By Sarina Kopinsky, MS, CGC and Amy Adams, MS

Reviewed by Miriam Komaromy, MD and Andrea Fishbach, MS, MPH



Since 1998, women at high risk for breast cancer have been able to reduce their risk for the disease by taking a drug called tamoxifen. However, researchers still aren't sure whether tamoxifen's cancer-preventing effects extend to women with mutations in the BRCA1 and BRCA2 genes – mutations that greatly increase a woman's risk of developing breast cancer. One recent study found that taking tamoxifen to treat an existing breast cancer can prevent second breast cancers from forming in this group of women. Although this study does hint at the fact that tamoxifen also prevents initial cancers, it is far from conclusive. The study that should provide better answers to this question won't be finished until next year. Until then, women with BRCA1 or BRCA2 mutations and their doctors are left with incomplete information on which to base their decisions about taking tamoxifen.

More on the Genetics of Breast and  Ovarian Cancer     More on Chemoprevention for Breast Cancer

Tamoxifen as Chemoprevention

Tamoxifen reduces a woman's risk of breast cancer by 49 percent.

However, the BCPT study also revealed some serious medical risks, such as an increased risk for endometrial cancer, pulmonary embolism (blood clot in the lung), stroke, and deep vein thrombosis. Women who took tamoxifen also experienced side effects such as hot flashes, vaginal dryness, and nausea. Although these side effects were not life-threatening, they were annoying enough that they caused some women to discontinue use of the drug. (For recent news about tamoxifen side-effects, see Related News below.)

Victor Vogel, professor of medicine at the McGee Women's Hospital in Pittsburgh and one of the leaders of the BCPT tamoxifen trial says that all groups of women — in terms of age and risk level — responded equally well to tamoxifen. However, because the BCPT trial did not screen women for BRCA mutations, it's not clear if these women responded better or worse than women without the mutations. Nor is it clear whether the side effects were more or less pronounced in women with these mutations.

top

Tamoxifen's Role in Treating Women with BRCA Mutations

A recent study began to address some issues about tamoxifen in women with BRCA1 and BRCA2 mutations. This study found that tamoxifen reduced the risk of developing cancer in the second breast in women with BRCA1 or BRCA2 mutations who took the drug to treat an existing cancer. Doctors aren't sure if this result is because tamoxifen prevents new cancers from forming or if it fights undetected cancers in the second breast. Kevin Fox, an associate professor of medicine at the University of Pennsylvania Cancer Center, says that this study validates tamoxifen as an option for women with mutations in BRCA1 or BRCA2.

However, this study cannot be taken as conclusive evidence that tamoxifen prevents cancer in women with BRCA mutations, Fox says. It looked back in time at women who may have had very different treatment, or been given those treatments for different lengths of time. The differences between women who took tamoxifen and those who did not may be a result of factors other than tamoxifen use. Fox says that because the study only looked indirectly at tamoxifen's effects, the results are still questionable.

A study that's currently underway should help researchers understand whether tamoxifen is effective in women with mutations in BRCA1 or BRCA2.

This study should help answer which high-risk women are most likely to benefit from taking tamoxifen. However, results from this study aren't expected for about a year. Each gene sequence keeps a lab technician busy for about two weeks full-time, says Vogel, explaining why this research takes so long.

top

How Tamoxifen Works

Tamoxifen binds to estrogen receptors, preventing estrogen from fueling a tumor's growth.

In women who have an ER+ tumor, tamoxifen is the standard treatment says Craig Jordan, pharmacologist at Northwestern University Medical School's Robert H. Lurie Comprehensive Cancer Center in Chicago. In this role, Jordan claims that tamoxifen has already saved the lives of 350,000 women worldwide. At this time, researchers don't know if tamoxifen can treat or prevent ER- tumors. Drug information from tamoxifen's manufacturer AstroZeneca describes tamoxifen's role for ER- tumors as "still investigational."

Because Tamoxifen is so effective at treating ER+ tumors, many researchers also believe that it is these ER+ tumors that it prevents. In fact, Lawrence Wickerham of Allegheny University Hospitals and the NSABP in Pittsburgh, is convinced that all tumor prevention in the BCPT tamoxifen trial was because of effects on ER+ and not ER- tumors. However, Wendy Rubinstein, a medical geneticist at University of Pittsburgh's Cancer Institute and McGee-Women's Hospital points out that they really don't know which women would have been destined for an ER+ or ER- tumor in the future. She says of tamoxifen, "Its role is not limited to estrogen receptors, since it could have other benefits. This field is totally unexplored."

According to several studies, breast tumors in women with mutations in either gene are one third to one half as likely to be ER+ than in women of the same age in the general population. Although researchers haven't pinned down the exact number, only about 33 percent of tumors in people with BRCA1 or BRCA2 mutations are likely to be ER+. Because of this lower percentage of ER+ tumors, many researchers had thought that tamoxifen would be less effective at preventing cancers in this group of women. However, Fox points out that this concern may not be warrented because in the one study to date, tamoxifen was able to prevent some cancers in these women.

top

Making Decisions About Tamoxifen

Although tamoxifen may be useful in preventing breast cancers in women with BRCA1 or BRCA2 mutations, Barbara Brenner, executive director of Breast Cancer Action (BCA), a patient advocacy organization in San Francisco, warns that for some women, the harmful side-effects result in disease substitution rather than disease prevention. And in other women, the nausea, vaginal dryness, and hot flashes alone are enough to make them discontinue use of the drug. She also worries that with the new data, women may choose to take tamoxifen without understanding the limitations of the trial, or carefully considering the side-effects. "I'm most concerned that patients are well infomed," she says. "We frequently get complaints that women have symptoms that their doctor didn't tell them about."

Rubinstein's advice to women with BRCA mutations is to examine their increased breast cancer risk. The higher that risk, the more they may benefit from tamoxifen. "For instance, if tamoxifen changes a 10 percent breast cancer risk to 5 percent, the net gain is 5 percent. If it halves it from 5 percent to 2.5 percent, the net gain is only 2.5 percent" she says.

Leslie Bernstein, professor of preventive medicine at USC/Norris Comprehensive Cancer Center, points out that between breast and endometrial cancer:

• Breast cancer is five times more common than endometrial cancer.
  
• Women with breast cancer are more likely to die of it than from endometrial cancer.
  
• Endometrial cancer can be detected early and treated by hysterectomy.
  

Unlike breast cancer, endometrial cancer can usually be detected and treated in its early stages, and is rarely fatal.

An additional consideration for some women is choosing which five year period to take the drug (five years is the normal course for tamoxifen when it is used as a preventative drug). Because tamoxifen is not recommended for women who plan to have children, they must decide when to take the drug around pregnancy and breast-feeding. This timing may be more of an issue for women with BRCA mutations than women with sporadic cancers, because BRCA mutations put women at risk for getting breast cancer at a younger age.

top

Related News

In order to view these articles you will need to have a MyGeneticHealth account. If you are not already a member, selecting the article will automatically take you to a page where you can sign up. Tamoxifen plus soy prevents breast cancer in rats Tamoxifen may protect heart Tamoxifen reduces risk of contralateral breast cancer in BRCA carriers Device may prevent tamoxifen side effect Tamoxifen does not seem to help or hurt the heart

References

Verhoog, et al. (1999) Survival in Hereditary Breast Cancer Associated with Germline Mutations of BRCA2. Journal of Clinical Oncology 17 (11): 3396-3402

Verhoog et al. (1998) Survival and tumor characteristics of breast-cancer patients with germ line mutations of BRCA1. Lancet 351: 316 - 321.

Fisher B, et al. (1998)Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Natl Cancer Inst; 90(18):1371-88.

Spillman MA and Bowcock AM (1996) BRCA1 and BRCA2 mRNA levels are coordinately elevated in human breast cancer cells in response to estrogen. Oncogene 13:1639-1645.

Narod, S. A., et al. (2000) Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Lancet 356:1876-1881.

Personal communication (2000). Victor Vogel, professor of medicine at the McGee Women's Hospital in Pittsburgh, one of the leaders of the BCPT.

Personal communication (2000). Craig Jordan, PhD pharmacologist at Northwestern University Medical School's Robert H. Lurie Comprehensive Cancer Center in Chicago.

Personal communication (2000). Lawrence Wickerham, MD, of Allegheny University Hospital and the NSABP in Pittsburgh

Personal communication (2000). Wendy Rubinstein, medical geneticist at University of Pittsburgh's Cancer Institute and McGee-Women's Hospital

Personal communication (2000). Barbara Brenner, executive director of Breast Cancer Action (BCA), a patient advocacy organization in San Francisco

Personal Communication (2000). Kevin Fox, MD, associate professor of medicine at the University of Pennsylvania Cancer Center.