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

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.

READ MORE: Are New Therapies in ER-Positive Breast Cancer Just the Tip of the Iceberg?

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.

READ MORE: Research Unravels New Ways to Treat HER2-Positive Breast Cancer

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.

To head off these tumor detours, clinicians are testing combinations of hormone therapies with drugs that block these alternate pathways. One combination pairs Afinitor, which inhibits the mTOR pathway, with exemestane. In fact, a recent phase 3 trial was stopped early when this combination proved effective in patients with ER-positive advanced breast cancer whose disease recurred or progressed while they were taking letrozole or anastrozole. In that study, nearly 10 percent of patients responded to the drug combo compared with fewer than 1 percent of those taking exemestane alone, and median progression-free survival improved from 4.1 to 10.6 months. The combination was approved by the FDA in July.

Several other combinations are showing promise against AI-resistant disease. Afinitor and tamoxifen, for example, increased the time to disease progression from 4.5 to 8.6 months and substantially reduced the risk of death compared with tamoxifen alone. And a recent phase 2 trial tested exemestane plus entinostat, one of a class of drugs called histone deacetylase (HDAC) inhibitors that turn genes on or off by altering DNA structure. This combination increased progression-free survival time from 2.27 months with exemestane alone to 4.28 months.

Side effects from these combinations were generally mild but in all cases were more frequent with combination therapy. “Hormone therapy is usually very well tolerated, so it is noticeable whenever you add a second drug,” Hortobagyi says. Studies have also shown benefit combining HER2-blocking agents such as Herceptin or Tykerb (lapatinib) with AIs in patients who have ER/HER2-positive disease, like Ann Silberman.

Silberman was 51 when she received a diagnosis of stage 2 breast cancer. Since her tumor was the more aggressive ER/HER2-positive variety, she had a mastectomy and chemotherapy followed by Herceptin, to inhibit the HER2 overexpression, and then a prescription of tamoxifen. But 16 months after starting Herceptin and four months after starting tamoxifen, the cancer showed up in her liver.

Silberman is now on Abraxane (paclitaxel) and Herceptin and will be continuing with chemotherapy. Her last scan doesn’t definitively show cancerous lesions, “So we don’t really know if I have cancer right now, but I’m going to be on chemo probably forever,” she says.

Drug combinations may also help to prevent the development of drug resistance in the first place if given as first-line therapy. Indeed, combining anastrozole with Faslodex as first-line treatment in postmenopausal patients with metastatic ER-positive disease increased both progression-free survival and overall survival over anastrozole alone.

These combination strategies would be most effective if it were clear which detour route each patient’s tumor had taken or was going to take. But unfortunately, says Osborne, “There haven’t been a lot of studies in which tumors that have become resistant to tamoxifen or AIs have been biopsied to see what happened.”

Albain also stresses the importance of repeat biopsies in patients who relapse. “You do the biopsy to see if the disease is still what you think it is … and to tailor the therapy in the best way possible,” she says. Indeed, in a small study of patients with ER-positive tumors who relapsed after treatment with tamoxifen, 17 percent of resistant tumors had lost ER expression, and 11 percent had begun to overexpress HER2.

Some scientists, including Ellis, are also testing the efficacy of hormone therapy given prior to surgery (called neoadjuvant) in an effort to identify up front which tumors are responsive and which are not. Patients whose tumors respond well may be offered more conservative surgical options and could avoid unnecessary chemotherapy.

Roughly 230,000 new cases of breast cancer will be diagnosed in the U.S. in 2012, mostly in postmenopausal women. Age is one of the biggest risk factors for developing breast cancer, but being overweight, consuming alcohol and having a family history of breast cancer also increase the odds. Uninterrupted and prolonged stimulation of the breast tissue with estrogen seems to play a role. That is why early puberty, late menopause, older age at first pregnancy, never having given birth and lack of breastfeeding appear to be additional risk factors.

Breast cancer was once thought to be a single disease, but molecular science has changed all that. It is now known that the disease comes in many varieties, distinguished in part by the proteins expressed within and on the surface of the tumor. The most common variety, accounting for three-fourths of all cases, is hormone receptor-positive breast cancer. These tumors express a protein—called estrogen receptor (ER)—that binds to the female hormone estrogen. When binding occurs, the estrogen-ER complex enters the cell and turns on genes that promote cell division and survival.

Other distinguishing proteins include the progesterone receptor (PR) and a protein called human epidermal growth factor receptor 2, or HER2. In normal cells, HER2 sends signals into the cell that trigger survival and division in response to growth factors. But when HER2 levels are elevated—as occurs in 20 to 30 percent of breast cancers—it acts like a switch that’s always on, telling the cell to divide even in the absence of growth factors. This can be counteracted by the drug Herceptin (trastuzumab), which slows tumor growth by binding to HER2.

ER expression is generally associated with slower-growing tumors and a more favorable clinical course. Tumors with both ER and HER2 positivity tend to be more aggressive and are less likely to respond to hormone therapy. Tumors that do not express ER (called ER-negative) tend to grow more quickly than ER-positive tumors, possibly explaining their heightened sensitivity to chemotherapy drugs, which target rapidly dividing cells.

Chemotherapy is often bypassed in these lower-risk patients, except for those whose tumors have more aggressive features—such as high levels of Ki67, a protein expressed in rapidly dividing cells. New genetic tests, including Oncotype DX and Mammaprint, report on the expression of multiple genes involved in growth and drug responsiveness in the tumor. These tests help predict the risk of recurrence, and in the case of Oncotype DX, predict the likelihood of benefit from chemotherapy.

These tests can be used to determine which patients are unlikely to benefit from the addition of chemotherapy, thus sparing them from its toxicities, inconvenience and expense. As with all cancers, the more advanced the disease, the less favorable the outlook.

“By and large, the vast majority of patients with metastatic breast cancer [disease that has spread to distant sites] are not curable with currently available therapies,” Hortobagyi says. And only about half of patients with ER-positive tumors will benefit from hormone therapy.

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Sequential hormone therapy has been the story of Cohen’s life for the past decade, something she’s coped with by making a deal with her cancer. “The cancer can live in my body as long as it wants, provided it’s a quiet tenant,” she says. “And when it gets out of hand, we slap it down.” Since her cancer was detected in her bones in 2002, she has been treated with a sequence of hormone therapy drugs, including letrozole, Faslodex, tamoxifen, anastrozole and exemestane—all of which kept her tenant quiet for a while.

Some cases of hormone resistance (up to 20 percent) are due to the loss of ER expression on the tumor cells, but more often, the tumor simply learns to survive using alternative growth pathways. “When you block one bridge over the river, in this case estrogen receptor, the tumor can take other bridges—maybe smaller, downstream ones—to get to the other side,” Osborne says. One example is a growth pathway involving a protein called mTOR, which activates the ER in the absence of estrogen.

After taking Faslodex, Cohen’s doctor introduced the Afinitor/exemestane combo and is hoping the new regimen will be enough to disrupt her cancer. She says her oncologist told her: “You have to stay alive long enough for the next new thing to come down the road. And there is always something new coming down the road.”

Her latest scan shows the metastases in her brain and lungs have melted away, and the rest are stable. Her recently noisy tenant may not have been completely evicted, but this powerful combination has quieted it once more.