Prophylactic Oophorectomy in BRCA Carriers Reduces Mortality

Removal of the ovaries (oophorectomy) in women who carry harmful BRCA mutations prevents both ovarian and breast cancer, and reduces overall mortality.

In a landmark study published last week in JAMA, researchers followed 2343 women with BRCA1 and BRCA2 mutations for a mean of 3-6 years (range 0.5-27 yrs), and compared cancer and mortality outcomes between those who had risk-reducing surgery (172 had mastectomy and 993 had removal of the ovaries) and those who chose not to have surgery. Those who did not have surgery were offered aggressive surveillance for breast cancer (annual mammography and breast MRI) and ovarian cancer (ultrasound and Ca125 testing every 4-12 months).

In women who underwent risk-reducing salpingo-oophorectomy, 1.1% were subsequently diagnosed with ovarian cancer (ie, primary peritoneal cancer), 11.4% were subsequently diagnosed with breast cancer, and 3.1% subsequently died of any cause. In women who did not undergo risk-reducing salpingo-oophorectomy, 5.8% were subsequently diagnosed with ovarian cancer, 19.2% with breast cancer, and 9.8% subsequently died from any cause.

Ovarian cancer risks were higher in BRCA 1 (7-8%) than BRCA2 carriers (3%) who kept their ovaries. No BRCA2 carriers who had their ovaries removed got peritoneal cancer during the follow up. (This is consistent with prior literature on these mutations and ovarian cancer risks.) Nine women who had their ovaries removed had small occult ovarian cancers diagnosed in the removed ovaries.

Prophylactic oophorectomy was also protective against primary breast cancer, cutting the risk in half – from 22% to 11%. In women who had prior breast cancer, oophorectomy reduced the odds of a second breast cancer from 14% to 11%.

Prophylactic oophorectomy appears to be more effective in BRCA2 than BRCA1 carriers – there were no breast or ovarian cancer-related deaths in BRCA 2carriers who had their ovaries removed.  The surgery appeared to be of equal value in women over and over age 50.

While prophylactic mastectomy indeed reduced the risk of acquiring breast cancer (no women who had the surgery got breast cancer), it did not impact mortality.

Bottom Line

Women who carry harmful BRCA mutations have a markedly increased cancer risk ; 15-40% will develop ovarian cancer in their lifetime (compared to about 1% of the general population) and 6-% will develop breast cancer (compared to 12% of the general population of women).

While we can offer BRCA mutation carriers effective screening for breast cancer (mammogram, sonogram and MRI), we do not have an equally effective screening tool for ovarian cancer. Even the much touted ultrasound and Ca125 tests have not been shown to reduce mortality from ovarian cancer. In this study, in fact, women were offered sonograms and Ca125 testing, and although we do not know to what extent they actually availed themselves of the surveillance, it clearly did not offer them the same protection against ovarian cancer as oophorectomy.

The protective effect of oophorectomy in carriers of harmful BRCA mutations stands in marked contrast to oophorectomy in women at average risk of ovarian cancer, which has been shown to actually increase mortality when performed in women under age 65.

What are the risk factors for having a harmful BRCA mutation?

About 2% of women have risk facotrs for BRCA 1 and 2 mutations. According to the NCI, these are –

For women who are not of Ashkenazi Jewish descent :

• two first-degree relatives (mother, daughter, or sister) diagnosed with breast cancer, one of whom was diagnosed at age 50 or younger;
• three or more first-degree or second-degree (grandmother or aunt) relatives diagnosed with breast cancer regardless of their age at diagnosis;
• a combination of first- and second-degree relatives diagnosed with breast cancer and ovarian cancer (one cancer type per person);
• a first-degree relative with cancer diagnosed in both breasts (bilateral breast cancer);
• a combination of two or more first- or second-degree relatives diagnosed with ovarian cancer regardless of age at diagnosis;
• a first- or second-degree relative diagnosed with both breast and ovarian cancer regardless of age at diagnosis; and
• breast cancer diagnosed in a male relative.

For women of Ashkenazi Jewish descent –

• any first-degree relative diagnosed with breast or ovarian cancer; and
• two second-degree relatives on the same side of the family diagnosed with breast or ovarian cancer.

Women who have none of these family history patterns have a low probability of having a harmful BRCA1 or BRCA2 mutation.

How I Will Use these Study Results

I encourage women with suggestive family histories to see a genetic counselor to discuss BRCA testing. Despite making many such referrals,  I find most women don’t follow through.  “Why should I want to know?” they ask.  “What would I do differently if I had the BRCA gene other than worry?”

It’s an important question that deserves an answer. So I tell them –

We would offer prophylactic oophorectomy. That’s because we have no good screening that has been proven to reduce ovarian cancer mortality. But if we remove the ovaries, we can significantly reduce the odds of getting both ovarian and breast cancer.  With this new study, I can now tell these women that this cancer risk reduction also translates to a significant reduction in mortality. And give them some numbers to chew on as they think about what, if anything, they want to do.

The decision to proceed to oophorectomy is never undertaken lightly. Which is why BRCA testing is helpful – it may allow us to avoid surgery in women who test negative for harmful mutations. It is also why we offer oophorectomy at too young an age and certainly not until childbearing is completed in women who do carry harmful mutations. Sometime in the 40’s seems about the right age for oophorectomy in BRCA mutation carriers. The surgery can usually be done laparoscopically, with same day discharge in many cases.

The price we pay for oophorectomy, of course, is menopause. Menopause that we may not want to treat with estrogen because of your predisposition to breast cancer. However, there are non-hormonal ooptions for hot flashes that can be effective. And here it can get complicated, as some patients decide to have a hysterectomy as well as an oophorectomy, so that they can take unopposed estrogen, which (at least in the WHI) is not associated with an increased risk for breast cancer. (Not unreasonable thinking, in my opinion…) But these are just some of the things you’ll want to think about before considering prophylactic oophorectomy.

I don’t push prophylactic mastectomy, although it is certainly an option for BRCA carriers. This study makes this feel even more reasonable, because while mastectomy certainly prevented breast cancer, it did not significantly reduce mortality from breast cancer. I suspect that is because we’re pretty darned good at screening for breast cancer, and have very effective treatments. But some women will choose mastectomy regardless.

For women with suggestive family histories who choose either not ot know their BRCA status, or who opt for surveillance only, I encourage enrollment in a clinical trial of new screening methods for ovarian cancer. For those who don’t do this, I will do ca125 and sonograms, simply for the lack of anything else better to do.

One of these days, we’ll hopefully have an effective screening test for ovarian cancer. But until then, prophylactic oophorectomy remains an important option for women at increased risk for ovarian and breast cancer due to harmful BRCA mutations.

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NCI Fact Sheet on BRCA mutation testing

NCI Bulletin on this research study