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When Estrogen Goes from Friend to Foe

  • From Turning Point 2015

    When Estrogen Goes from Friend to Foe banner

    by Robert Levy

    An essential part of women's reproductive health, the hormone estrogen also fuels the majority of breast cancers. Susan F. Smith Center investigators are exploring new ways of halting such tumors, particularly those that have become metastatic.

    For many cancer survivors, the five-year anniversary of finishing treatment is a biological as well as psychological milestone. By that point, the cancer may be so unlikely to return that it can realistically be considered cured. Some survivors treat themselves to a "cancerversary" party to mark the occasion.

    For women with the most common form of breast cancer, however, the benchmarks can be somewhat different. Although the vast majority are treated successfully, breast cancers apparently banished from the body can recur — often more than five years after treatment, and often at a location, such as the bones, far from the site of the original tumor.

    Preventing this stealth metastasis, and treating it more effectively when it does occur, has become the next frontier in the treatment of this form of breast cancer, known as estrogen receptor-positive (or ER-positive). At the Susan F. Smith Center for Women's Cancers at Dana-Farber, investigators are leading the attack on the problem – both in developing new agents and testing them in patients.

    "Most women with ER-positive breast cancer have an excellent prognosis, especially in the United States and Europe, where there is widespread screening for the disease," says Harold Burstein, MD, PhD, a breast cancer specialist at the Susan F. Smith Center. "Still, there is a substantial subset of patients who could benefit from innovative therapies. These patients are the center of a renewed research effort."

    A Clear Majority

    ER-positive breast cancer is diagnosed in an estimated 175,000 women in the U.S. every year, accounting for about 70 percent of all breast cancer cases. As its name implies, ER-positive breast cancer grows in response to the hormone estrogen. The tumor cells carry receptors for the estrogen molecule: When estrogen docks there, the cells get a signal to grow and divide.

    Despite being needed by ER-positive tumor cells, estrogen usually is a most beneficial hormone. It plays a key role in the development of the breasts, regulates the menstrual cycle and reproductive system, helps maintain bones, protects against coronary artery disease, protects nerves from damage, and more.

    Treatment for ER-positive breast cancer can include surgery and/or radiation therapy to remove or destroy the tumor, chemotherapy to eliminate remaining tumor cells, and hormonal therapy. Hormonal therapy seeks to deprive tumor cells of estrogen — either by lowering the amount of estrogen in the body or barring estrogen from acting on the cancer cells.

    These treatments are compellingly effective, particularly for women with small, newly-formed tumors: Five years later, virtually 100 percent of patients who had small, stage I tumors are alive, according to the American Cancer Society. The five-year survival rate for patients who had stage II tumors (which are still small and confined to the breast) is 93 percent, and, for those with invasive, stage III tumors, 72 percent. For women with metastatic, stage IV disease, the five-year survival rate drops significantly.

    From Five to 10

    The divergence in survival rates for patients with early- and late-stage ER-positive breast cancer has spurred efforts to prevent the cancer from coming back after years of dormancy. One strategy is to extend the period in which patients take anti-estrogen therapies.

    Clinical studies have shown that extending the duration of treatment beyond five years — and closer to 10 years — can lower the risk of recurrence. Another approach, using drugs that curb estrogen production in the ovaries, can also reduce the recurrence risk in young women with breast cancer.

    In a clinical trial co-led by Dana-Farber biostatisticians, investigators found that a combination of tamoxifen and an ovary-suppressing, injectable medication was better than tamoxifen alone in preventing a recurrence of the cancer in women age 35 and younger and in women who had been treated with chemotherapy but remained premenopausal.

    In both sets of patients, adding an aromatase inhibitor, a drug that blocks the formation of estrogen, decreased recurrence rates even further. (A downside of these ovary-suppressing treatments is that they can cause more menopausal-type symptoms such as hot flashes and night sweats, contribute to sexual dysfunction, and lead to osteoporosis. It remains unclear, however, which premenopausal patients should receive this new treatment approach; the potential benefits need to be weighed against the risks.)

    For the thousands of ER-positive breast cancer patients whose cancer recurs at a distant part of the body — and for women first diagnosed with an advanced, metastatic form of the disease — researchers are finding novel ways of bringing the disease to heel.

    One area of focus is the estrogen receptor itself. "We've worked for a long time to understand why some women with this form of breast cancer respond well to hormone-blocking therapies while others have a relapse of disease," says Dana-Farber's Myles Brown, MD, who is leading research in this area. He and Rinath Jeselsohn, MD, of his lab, recently found that some women who experience a relapse have mutations — structural abnormalities — in the estrogen receptor that allow it to function even when estrogen is absent. "We've started looking at drug agents that may be able to overcome this mechanism of resistance to standard therapy," says Dr. Brown.

    Myles Brown, MD (right), and Rinath Jeselsohn, MD, are working to outsmart the estrogen receptor.

    Dr. Jeselsohn is looking for other signs of whether — and why — some ER-positive breast cancers are likely to barge past conventional agents. She's found that tumor cells that underproduce two microRNAs (molecules that prevent certain genes from acting) resist anti-estrogen therapies. She and Dr. Brown recently reported that tumors with certain genetic abnormalities often shrink in response to a long-approved but little-used ER-blocking drug called fulvestrant.

    A particularly promising class of drugs for advanced, metastatic ER-positive breast tumors is known as selective estrogen receptor degraders (or SERDs). These work by clamping onto the estrogen receptor and causing it to crumble, blinding tumor cells to the presence of estrogen. Dr. Brown has studied the drugs' activity in laboratory cultures of tumor cells, and Dr. Jeselsohn is working with a pharmaceutical company to bring the drugs to patients in clinical trials.

    An Added Punch

    Even as new drugs are being developed, investigators are exploring whether "piggybacking" existing agents with tamoxifen or aromatase inhibitors can improve results in both early- and late-stage ER-positive cancers. Researchers hope that by attacking multiple vulnerabilities within tumor cells — a dependence on estrogen and on certain growth-related proteins — the cells will succumb more easily than they would with a single agent.

    One approach takes advantage of the fact that ER-positive breast cancer cells tend to have an oversupply of cyclin D, a protein that propels the cycle of growth and division. Drugs known as CDK4/6 inhibitors block cyclin D, essentially putting the tumor cells to sleep. Early testing suggests that these drugs, in combination with standard hormone-blocking therapy, can control ER-positive breast cancers twice as long as standard therapy alone.

    Susan F. Smith Center researchers are leading clinical trials of CDK4/6 inhibitors in women with early-stage ER-positive breast cancer, as well as those whose cancer has metastasized. Erica Mayer, MD, MPH, directs a clinical trial of palbociclib — a CDK4/6 inhibitor that has already showed promise in controlling metastatic breast cancer — and standard hormonal therapy in women with early-stage disease.

    In a recently completed phase 1 trial, Sara Tolaney, MD, MPH, and colleagues found that the CDK4/6 inhibitor abemaciclib caused tumors to shrink or stop growing in one-third of participants with hormone- receptor-positive metastatic breast cancer.

    Another candidate for combination therapy is a class of drugs known as PI3-kinase (or PI3K) inhibitors, which foil a gene pathway that is often overactive in metastatic ER-positive breast cancers. A phase 2 trial led by Ian Krop, MD, PhD, director of clinical research for the Susan F. Smith Center's Breast Oncology Program, found that adding a PI3K inhibitor to a hormone blocker may restore the blocker's effectiveness and delay the advance of the disease.

    Bringing much of this work full-circle, Dr. Tolaney is running a trial that teams a PI3K inhibitor (either BYL719 or BKM120) with a CDK4/6 inhibitor called LEE011, and an anti-hormone agent for women with metastatic disease. "Discoveries about the basic biology of ER-positive breast tumors have reinvigorated the search for new treatments," she says. "Some of the agents currently being tested are showing great promise."

    Turning Point 2015 Table of Contents 

Posted on May 19, 2015

  • Cancer Genetics
  • Metastatic Breast Cancer
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