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PROSE Research Provides Answers

For Women with BRCA Mutations

by Kathy Steligo

Women with BRCA mutations must decide how to best manage their risk of breast and ovarian cancer. They may choose to take chemoprevention medication, increase surveillance, or have prophylactic surgery. Unfortunately, there is still limited data about the appropriate use or efficacy of these risk reduction options. At best, these choices can be difficult, confusing and highly personal—what is right or appropriate for one individual may be unacceptable for another.

Funded primarily by the National Institutes of Health, the PRevention and Observation of Surgical Endpoints (PROSE) Study is an ongoing project examining outcomes in BRCA carriers from 23 participating North American and European medical centers. This collaborative approach is critical to obtain appropriate sample size, according to lead researcher Tim Rebbeck, Ph.D., Professor at University of PA School of Medicine. “Because women with BRCA mutations are often seen in high-risk referral clinics, studies done in the general population may not best represent individuals who are found to have BRCA1/2 mutations,” says Rebbeck. “Individual centers don’t have enough BRCA carriers for adequate study, but pooling our data provides the study and control groups we need for statistically significant results.” Participating centers operate independently, but follow a common set of standards for participant screening, data collection, and analytical methods.

While bilateral prophylactic mastectomy (BPM) is the most extreme breast cancer risk reduction strategy, PROSE research confirms it reduces breast cancer risk in BRCA carriers by 90%. (Because breast tissue blends with other tissue in the chest, it’s never possible to remove it all. That’s why a small risk of breast cancer remains after mastectomy.) During the study, 105 BRCA women who had BPM were compared to a control group of 378 BRCA women who did not. Neither group had previous diagnoses of breast cancer. After an average followup of 6.4 years, only two (1.9%) women in the BPM group developed breast cancer compared to 184 (48.7%) in the control group. Average age of study participants was mid-30s (for those who had BPM, average age was 35-38 at the time of surgery; average age of control group participants was 34-36). BRCA carriers who had BPM but kept their ovaries reduced their breast cancer risk by 90%. Those who also had bilateral prophylactic oophorectomy (BPO) reduced their breast cancer risk by 95%. (Prior PROSE research found BPO alone, if performed prior to menopause reduces ovarian cancer risk by 90% in BRCA mutation carriers and lowers breast cancer risk by about 50%.)

Although a previous study suggested greatly reduced breast cancer risk after BPM, limited data hindered accurate risk estimates. The PROSE group results are especially meaningful to the BRCA-positive community, because the study data is specifically applicable to them. This knowledge may not make a woman’s risk management decisions easier, but it removes much of the confusion and mystery about the extent of risk reduction after prophylactic surgery.

Additional PROSE research of short-termhormone replacement therapy (HRT) may help premenopausal BRCA women decide whether to pursue BPO to reduce their risk of breast and ovarian cancer. There’s little doubt about the effectiveness of oophorectomy for women with BRCA mutations; it has been shown to reduce ovarian cancer risk by 90% and, if done premenopausally, to reduce breast cancer risk by at least 50%.

In premenopausal women, however, BPO produces surgically-induced menopause, and for many, the dreaded hot flashes, fatigue, vaginal dryness, reduced libido or other symptoms are a cruel tradeoff for lowered cancer risk. Although hormone therapy is one way to deal with these symptoms, previous research of post-menopausal women without BRCA mutations suggested HRT (estrogen plus progesterone) increases the risk of breast cancer, raising concern it may offset the risk reduction achieved by BPO. An increased risk for breast cancer was not seen in women who took ERT (estrogen alone). However, the application of this research to the BRCA community remains uncertain.

In a recent PROSE study, a group of 155 BRCA women who had BPO were compared to a control group of 307 BRCA women who did not have BPO. Ninety percent of the BPO group had surgery before age 50; the group’s average age at time of surgery was 42.7 years. After an average follow-up of 3.6 years, women who took hormones of any type after BPO still had significantly reduced breast cancer risk. In fact, they had only a third the risk of developing breast cancer as women who kept their ovaries.

More study is needed regarding the duration of HRT, the benefi ts and risks of taking estrogen alone compared to estrogen combined with progesterone, and timing of BPO relative to age or natural menopausal status. It is important for women to discuss BPO and the risk of hormone replacement with their healthcare team to make an informed decision.

PROSE Dinner

At the annual meeting of the American Society of Human Genetics, Sue Friedman was invited to speak at a dinner for PROSE participating institutions. The group listened intently as the following issues were discussed:

  • A previvor population (individuals who are predisposed to cancer but haven’t yet been diagnosed) with more time to research options is leading to “empowered patients.” This group wants to know about all their medical options and issues that relate to their high-risk status, including:
    • Research into satisfaction and longterm outcomes that examines results by type of mastectomy and type of reconstruction
    • Long-term data on outcome, satisfaction and quality of life after prophylactic oophorectomy in premenopausal women based on type of surgery and use/type of hormone replacement
  • FORCE anecdotal perception that more people are being offered genetic testing without genetic counseling, or counseling by inadequately trained providers
  • Misinformation regarding hereditary cancer, and certain organizations or media polarizing issues rather than presenting balanced information
  • Patient confusion from lack of consensus on risk management recommendations between different facilities

During the ensuing discussion, the group expressed interest in working together with FORCE to assure their research has input from our community and relevance to our members.

References

T Rebbeck, T Friebel, H Lynch, S Neuhausen, et. al. Bilateral Prophylactic Mastectomy Reduces Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. Journal of Clinical Oncology, March 2004; vol. 22, no. 6: p. 1055-1062

T Rebbeck, T Friebel, T Wagner, H Lynch, et. al. Effect of Short-Term Hormone Replacement Therapy on Breast Cancer Risk Reduction After Bilateral Prophylactic Oophorectomy in BRCA1 and BRCA2 Mutation Carriers: The PROSE Study Group. Journal of Clinical Oncology, November 2005; vol. 23, no. 31: p. 7804-7810.

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