For women with BRCA1 or BRCA2 mutations who choose to have salpingo-oophorectomy to reduce their risks of ovarian and breast cancer, also choosing to have a hysterectomy is “reasonable but not required,” noted Noah D. Kauff, MD, Director of the Ovarian Cancer Screening and Prevention Program and Associate Attending Physician on the Clinical Genetics and Gynecology Services, at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York. The decision to have a concurrent hysterectomy should be individualized, Dr. Kauff stressed, and based on a careful appraisal of the risks and benefits of also removing the uterus.
While not new, risk-reducing surgery has been in the news lately. “Particularly in the last 6 months, following Angelina Jolie’s revelation that she carries a BRCA1 mutation, the discussion of risk-reducing surgery, be it risk-reducing mastectomy or risk-reducing salpingo-oophorectomy, has been brought again to the forefront. People are reexamining the pros and cons of these procedures,” Dr. Kauff said.
A recent article in The New York Times1 begins with the case of a woman who tested positive for a BRCA mutation and chose to have her ovaries and fallopian tubes removed, but not her uterus. Five years later, she was diagnosed with stage III cancer of the uterus. “If I had known, I would have absolutely taken it out,” she told the Times.
To put the risk in context, Dr. Kauff pointed out in an interview with The ASCO Post that “1 out of 40 women in the United States will get uterine cancer in their lifetime. So if you leave behind 100 uteruses at risk-reducing surgery, you would expect 2 to 3 of those women to get uterine cancer,” he explained.
“What the article in The New York Times did not say, and what is not clear from the literature, is whether there is an increased risk of uterine cancer in women with BRCA1 or BRCA2 mutations. The data on this has been controversial,” Dr. Kauff noted.
Changed Standard of Care
“Surgery to reduce breast and ovarian cancer risk should only be recommended for women with a documented BRCA1 or BRCA2 mutation,” Dr. Kauff stressed. Two studies2,3 published simultaneously in the The New England Journal of Medicine in 2002, looking at the impact of risk-reducing salpingo-oophorectomy, “very rapidly changed the standard of care for women with BRCA1 or BRCA2 mutations,” according to Dr. Kauff, who was the lead author of one of those studies.
“Our study showed a reduction in the combined risk of breast and gynecologic cancer by 75% in women who had risk-reducing surgery,” he said. “Since then, multiple additional studies have shown that BRCA1 and BRCA2 mutation carriers get anywhere from a 70% to 96% reduction in ovarian cancer risk and anywhere from a 40% to 70% reduction in breast cancer risk if the procedure is performed premenopausally,” Dr. Kauff stated.
“It is very unusual for a woman at Memorial who is otherwise healthy and has a BRCA1 or BRCA2 mutation not to ultimately undergo risk-reducing salpingo-oophorectomy, either after childbearing is complete or after menopause. The vast majority of patients do have risk-reducing salpingo-oophorectomy,” Dr. Kauff said. “The reason risk-reducing salpingo-oophorectomy is so commonly used is that there is no good screening alternative for ovarian cancer.”
Guidance for Women and Physicians
Dr. Kauff has contributed to several documents4-6 that can provide guidance on risk-reducing salpingo-oophorectomy. “Probably the most important is a practice bulletin4 that the American College of Obstetricians and Gynecologists (ACOG) put out in April 2009 on hereditary breast and ovarian cancer syndrome,” he said.
According to the ACOG practice bulletin:
The decision to perform a concurrent hysterectomy should be individualized. Salpingo-oophorectomy alone confers a significant cancer risk reduction with less surgical risk and shorter postoperative recovery. Arguments in favor of hysterectomy include a more simplified hormone therapy strategy (with estrogen only) and a theoretical increased risk of cancer in the cornual fallopian tube. In addition, hysterectomy may be considered where there are other medical indications for removal of the uterus and cervix. For women taking tamoxifen, hysterectomy may be considered to reduce their endometrial cancer risk.
Residual Fallopian Tube Risk?
Concern has been raised about cancer developing in the small amount of fallopian tube that is in the body of the uterus and is left behind when the fallopian tubes, but not the uterus, are removed. “That has been a theoretical risk that has become less of a concern over the past 4 to 5 years for several reasons,” Dr. Kauff said.
“Although we think the fallopian tube is likely very important at least for a fraction of BRCA-associated ovarian and fallopian tube cancers, the areas that are most important are the fimbrial ends, which are the farthest away from the uterus and the nearest to the ovary. And the fimbriae are always removed in their entirety when you do a risk-reducing salpingo-oophorectomy,” Dr. Kauff remarked.
“What is not as clear is if the residual tube, which has a very different biology, is particularly important from an ovarian cancer standpoint. Additionally, there is not a single well-documented case in the literature of a fallopian tube cancer arising in a stump of a fallopian tube following a risk-reducing surgery in a BRCA mutation carrier,” he continued. “It’s a theoretical risk only.”
Another area that has been “somewhat controversial,” Dr. Kauff said, concerns whether BRCA mutations are associated with “an increased risk of a more aggressive type of uterine cancer—serous uterine cancer—which in many ways behaves more similarly to ovarian cancer than it does to more common uterine cancers.” Some studies have suggested that serous cancers are more common among women with a BRCA1 or BRCA2 mutation, but this has not been confirmed, Dr. Kauff noted.
Even if there is an increased risk of serous cancer, “the lifetime risk of this cancer is still likely less than 1%,” Dr. Kauff noted. “So from a biologic standpoint, it may have an impact, but it is not as clear how much of an impact it has from a clinical standpoint.”
Hysterectomy Rate Is ‘Center-Dependent’
The New York Times article reported that about half of women who have BRCA mutations and have their ovaries and fallopian tubes removed to reduce the risk of ovarian cancer, also opt for removal of the uterus. But that percentage “is actually very center-dependent,” Dr. Kauff said. “For example, at Memorial, it is a much lower number than 50%.” On average over the past 15 years, “about 16% of our patients who undergo risk-reducing salpingo-oophorectomy elect concomitant hysterectomy,” Dr. Kauff said. “If you go out to the West Coast, that number is probably closer to 70% to 80%. At a national level, it would not surprise me if it was 50%, but those data are not currently available.”
He added that those numbers have been changing and that for 2013, the percentage of women treated at MSKCC who elect concomitant hysterectomy with salpingo-oophorectomy “is probably in the low 20% range. Our rate is probably going up, and the West Coast rate is coming down. Everyone is being more conscious of this issue and having better discussions with patients,” Dr. Kauff said.
“At Memorial, we believe that if you need to remove an organ surgically, we absolutely do it. But I think we are very cognizant of the need to ask ourselves why we are removing a particular body part and whether it is necessary. I don’t think there is convincing evidence that we have to remove the uterus in the case of a woman with BRCA mutation, and this is why we have a very detailed discussion. When we have this discussion, the vast majority of our patients with BRCA mutations elect not to have a hysterectomy, unless there is another gynecologic reason,” he noted.
“We have already put together a team to look at our data again and reassess whether there is an increased risk of subsequent uterine cancer in our prospective follow-up. So it is something that we are going to readdress. At this point, I don’t know whether we are going to come to any new conclusions, but I think it does make sense to reconsider it, and we are uniquely positioned to be able to do that.”
Dr. Kauff’s team is uniquely positioned because “Memorial has the United States’ largest single-institution prospective cohort of BRCA mutation carriers,” he explained. “Currently we are following over 1,400 individuals who have documented BRCA1 or BRCA2 mutation with annual prospective follow-up, looking at cancer risk-reduction strategies and the occurrence of subsequent cancers.”
The women are offered enrollment in the studywhen they come in for genetic testing, “but before we know the results,” Dr. Kauff said. “Almost 83% of the women who have undergone BRCA1 and BRCA2 mutation testing at MSKCC in the past decade have enrolled on this prospective follow-up study.”
Potential Markers for Uterine Cancer
Asked if there were any markers or other indications to gauge who might be likely to develop uterine cancer, Dr. Kauff noted that there is a genetic marker for Lynch syndrome, “which is associated with a very high risk of both colon and uterine cancer, and it is actually the most important inherited cause of uterine cancer. For Lynch syndrome, the lifetime risks of uterine cancer can be as high as 40% to 60% vs 2.5% in the general population. So for that group, as opposed to the group with BRCA1 or BRCA2 mutations, if you are going to do risk-reducing surgery, hysterectomy is a required procedure,” Dr. Kauff stated.
“But by far the most important marker of risk of uterine cancer is obesity. That is the single biggest risk factor for uterine cancer, and that is modifiable,” he added. “Patients who are severely obese may have a 10-fold increased risk of uterine cancer compared to the general population.” ■
Disclosure: Dr. Kauff has consulted and provided expert testimony for Pfizer relating to hormone replacement therapy.
References
1. Harris JW: Weighing surgeries in light of a breast cancer gene. New York Times, October 7, 2013.
2. Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346:1609-1615, 2002.
3. Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346:1616-1622, 2002.
4. American College of Obstetricians and Gynecologists: Hereditary breast and ovarian cancer syndrome: Clinical management guidelines for obstetricians-gynecologists. ACOG Practice Bulletin 103:957-966, 2009.
5. Society of Gynecologic Oncologists Clinical Practice Committee: Statement on prophylactic salpingo-oophorectomy. Gynecol Oncol 98:179-181, 2005.
6. Kauff ND, Barakat RR: Risk-reducing salpingo-oophorectomy in patients with germline mutations in BRCA1 or BRCA2: J Clin Oncol 25:2921-2927, 2007.
