he road of scientific discovery is often long and demands both perseverance and open dialogue among researchers and clinicians to reach a goal. This was true in the more than 30-year process of discovery and development of tamoxifen. First developed as a breast cancer treatment, tamoxifen now has been proven to help reduce the risk of breast cancer in women at high risk for developing the disease. The discovery of tamoxifen's dual role as a cancer treatment and risk reduction strategy was fostered by the dedicated efforts of many researchers around the world who pursued the use of tamoxifen as a treatment and ultimately recognized its potential for breast cancer prevention, and by the efforts of thousands of patients who volunteered for clinical trials testing tamoxifen.

Tamoxifen, first discovered in 1962, is an anti-estrogen – a substance that stops estrogen from working in specific tissues by preventing the hormone from docking in estrogen receptors found in these tissues. Because of this activity, tamoxifen was first tested as a contraceptive; surprisingly, however, women in the clinical trials who took tamoxifen became more fertile.

Because tamoxifen was not an effective contraceptive, scientists looked for other ways the compound could be used. Through these investigations, they discovered that tamoxifen's anti-estrogen activity appeared to be selective: it stopped estrogen from working only in certain tissues, such as breast tissue. Knowing that estrogen must bind to its receptors in breast cancer cells to promote tumor growth, and that tamoxifen prevents estrogen from reaching its receptors, scientists began to wonder if the drug might stop breast cancer growth. Therefore, researchers began looking at the drug's ability to combat the growth of human breast cancer cells in animals, as well as in cancer cells grown in the laboratory. In both settings, tamoxifen successfully robbed the cancer cells of the estrogen they needed for tumor growth. These results led to testing of tamoxifen as a treatment for patients with advanced breast cancers. These first clinical trials were successful, and in 1977, the Food and Drug Administration (FDA) approved tamoxifen for advanced breast cancer therapy.

Tamoxifen's success as a treatment for advanced breast cancer fueled many scientists' desire to continue looking for new ways to use the drug to help cancer patients. Tamoxifen was next tested with success as an adjuvant therapy, a treatment given following surgery. Taken as an adjuvant, tamoxifen extended patient survival time prompting researchers to begin testing it as a treatment for women with estrogen-dependent breast cancers that had spread to the lymph nodes. Its success as an adjuvant therapy and in treating women with lymph-node involvement led to FDA approval of tamoxifen's use for these patients in the early 1980s. As the results of the different trials were reported, open dialogue between researchers in the laboratory and clinic became critical to refining the design of new trials and uncovering trends in the data. When this growing pool of data was analyzed, three themes began to emerge: women who received tamoxifen had increased rates of survival; women who took the drug had fewer recurrences of cancer; and, it seemed that tamoxifen might prevent breast cancer – an observation supported by evidence from animal studies.

Responding to this analysis, researchers at the National Surgical Adjuvant Breast and Bowel Project (NSABP) launched B-14, a pivotal trial to see if tamoxifen therapy enabled women whose estrogen-dependent breast cancers had not yet spread to live longer and have fewer recurrences of cancer. The results of B-14 not only demonstrated that tamoxifen did indeed increase survival and decrease recurrence, it also showed that women who already had cancer in one breast and took tamoxifen following other treatment regimens had a 40 percent decrease in the number of breast cancers diagnosed in the opposite (unaffected) breast. This confirmed that tamoxifen did appear to prevent breast cancer and that prevention studies were needed for women who had not yet had breast cancer, but were at high risk for developing the disease.

Now that more than two decades of study had proven tamoxifen to be a safe and effective treatment for early-stage breast cancers and a preventive for women who already had the disease, researchers and clinicians were ready for a study to answer the next question: could tamoxifen prevent breast cancer in women who had not yet developed the disease? Thus, in 1992, NSABP launched the NCI-funded Breast Cancer Prevention Trial (BCPT).

Over 13,000 women at high risk for developing breast cancer volunteered for the BCPT and were randomly assigned to receive either tamoxifen or a placebo. After following the progress of these women and analyzing the data, researchers showed that tamoxifen reduces the rate of developing primary breast cancer by 49 percent in women who are at high risk for developing the disease. The success of tamoxifen in reducing the risk of breast cancer among high-risk women led to the early announcement of the trial's results. Despite potential side effects, such as an increased risk of developing endometrial cancer in women over age 50, and a risk of developing blood clots in the major veins and lungs (similar to hormone replacement therapy), tamoxifen's results mark an historic achievement in cancer prevention research.

However, tamoxifen's story has not yet come to a close. Researchers are already creating and testing a second generation of breast cancer prevention agents, such as raloxifene, which may help prevent the disease without some of tamoxifen's potential side effects. Later this year NCI will launch the Study of Tamoxifen and Raloxifene (STAR), a trial comparing the two drugs' abilities to prevent the onset of breast cancer in high-risk, post-menopausal women, as well as comparing their side effects.

As we continue our quest for a drug that will help prevent breast cancer for all women, we can mark the discovery and development of tamoxifen as a major milestone, one that has established a whole new avenue of prevention research that should continue to foster prevention discoveries and successes well into the future.