For breast cancer survivors, the idea of taking estrogen pills is almost a taboo. In fact, their doctors give them drugs to get rid of the hormone because it can fuel the growth of breast cancer. So these women would probably be surprised by the approach taken by breast cancer physician Matthew Ellis, M.B., Ph.D., associate professor of medicine at Washington University School of Medicine in St. Louis — he has demonstrated that estrogen therapy can help control metastatic breast cancer.

In a study presented at the 31st annual San Antonio Breast Cancer Symposium, he showed that for about a third of the 66 participants - women with metastatic breast cancer that had developed resistance to standard estrogen-lowering therapy - a daily dose of estrogen could stop the growth of their tumors or even cause them to shrink. The study was funded by the Avon Foundation through the National Cancer Institute and included six cancer centers in the United States.

Ellis believes that estrogen therapy offers an appealing alternative to chemotherapy for metastatic breast cancer that has become resistant to estrogen-lowering agents called aromatase inhibitors, such as exemestane, anastrazole and letrozole. These drugs deplete the body of estrogen and are standard treatments for hormone-receptor positive breast cancers, which account for about 75 percent of breast cancer cases.

"By stabilizing or shrinking tumors in some women with metastatic breast cancer, estrogen therapy can relieve pain and other symptoms of cancer and can potentially prolong lives," says Ellis, an oncologist with the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital. "And unlike chemotherapy, estrogen enhances the quality of life. For many of our patients, their hot flashes disappear, and they lose other symptoms of menopause. It's a natural treatment for breast cancer. Not only that, it's much cheaper than chemotherapy, costing less than a dollar a day."

Furthermore, estrogen seems able to return metastatic tumors to a vulnerable state in which they again can be affected by aromatase inhibitors. "We thought acquired resistance to aromatase inhibitor therapy was permanent," Ellis says. "But now we've shown that in some patients giving estrogen can make it possible to cycle back to aromatase inhibitors, and they can work again."

About 40,000 women die of metastatic breast cancer each year, and estrogen therapy potentially could help thousands of women with hormone receptor-positive disease, Ellis says.

The study measured how many women with aromatase inhibitor therapy-resistant metastatic breast cancer responded to estrogen therapy. All study participants had estrogen-receptor positive tumors that had spread to their bones, livers or lungs. The women were postmenopausal with an average age of 59.

Coming into the study, all the participants were taking aromatase inhibitors to slow or stop the growth of their tumors. But their tumors had stopped responding to the treatment and had begun to grow again. Half of the patients got a high dose of estrogen (30 milligrams a day) and half got a low dose (6 milligrams a day).

Ellis points out that decades ago, high-dose synthetic estrogen was an accepted breast cancer therapy and was only abandoned when the estrogen-blocker tamoxifen came along in the 1970s and proved just as effective with fewer side effects. The high dose in the current study was based on the amount given to breast cancer patients in many of those earlier regimens.

Both the high- and low-dose treatments led to stabilization or shrinkage of metastatic tumors in about 30 percent of the participants. But the high-dose regimen had significant side effects such as nausea, vomiting, vaginal bleeding, fluid retention or calcium imbalances. In contrast, the low-dose regimen had few side effects and was well tolerated.

The researchers found that if study participants eventually experienced disease progression on estrogen, they could go back to an aromatase inhibitor that they were previously resistant to and see a benefit - their tumors were once again inhibited by estrogen deprivation. That effect sometimes wore off after several months, but then the tumors might again be sensitive to estrogen therapy. In fact, some patients have cycled back and forth between estrogen and an aromatase inhibitor for several years, thereby managing their metastatic disease.

The researchers also found that PET (positron emission tomography) scans could predict whose tumors would respond to estrogen therapy. They measured tumor glucose uptake before starting the women on estrogen and again 24 hours later. The patients whose tumors showed an increased glucose uptake, called a PET flare, were the same patients who benefited from estrogen therapy.

It's too early to know why estrogen has a negative effect on metastatic breast cancer tumors. But Ellis has found one clue - estrogen reduces the amount of a tumor-promoting hormone called insulin-like growth factor-1 (IGF1).

"I think that in order for breast cancer cells to survive in the absence of estrogen (when patients are on aromatase inhibitors), the cells have to learn to alter their cellular programs to utilize alternative growth signals like IGF1," Ellis says. "In theory, when you give estrogen back, IGF1 decreases and cancer cells die as a consequence. But surviving cancer cells prefer to switch back to living on estrogen - to them it's like eating out at McDonald's every day instead of foraging on roots and berries. These cells eventually reappear as estrogen dependent tumors and the cycle starts over."

Ellis plans to continue to follow metastatic breast cancer patients to quantify the response rate to retreatment with aromatase inhibitors when estrogen therapy stops working.

In addition to the Siteman Cancer Center, participating institutions included the University of Chicago, Case Western Reserve University, Memorial Sloan-Kettering Cancer Center, the University of North Carolina at Chapel Hill and Duke University Medical Center.

Funding from the Avon Foundation and the National Cancer Institute supported this research.

About Cancer

Cancer (medical term: malignant neoplasm) is the general name for a group of more than 100 diseases in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, do not invade or metastasize. Most cancers form a tumor but some, like leukemia, do not. The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is oncology.

Cancer cells can spread to other parts of the body through the blood and lymph systems. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer that begins in basal cells of the skin is called basal cell carcinoma.

• Carcinoma - a cancer which is derived from the lining cells, or epithelium, of an organ. There are 4 major types of epithelium in the body (Glandular, squamous, transitional, and pseudostratified). Some types are only found in a few select organs such as the lung (pseudostratified) or urinary bladder (transitional).  Carcinomas can arise from any of these epithelial types. For example, breast carcinoma is most commonly derived from the lining cells of the milk producing glands. A carcinoma with a glandular growth pattern is an adenocarcinoma.  Common adenocarcinomas include prostate, colon, and breast.  A carcinoma with a growth pattern resembling the squamous lining cells is termed a squamous cell carcinoma.  Common squamous cell carcinomas are found in the esophagus and skin.  However, any of these organs may have either type of carcinoma arising from it, although these latter diagnoses are exceedingly rare.
• Central nervous system cancers - cancers that begin in the tissues of the brain and spinal cord.
• Leukemia - cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced and enter the blood.
• Lymphoma - a cancer derived from the white blood cells that are present in the lymphoid tissues of the body.  These sites most commonly include the lymph nodes and spleen. However, lymphomas may arise from any organ and body site.
• Sarcoma - cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.

Today, millions of people are living with cancer or have had cancer. The risk of developing most types of cancer can be reduced by changes in a person's lifestyle, for example, by quitting smoking, limiting time in the sun, being physically active, and eating a better diet. Half of all men and one-third of all women in the US will develop cancer during their lifetimes.

• Growing Older
• Family history of cancer
• Poor diet, lack of physical activity, or being overweight
• Alcohol
  

About Breast Cancer

• Ductal carcinoma in situ (DCIS): This is the most common type of non-invasive breast cancer (85 - 90% of all cases). DCIS means that the cancer is only in the ducts. It has not spread through the walls of the ducts into the tissue of the breast. Nearly all women with cancer at this stage can be cured. Often the best way to find DCIS early is with a mammogram.
• Lobular carcinoma in situ (LCIS): This condition which occurs in approximately 8% of all cases, begins in the milk-making glands but does not go through the wall of the lobules. Although not a true cancer, having LCIS increases a woman's risk of getting cancer later. For this reason, it's important that women with LCIS to follow the screening guidelines for breast cancer.

• Inflammatory breast cancer (IBC): This uncommon type of invasive breast cancer accounts for about 1% to 3% of all breast cancers. Usually there is no single lump or tumor. Instead, inflammatory breast cancer (IBC) makes the skin of the breast look red and feel warm. It also gives the skin a thick, pitted appearance that looks a lot like an orange peel. Doctors now know that these changes are not caused by inflammation or infection, but by cancer cells blocking lymph vessels in the skin. The breast may become larger, firmer, tender, or itchy. IBC is often mistaken for an infection in its early stages. Because there is no defined lump, it may not appear on a mammogram, which may make it even harder to catch it early. It usually has a higher chance of spreading and a worse outlook than invasive ductal or lobular cancer.
• Paget's disease of the nipple. Paget's disease of the nipple or breast is a rare type of breast cancer, which can occur in women and men. It shows up in and around the nipple, and usually signals the presence of breast cancer beneath the skin. Most cases are found in menopausal women, but can also appear in women that are as young as 20.  Early stages symptoms include redness, scaly and flaky, and  mild irritation of  nipple skin. Advanced stages may include: tingling in nipple skin, very sensitive skin on the nipple, burning or painful nipple skin, ooze or bloody discharge from the nipple (not milk), itchiness that doesn't respond to creams, nipple retraction (pulls into the breast), scaly rash on areola skin, and/or breast lump beneath the affected skin.

• a lump or a thickening in the breast or in the armpit. Note Most breast lumps are benign (be-nine); that is, they are not cancer. Benign breast tumors are abnormal growths, but they do not spread outside of the breast and they are not life threatening. But some benign breast lumps can increase a woman's risk of getting breast cancer. Most lumps turn out to be caused by fibrocystic (fi-bro-sis-tik) changes. Cysts are fluid-filled sacs. Fibrosis is the formation of scar-like tissue. Such changes can cause breast swelling and pain. The breasts may feel lumpy, and sometimes there is a clear or slightly cloudy nipple discharge.
• a change of size or shape of the mature breast
• fluid (not milk) leaking from the nipple
• a change of size or shape of the nipple
• a change of color or texture of the nipple or the areola, or of the skin of the breast itself (dimples, puckers, rash)
• a discharge from the breast

About Washington University's School of Medicine

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

About The Siteman Cancer Center

Siteman Cancer Center is the only federally designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine. Siteman has satellite locations in West County and St. Peters, in addition to its full-service facility at Washington University Medical Center on South Kingshighway.

About the Avon Foundation

The Avon Foundation, a 501(c)(3) public charity, was launched in 1955 with a single scholarship of $400 and has grown to be a leader in the breast cancer and domestic violence causes worldwide. By the end of 2008, Avon philanthropy will have raised and awarded more than $660 million in over 50 countries in support of the mission to improve the lives of women globally. The Avon Breast Cancer Crusade launched in 1992 and focuses on advancing access to care for all, regardless of ability to pay, and eradicating breast cancer. Funds are awarded for breast cancer education and awareness; screening and diagnosis; access to treatment; support services; and medical research. The Speak Out Against Domestic Violence initiative was launched in 2004, focusing on awareness, education, direct service programs and prevention, with a special emphasis on children affected by domestic violence. More information: www.avonfoundation.org.