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The Estrogen Effect: New Ways to Treat Hormone-Positive Breast Cancer

Patients whose breast cancers are estrogen-positive have a wide variety of treatments available. 

BY HEATHER L. VAN EPPS, PHD
PUBLISHED FRIDAY, SEPTEMBER 14, 2012
In the late 1970s, treatment of hormone receptor-positive breast cancer was revolutionized by the introduction of the drug tamoxifen. Since then, a multitude of successful new hormone-based (endocrine) drugs have followed. But despite this formidable arsenal, not all patients respond to these drugs, and many who do respond eventually relapse. 

This was the case for 53-year-old Seattle resident Jill Cohen. In 2002, doctors discovered that her breast cancer—initially diagnosed as early-stage disease in 1998—had returned and spread to her bones. Cohen is alive thanks to a series of hormone therapy drugs. 

“I feel extraordinarily lucky,” Cohen says. “I have long outlived the statistical odds.”

But Cohen’s cancer has spread throughout her body. As Cohen and many other women whose cancers develop resistance to hormone therapy drugs have learned, there are often new therapies being studied for just such an occasion. Recent clinical trials have shown that new anti-cancer drugs, often given in specific combinations or sequences with existing hormone therapy drugs, can help keep these tenacious tumors at bay. 

When Cohen’s doctor broke the latest news­–that the cancer had spread to her lungs, brain, liver and scalp—Cohen suggested a plan. Her oncologist helped her receive an investigational regimen, Afinitor (everolimus) and an aromatase inhibitor (AI), and worked with her insurance company to cover it. Afinitor was approved in July for metastatic breast cancer, and recent studies suggest it could be the next step for women whose cancer has progressed on other approved treatments. 

Hormone signal-blocking drugs work on ER-positive cancers by lowering estrogen levels or by blocking or downregulating the receptor. Tamoxifen and Fareston (toremifene) bind to the ER and block its association with estrogen, thereby preventing tumor growth. Faslodex (fulvestrant) also binds to the ER but triggers its destruction, lowering estrogen receptor activity in the cell. AIs, on the other hand, prevent estrogen from being produced in the first place. These drugs, which include anastrozole, exemestane and letrozole, target an enzyme called aromatase, which converts androgens into estrogen, the main source of estrogen in postmenopausal women. AIs have recently become the drug of choice in postmenopausal patients. Faslodex and AIs are approved for use in postmenopausal women only.

“Faslodex doesn’t work very well in premenopausal women because the ovaries are still cranking out estrogen,” says Kent Osborne, MD, director of the Dan L. Duncan Cancer Center at the Baylor College of Medicine in Houston. “We simply can’t get enough of the drug into the body to compete with the high estrogen levels.” If AIs are used before menopause, reductions in estrogen trigger a feedback loop that stimulates the production of more estrogen. 

These drugs also come with distinct side effects, although they are all generally well tolerated. Tamoxifen is associated with an increased risk for uterine cancer and clotting, whereas AIs can increase the risk of bone loss and fractures and are thus often paired with drugs such as bisphosphonates (which have their own associated risks) that combat bone loss.

The choice of treatment for breast cancer patients depends on a variety of factors, including the size and stage of the tumor, how fast it grows and whether it expresses ER. “There are clinical signals along with the biology of the tumor that usually take you in the right [treatment] direction,” says Kathy Albain, MD, director of the Breast Clinical Research Program at the Cardinal Bernardin Cancer Center of Loyola University Medical Center in Maywood, Ill.

In patients with early-stage disease, which accounts for the majority of cases, the local tumor is surgically removed by lumpectomy or mastectomy, often followed by radiation to kill any remaining tumor cells. Most patients with ER-positive tumors then take tamoxifen or an AI, or both in sequence for five to 10 years—an approach proven to cut the risk of relapse in half. 

“Patients with early-stage breast cancer are always treated with curative intent,” says Gabriel Hortobagyi, MD, chairman of the breast medical oncology department at M.D. Anderson Cancer Center in Houston. Nonetheless, disease recurs in about 25 percent of these patients. 

The cancer can live in my body as long as it wants, provided it’s a quiet tenant. And when it gets out of hand, we slap it down.

With metastatic disease, “We often see a pattern where endocrine therapy works for a while and then the tumor starts to progress,” says Matthew Ellis, MD, PhD, chief of the breast oncology section at Washington University in St. Louis. Luckily, patients with responsive tumors can be switched to other hormone therapies if resistance to one develops.

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