma in situ who have undergone lumpectomy and radiation therapy.

This early-stage cancer has been diagnosed more frequently, probably because of the increased use of screening mammography.

That trial, known as B-35, began enrolling women in January at the breast and bowel project's 200 sites.

ADDITIONAL INFORMATION:

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Information on breast cancer trials (www.breastcancerprevention.org)

National Cancer Institute, information on breast cancer treatment (www.cancer.gov/cancerinfo/pdq/treatment/breast/patient)

National Breast Cancer Coalition's position statement on tamoxifen and raloxifene use in healthy women, April (www.stopbreastcancer.org/bin/index.asp?strid=435&depid=9)