SAN ANTONIO – Prophylactic bilateral oophorectomy is the standard of care for prevention of breast and ovarian cancer in BRCA1 and -2 mutation carriers, but the benefit may be outweighed by sharply increased subsequent all-cause mortality, mostly due to cardiovascular disease, when oophorectomy is performed in obese women at a young age, a study has shown.
"This could have very clear relevance for clinical practice. Those women who’ve had oophorectomy in the past may need to be followed more carefully and encouraged to maintain a healthy weight. And these findings may also play into planning about prophylactic surgery, as well – weighing a woman’s cardiovascular risk and obesity level in deciding whether to do a prophylactic oophorectomy," Dr. Anne Marie McCarthy said at the San Antonio Breast Cancer Symposium.
Prophylactic oophorectomy as a strategy for prevention of ovarian and breast cancer in BRCA mutation carriers is too recent a development for follow-up studies to be sufficiently mature to assess the cardiovascular impact of abrupt surgical deprivation of estrogen and androgens in premenopausal women. After all, the longest follow-up reported to date in such studies is only 6 years.
For this reason, Dr. McCarthy and her coworkers turned instead to the third National Health and Nutrition Examination Survey (NHANES III), where they zeroed in on a nationally representative sample of women aged 40 or older when interviewed during 1988-1994. They compared 474 women who had previously undergone bilateral oophorectomy, with 3,047 women with intact ovaries. Through 2006, 1,106 women had died.
Women with bilateral oophorectomy were typically older, more likely to be of lower socioeconomic and educational status, and had higher usage of hormone therapy than did those with intact ovaries. In a multivariate analysis adjusted for these and other potential confounding factors, women with a body mass index of 30 kg/m2 or more who underwent oophorectomy before age 40 had a 2.4-fold greater risk of all-cause mortality than women with intact ovaries (P = .004). The risk was similarly increased in users and never-users of hormone therapy, according to Dr. McCarthy of Johns Hopkins University, Baltimore.
Obesity was also independently associated with increased all-cause mortality in the overall study population, where a BMI of 30 kg/m2 or more conferred a 37% greater risk than seen in women with a BMI of less than 25 kg/m2 (P = .001). However, this adiposity-related increase in mortality risk was further magnified nearly sevenfold when obese women who underwent oophorectomy prior to age 40 were compared with obese women with intact ovaries.
Session cochair Dr. Graham Colditz said the new NHANES III analysis is consistent with an earlier report from the Nurses’ Health Study (Obstet.Gynecol. 2009;113:1027-37), which showed increased mortality from coronary heart disease and stroke in participants who underwent bilateral oophorectomy. Moreover, this risk was increased most dramatically in nurses with oophorectomy at a young age.
But there is an important and potentially worrisome difference between the Nurses’ Health Study population and women who undergo prophylactic bilateral oophorectomy today, he added. Enrollment in the Nurses’ Health Study began in the mid-1970s, and 70% of participants had a BMI below 25 kg/m2.
"Many of us can barely remember the days when the majority of U.S. women had a BMI less than 25 kg/m2; we’ve now shifted to where 70% are over 25 kg/m2," noted Dr. Colditz, professor of surgery at Washington University in St. Louis.
If the new NHANES III analysis is indeed correct and adiposity accentuates the adverse cardiovascular impact of bilateral oophorectomy performed at a young age, then the ongoing obesity epidemic spells trouble for the strategy of prophylactic oophorectomy for the prevention of breast and ovarian cancer.
"Are women really thinking about their overall mortality risk when they decide about prophylactic oophorectomy, or are they focusing on breast cancer mortality and disease-free survival?" he asked.
Dr. Carol J. Fabian commented that Dr. McCarthy’s study dovetails nicely with an earlier Mayo Clinic report (Lancet Oncol. 2006;7:821-8) showing that women who underwent oophorectomy before age 45 not only had a dramatic increase in cardiovascular mortality, they also had increased rates of Parkinson’s disease and self-reported cognitive deficits.
The good news: All of these increased risks were negated by hormone therapy with estrogen alone, which was an option because many of these women underwent hysterectomy at the time of oophorectomy, she said.
"It’s a really important point: If we’re going to perform oophorectomy on these very high-risk women at a very young age, there are going to be more cardiovascular outcomes, and we have to really think hard about how to prevent these," noted Dr. Fabian of the University of Kansas Cancer Center in Kansas City.