"It is a very difficult thing to recommend prophylactic oophorectomy when it is healthy women you are talking about," said Mary-Claire King, Ph.D. "It is a radical thing to consider in a feminist age."
Yet Kingwho discovered the BRCA1 gene in 1990said that her thinking has "evolved a lot in the last 25 years." King, who is an American Cancer Society professor of medicine and genetics at the University of Washington at Seattle, said that at first, neither the genetic connection of ovarian and breast cancer, nor the value of prophylactic oophorectomy for both cancers, was yet known.
Experience with genetic testing and follow-up of women who carry the high-risk gene has sharpened her perspective.
"I have seen too many women [carriers] die of ovarian cancer," King observed. Recent studies suggesting that oophorectomy may substantially lower gene carriers risk for both ovarian and breast cancer have also influenced her thinking.
Today, King said that she would advise a woman who tests positive for a BRCA1 or BRCA2 gene mutation to "think seriously and discuss with her physicians having a prophylactic oophorectomy as soon as she has finished having children."
Cancer Risk Reduction
The rationale behind recommending prophylactic oophorectomy for ovarian cancer risk reduction to high-risk women in their forties is twofold. The risk for hereditary ovarian cancer does not become high until the forties, and by delaying the surgery until then, high-risk women need not forego having children.
Right now, many researchers and clinicians agree with King that oophorectomy looks like a high-risk womans best shot at reducing her risk for ovarian cancer. At the same time, few people consider bilateral prophylactic oophorectomy a magic bullet. Many researchers are quick to acknowledge that the data to back using it widely is wanting and that the ideal circumstances for performing it remain unclear.
One reason why prophylacticor "risk-reducing"oophorectomy (as many more clinicians say)looks appealing is that without it, ovarian cancer is usually detected at an advanced, incurable stage. The lack of a proven screening test also pushes oophorectomy out front.
Oophorectomy is also associated with a large reduction in the risk for breast cancer. In the Sept. 1, 1999, Journal of the National Cancer Institute, Timothy R. Rebbeck, Ph.D., associate professor of epidemiology at the University of Pennsylvania, Philadelphia, and co-authors reported a 50% breast cancer risk reduction in gene-carrier women who had prophylactic oophorectomies, compared with those who did not. When the data was limited to women followed for 10 years, the breast cancer risk reduction rose to 70%. New analysis from the same data set, but extended to 250 cases and 250 controls, showed the same "50% and 70% risk reduction numbers," according to Rebbeck, who reported it at an update at the American Society of Human Genetics meeting in October.
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Data on ovarian cancer risk reduction with oophorectomy for high-risk women carrying BRCA1 and BRCA2 mutations are scarce, but at the ASHG meeting, Rebbeck presented the first study of oophorectomy in gene-carrier women, showing a 90% to 95% ovarian cancer risk reduction associated with the operation.
"There have been other studies, but they have included women in the general population who had surgery for other reasons than to reduce ovarian or breast cancer risk, and many employed case series and descriptive study designs," said Rebbeck.
Other data reveal that early stage ovarian cancers are being detected in ovaries removed prophylactically. "We are beginning to believe that we may be showing some first evidence of lives saved because of the genetic testing that we are doing," Kenneth Offit, M.D., chief of clinical cancer genetics at Memorial Sloan-Kettering Cancer Center, New York, told attendees at an American Society of Clinical Oncology meeting in New York called Human Genetics and Its Implications for Cancer. "We have now followed over 200 women with BRCA mutations, and we have found four early-stage ovarian cancers in almost 100 preventive surgeries. For many of us, it is exciting. I have been at Memorial for 10 years and didnt see a stage I ovarian cancer until we started doing BRCA testing."
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These developments have energized investigators to press ahead. That said, fundamental questions that must be resolved include determining the best surgical strategy, the ideal age at which oophorectomy should be performed, the role of oral contraceptives and tamoxifen, and the relationship between peritoneal carcinomatosis and surgery in this subset of women, according to Steven A. Narod, M.D., chief of breast cancer research at the University of Toronto.
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Surgical Technique
There is no consensus on the optimum surgical technique. Narod favors performing a hysterectomy because it offers more flexibility. "An advantage of adding a hysterectomy [compared with a laporoscopic oophorectomy] is that tamoxifen can be given without fear of endometrial cancer," Further, he stressed: "It is important to remove the Fallopian tubes, as they can be a site of cancer."
However, surgeons at Memorial Sloan-Kettering Cancer Center believe that a laparoscopic oophorectomy is best, according to Offit. "Patients find the laparoscopic procedure much less of an ordeal [than a hysterectomy] and patients report high levels of patient satisfaction," he added.
The age for a prophylactic oophorectomy in high-risk women depends on whether you are seeking breast cancer protection as well, Narod said. "If you want breast cancer protection, performing an oophorectomy at age 35 makes sense," he said, but he added that performing it that young is much more controversial because it leads to premature menopause.
Rather than focus on oophorectomy, NCIs PLCO trial and trials in the United Kingdom are funneling money into studying ovarian cancer screenings value. Narod questioned whether that money is well spent. "If the surgery does not work, there is no way that a screening strategy will prove effective," said Narod.
Study Limitations
Mark H. Greene, M.D., chief of NCIs clinical genetics branch, saw limits to existing studies. He questioned whether prior studies offer "reliable risk estimates." Besides using primarily retrospective study designs, the studies consist of "relatively small numbers." He also observed that "in some families, all you see is breast cancer, and ovarian cancer just doesnt occur. This makes it very difficult to quantify risk estimates."
NCI is in the early planning stages of establishing a national prospective cohort study that would identify mutation carriers and follow them as they opt for prophylactic surgery or do not. Additionally, Greene observed that existing data "still does not answer questions about costs, benefits, and harms."
Kathy J. Helzlsouer, M.D., suggested that the downsides to the surgery may be getting short shrift. "It is just not a great or easy option," said Helzlsouer, epidemiologist at the Johns Hopkins School of Public Health. "When women have a positive gene test, they have really difficult options. On the one hand, some women feel like they have nothing left. On the other hand, many get peace of mind." Data on quality of life with the procedure are scant, she acknowledged.
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Besides focusing on prophylactic oophorectomy and cancer risk reduction, researchers need to be attentive to a womans overall health, Helzlsouer observed. Investigating how modifying other factors affects cancer risk and exploring medical alternatives should also be pursued, she said. In addition, she said: "We need to learn about each specific mutation and have more precise penetrance information."
Helzlsouer continued: "There is a lot we dont know. We really need much better information so that we do oophorectomies on only those who would go on to get ovarian cancer."
Greene echoed many of Helzlsouers concerns, warning: "Everybody wants to try something effective, but there is not a lot of data," he said. "What has emerged is peoples best clinical judgment."
In the March 7 issue: How does prophylactic mastectomy for breast cancer factor into the picture for BRCA1/BRCA2 gene carriers?
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