Ovarian Cancer | The Blog That Ate Manhattan

Removing the Fallopian Tubes to Prevent Ovarian Cancer – Something to Consider

January 23, 2015

Uterus Tubes and Ovaries New information strongly suggests that most ovarian cancers originate, not in the ovary, but in the fallopian tube. If this is so, then removal of the fallopian tubes may actually prevent ovarian cancer.

The evidence is powerful enough that the American Congress of Obstetricians & Gynecologists is now recommending that fallopian tube removal be considered in women planning to undergo surgical sterilization or hysterectomy.

The Fallopian Tube Origin of Ovarian Cancer

We used to think that ovarian cancer originated in the peritoneal lining that covers the ovaries and abdominal organs. But the fallopian tube origin of ovarian cancer makes so much more sense when you consider what we know about ovarian cancer.

Think about it. The fallopian tube is an open tube that almost caresses the ovary at its distal end, where it is open to the abdominal cavity. Its blood supply is intimately shared with the ovary, and its inner surface is bathed in fluid that it shares with the fluid of the abdominal cavity. According to the theory, cancerous cells arise in the fallopian tube from small precancerous precursor lesions, where they grow undetected until they metastasize to the nearby ovary, or to the abdominal wall and surface of the pelvic and abdominal organs.

This goes a long way to explain why ovarian cancer is more often spread beyond the ovary to the pelvis and abdomen (Stage 3) and not just confined to the ovary (Stages 1 and 2) at diagnosis.

It also helps to explain how ovarian cancer has stubbornly eluded our attempts at screening. Because by the time the ovary appears abnormal on ultrasound, the cancer has already spread beyond its primary site. (Fallopian tubes are not easily visualized on pelvic sonogram.)

Note that the type of ovarian cancer thought to originate in the fallopian tubes is the so-called “serous” ovarian cancer. Serous cancers account for about two-thirds of ovarian cancers. The other third of ovarian cancers are endometriod and small cell cancers (which are thought to originate in the uterus or within the ovary), mucinous cancers (which may originate in the ovary or in the GI tract), and germ cell tumors (which originate from germ cells in the ovary).

What evidence is there?

Data a rapidly accumulating to support the fallopian tube origin of ovarian cancer. Here’s what we know so far –

In BRCA positive women at high risk for ovarian cancer, prophylactic removal of the tubes and ovaries finds hidden cancers in 7-15 % of women, but over half of these cancers are in the distal end of the tube, not the ovary.
The gene mutations found in serous ovarian cancers are the same ones found in the fallopian tube cancers, and the gene expression of serous ovarian cancer cells is more like that of a fallopian tube cell than an ovarian cell.
Scientists have found precursor lesions at the ends of the fallopian tube, that while not cancerous, look an awful lot like ovarian cancer cells.
Women who have had their tubes tied have 30% lower rates of ovarian cancer than those with intact tubes. The cancer prevented are the types (clear cell and endometriod) that would seem to originate in the uterus, based on the type of cells in the cancer.
Women who have their fallopian tubes removed have a 60% lower risk of ovarian cancer, and the type of cancer prevented are both the types that originate in the uterus and the type that we now think originates at the end of the fallopian tube nearest to the ovary (serous type).

So sign me up, already.

Not so fast.

As safe as it has become, surgery is not without risks. Operating on every woman to prevent a cancer that few (1% or less) will get may not make sense.

But for women who are already planning to undergo surgery for hysterectomy or tubal sterilization, it is not unreasonable at this juncture to consider removing the tubes while you’re there. This will add little to the risks of the procedure already planned, and may have the potential benefit of preventing ovarian cancer.

What if I am at high risk for ovarian cancer?

At this point in time, the standard of care for prevention of ovarian cancer in BRCA carriers and others at high risk is prophylactic removal of both the tubes and ovaries, a procedure called bilateral salpingo-oophorectomy, or BSO.

But there are downsides to salpingo-oophorectomy for ovarian cancer prevention. Even though the procedure is usually performed after completion of childbirth, it can cause early menopause, with its own risks of osteoporosis, heart disease and earlier death. If removal of the tubes proves to prevent ovarian cancer, this would be massively important for high risk women, who would have an option for ovarian cancer prevention that will NOT put them into menopause.

Large clinical trials are in progress to determine whether tubal removal will provide the same protection as BSO, but the results of these trials are years away. If the 60% reduction found in the general population holds up, this may not be a good enough for high risk women, who currently get a 95% risk reduction from salpingo-oophorectomy.

There are reasons other than cancer protection to recommend tubal removal at the time of sterilization

Tubal sterilization is not perfect.

We now know from large longitudinal studies that failures occur more than you’d expect after sterilization, and range from a low of 3.8/1,000 for post partum tubals to as high as 54/1,000 for cautery (burning) of the tube. Failure rates from the Essure procedure are even higher – 96 per 1,000 – that’s almost 10%. Pregnancies that occur after these failed tubals are very likely to be life threatening ectopic pregnancies.

Renowned family planning researcher Mitchell Crenin, MD and colleagues argued persuasively in a recent editorial that the time for sterilization by tubal removal is long overdue. Moreover, if we gynecologists had included women in the discussion from the get go as we began to bandy about sterilization options, including Essure, most women would tell us they want the most effective procedure there is – which happens to be tubal removal.

The recent discoveries of a link between the Fallopian tube and ovarian cancer have brought this issue to the forefront; however, women have not been included in the discussion about their desires, specifically around pregnancy prevention. If failure (pregnancy) is considered a major morbidity, how much more complicated is a bilateral salpingectomy as compared with laparoscopic tubal interruption… the question should not be focused only on ovarian cancer prevention; rather, the more important question should be why we are not offering women a chance for near 100% efficacy by removing the Fallopian tube completely for sterilization.

I’d have to agree.

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New 2-Stage Ovarian Cancer Screening Strategy Looking Interesting

August 27, 2013

Normal ovary One study does not a recommendation make, and results of a larger clinical trial are pending, but a new 2 stage approach to ovarian cancer screening is starting to look like something reasonable for ovarian cancer screening.

In a multi-center study led by researchers at MD Anderson Cancer Center, over 4,000 women were followed with annual Ca125 levels for 11 years, using an established algorithm (ROCA or Risk for Ovarian Cancer) that stratifies women into low, intermediate or high risk for ovarian cancer based on changes in ca125 levels over time, even when Ca125 levels are in the normal range. Based on the ROCA, which was re-calculated after each periodic screening, low risk women continued with annual Ca125 levels, intermediate risk women had repeat Ca125 levels done in 3 months, and high risk women went to immediate sonogram.

By confining sonogram use to only those women with concerning increases in Ca125 (0.9% annual rate of sonogram referral), the researchers were able to avoid the high rates of unnecessary surgery for false positives that has kept sonogram from being an effective screening tool for ovarian cancer. Their results are impressive for the small number of surgeries done – only 10 over 11 years – and the relatively high rate of pathology found at those surgeries –

The average annual rate of referral to a CA125 test in 3 months was 5.8%, and the average annual referral rate to TVS and review by a gynecologic oncologist was 0.9%. Ten women underwent surgery on the basis of TVS, with 4 invasive ovarian cancers (1 with stage IA disease, 2 with stage IC disease, and 1 with stage IIB disease), 2 ovarian tumors of low malignant potential (both stage IA), 1 endometrial cancer (stage I), and 3 benign ovarian tumors, providing a positive predictive value of 40% (95% confidence interval = 12.2%, 73.8%) for detecting invasive ovarian cancer. The specificity was 99.9% (95% confidence interval = 99.7%, 100%). All 4 women with invasive ovarian cancer were enrolled in the study for at least 3 years with low-risk annual CA125 test values prior to rising CA125 levels.

If the cost of Ca125 screens is low, this strategy could begin to make sense as a screening strategy for ovarian cancer. This all depends of course, on whether it actually reduces mortality. The answer to that question will await the results of the much larger UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which will randomize over 200,000 women to either Ca125-ROCA (as in the Texas study), annual sono or routine care. Enrollment in that study has closed, and initial results are expected in 2015. It’s also important to note that other ovarian cancer markers are currently under investigation, both alone and in combination with one another and Ca125, and may prove superior to Ca125 alone.

Bottom line

Interesting, but not yet practice changing. Stay tuned.

Angelina, BRCA, Mastectomies, etc…

May 15, 2013

Angelina_Jolie_Cannes_2011

In a beautifully written editorial in the NY Times entitled “My Medical Choice” Anjelina Jolie has come out publicly as a carrier of the BRCA 1 gene, which places her at high risk for both breast and ovarian cancer. She has undergone a prophylactic nipple-sparing mastectomy with plans for future removal of her ovaries to prevent ovarian cancer.

I choose not to keep my story private because there are many women who do not know that they might be living under the shadow of cancer. It is my hope that they, too, will be able to get gene tested, and that if they have a high risk they, too, will know that they have strong options. Life comes with many challenges. The ones that should not scare us are the ones we can take on and take control of.

Kudos to Jolie for choosing to tell her story in such a measured and informative manner. Having referred dozens of high risk women for BRCA testing, only to see them avoid it year after year, I for one hope that Jolie’s story will encourage women at high risk to get screened.

But I also recognize that not every woman with a suggestive family history wants to know her BRCA status.

And that, too, is a choice.

What Most of You Need to Know

For the overwhelming majority of the rest of the women I see, and for almost all of you reading this, the most important thing you need to know is buried within Jolie’s editorial, and it is this –

Only a fraction of breast cancers result from an inherited gene mutation.

About 2% of women have a family history that suggests the possibility of BRCA mutation, and only about 1/10 of one percent of women carry a BRCA gene mutation.

Thus, Jolie’s story, while compelling, is medically irrelevant to almost all women. But for a very few, it may be lifesaving.

Should you consider BRCA testing?

Not unless you yourself have had pre-menopausal breast cancer or have had ovarian cancer, or have a strong family history of breast/ovarian cancer. From the NCI, here are the recommendations for screening based on family history –

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.

What about prophylactic Mastectomy?

Mastectomy was not Angelina’s only choice. Mastectomy is effective at reducing the risk for breast cancer, but breast cancer mortality is not impacted due the effects of aggressive screening and excellent treatments for breast cancer when it is diagnosed in BRCA carriers who choose not to have a mastectomy on a preventive basis. Thus, Jolie could have opted for aggressive screening with breast mri and/or use of medication (tamoxifen or raloxifene) to cut her risk of breast cancer in half. But with the option for nipple sparing surgery, mastectomy appears less a barbaric operation than in the past, with only a small increase in risk for leaving the nipple behind.

The use of mastectomy is increasing, not just among BRCA carriers, but among women with early breast cancer or pre-invasive disease (DCIS and LCIS) that places them at higher risk for invasive cancer in the future. I for one worry that mastectomy may be getting over-used, and hope that Angelina’s story will not result in more women having surgery than is necessary.

What about Ovarian Cancer Protection?

As a gynecologist, I’m particularly concerned about ovarian cancer in BRCA carriers.

Angelina’s decision to remove her ovaries and fallopian tubes offers her the best odds of avoiding ovarian cancer, the disease that took her mother’s life. Unlike mastectomy, which prevents cancer but does not reduce mortality, oophorectomy does reduce mortality form ovarian cancer. Because the truth is, we have nothing to offer to women to effectively screen and diagnose ovarian cancer at early stages (although we offer it, ultrasound is not effective screening on a population basis), and treatments are just not as good as what we have for breast cancer. So BRCA carriers are offered prophylactic BSO in their 40’s or once childbearing is completed. The procedure itself can often be done as an outpatient laparoscopic surgery.

We are beginning to understand that ovarian cancer may actually originate in the fallopian tubes. Research is underway to determine if removal of the fallopian tubes alone might provide similar protection as removing of both the ovaries and tubes. It’s too soon to say how that will play out, but we are hopeful.

What most women do not realize is that we do have prevention for ovarian cancer. It’s called the Birth Control Pill, and taking it can lower the risk for ovarian cancer by 80%.

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Ovarian Cancer Screening Not Effective in Women at Average Risk

September 11, 2012

The United States Preventive Services Task Force has recommended against routine screening with ultrasounds or blood tests for ovarian cancer in asymptomatic women at average risk for the disease.

The reason is simple – these tests are not effective screening.

“There is no existing method of screening for ovarian cancer that is effective in reducing deaths,” Dr. Virginia Moyer, the chairwoman of the expert panel, said in a statement from the group, the United States Preventive Services Task Force. “In fact, a high percentage of women who undergo screening experience false-positive test results and consequently may be subjected to unnecessary harms, such as major surgery.”Yes, there is ultrasound and CA125. But doing these tests in healthy women without symptoms and at average risk causes more problems than it prevents, and most importantly, it does not prevent deaths from ovarian cancer.

Screening is recommended for women who carry genetic mutations that increase their risk of ovarian cancer (such as BRCA or MLH1 mutations), although its impact is still not entirely certain even in this group. More effective in this group is prevention by prophylactically removing the ovaries and fallopian tubes, which will prevent 95% of the ovarian cancers that occur in these women.

While ultrasound has no role in routine screening for ovarian cancer, it remains an important diagnostic tool when women present with symptoms that could be signs of ovarian cancer – bloating, abdominal pain, decreased appetite or early fullness after eating and new onset urgency and frequency of urination not due to other causes such as a UTI. Of course, almost all of the time these symptoms will not be due to ovarian cancer, but it’s important to rule it out.

We May Not Have Effective Screening, But We Do Have Effective Prevention for Ovarian Cancer

What does prevent ovarian cancer is birth control pills. Women who use the pill for as little as 1-2 years will see a 22% reduction in risk, and in long term users get a 60% reduction in risk. Although protection wanes with time, it persists as long as 30 years after stopping the pill. It is estimated that birth control pills have prevented over 100,000 deaths from ovarian cancer to date. (Not to mention pregnancy prevention and other health benefits.)

Users of Depo-Provera may get a similar reduction in risk as pill users do. In addition, tubal ligation may also reduce ovarian cancer risks. Studies are underway in high risk women to see if removal of all or part of the fallopian tube is effective as removal of the ovaries.

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More Posts on Ovarian Cancer from The Blog that Ate Manhattan

BRCA Gene Mutations & Ovarian Cancer – Tumor Type More Predictive than Family History

August 2, 2012

About 15% of women with ovarian cancer are found to carry a germline mutation in the BRCA gene. That’s the gene also associated with an increased risk for breast cancer in women, prostate cancers in men and gastrointestinal cancers and melanoma in both men and women.

Typically, the risks for carrying a BCRA mutation are predicted based on personal and family history of BRCA-related cancers.

Now, data from Canadian researchers suggests that, among women with ovarian cancer, the tumor type itself – not family and personal history – is most predictive of BRCA risk.

In their study of 131 women with ovarian cancer, 25% of those with high-grade serous ovarian cancers had a BRCA mutation. In contrast, none of the women with other tumor types carried the mutant genes. Had they instead referred these same patients for standard-of-care genetic counseling and screening, a significant number of BRCA carriers would have gone undetected – 35% if the counselor was their doctor and 20% if they had seen a trained genetic counselor.

While their data is similar to other studies in terms of the percentage of serous cancers associate with the BRCA gene, none to date has shown such a striking difference between tumor type and BRCA status. In this regard, it’s important to note that the researchers used the latest scientific methods for determining tumor type, basing it not just on morphology (what a tumor looks like), but on special biochemical tests (sort of like fingerprints).

The authors are recommending routine BCRA screening in all women with high grade serous ovarian cancer, regardless of their family history.

In view of the strong association and high incidence (25%) of underlying BRCA1 and BRCA2 mutations in women with high-grade serous ovarian (pelvic) carcinoma, genetic assessment for consideration of BRCA1 and BRCA2 germline testing should be offered to all women diagnosed with this histologic subtype of ovarian cancer regardless of age or family history.

This makes sense to me.

Family history is often incomplete or erroneous. But knowing about BRCA status is important for both ovarian cancer patients and their families, who can use the information to tailor screening and preventive strategies to reduce their risk and allow for early detection and treatment of BRCA-related cancers.

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Annual Sonogram Screening Prolongs Ovarian Cancer Survival, but Does it Save Lives?

January 12, 2012

Results from the Kentucky Ovarian Cancer Screening Study at first glance look incredibly promising. Among the over 37 thousand women who underwent annual pelvic sonograms, the 5-year survival rate for all women with ovarian cancer in the screened group was 75% compared with 54% for unscreened women with ovarian cancer from the same institution treated exactly the same otherwise. The investigators attribute this increased survival to earlier detection – 70% of the screened group were diagnosed at stage I or II, compared with only 27% in the un-screened group. Stage III cancers tended to be earlier (IIIa and IIIB instead of IIIC), and there were no stage IV cancers among women who were screened.

The investigators markedly improved on the positive predictive value of screening by boldly refusing to go where others have always gone before – to the operating room. They stood firm and watched cysts grow to as large as 10 cm before intervening, provided those cysts did not bear the defining characteristics of malignancy – namely solid areas and papillary internal growths. They also were not afraid to tweek their triage algorithm as experience with sonography improved. This is perhaps the biggest contribution from the study – permission to watch and wait.

Following a mean of 5.5 screens in 37,293 women, the authors achieved a specificity of 98.5% and a PPV of 8.9% with 11.1 operations per case of primary invasive epithelial ovarian cancer. This compares with a specificity of 98.4% and 19.5 operations per case of primary invasive epithelial ovarian cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial, in which both ultrasonography and CA 125 were used as first-line tests.

But a closer look reveals important questions that must be answered before we can begin to recommend screening in the general population.

1. Could the results be explained by the healthy volunteer effect? This was not a randomized trial, just a comparison between women in the screening program and the rest of the population who got ovarian cancer in the same time frame outside the program. We all know that folks who volunteer for studies such as this tend to be healthier in general than the overall population, thus skewing survival statistics in their favor. In this study, however, survival was equivalent between control and screened groups diagnosed in early stages, suggesting that it was indeed the stage shift that led to higher survival in screened groups and not just a healthy volunteer effect.

2. How about lead time effect? This happens when cancer is identified a little earlier, giving the false impression that folks are living longer when it is really that they have just learned a little earlier about the diagnosis that ultimately will lead to their demise. All screening studies have this potential bias. This is why overall mortality and not just survival time must be the relevant statistic to compare between screened and unscreened groups.

3. Not all cancers were caught by sono. Twelve women developed cancer in the year after a normal screening test, with 7 deaths due to cancer in this group. Such aggressive tumors may never lend themselves to early detection, no matter what modality is used.

4. Major surgery remains the only way to ultimately diagnose ovarian cancer. In the Kentucky trial, 523 women, or about 1.4% of participants screened ended up in the OR, and 86% of these women did not have cancer. Until we have a less invasive was to get reliable pathology on ovarian cysts, we are going to be exposing healthy women to unnecessary surgery while chasing the elusive early diagnosis. While this may be marginally acceptable in high risk women, expanding screening to the general population will lead to millions of avoidable operations, with their consequent risks, costs and mortality.

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Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening. van Nagell JR, Miller RW, DeSimone CP, Ueland FR, Podzielinski I, Goodrich ST, Elder JW, Huang B, Kryscio RJ, Pavlik EJ Obstet Gynecol. 2011 Dec; 118(6):1212-21

Jacobs,I; Menon,U. Can Ovarian Cancer Screening Save Lives? The Question Remains Unanswered. Obstet & Gynecol. 118(6):1209-1211, December 2011.

Annual Ovarian Cancer Screening – More Harm than Good

June 5, 2011

In a large multicenter study enrolling over 70,000 women, annual screening with transvaginal pelvic ultrasound and ca125 blood testing did not reduce deaths from ovarian cancer, and in fact led to an increase in complications due to screening.

Investigators in the NCI-sponsored Prostate, Lung and Ovarian Cancer (PLCO) Screening trial randomly assigned over 78,000 women age 55-64 years of age to either annual screening with transvaginal pelvic sonograms for 4 years plus CA125 testing for 6 years or usual care at 10 study sites across the US., and followed the groups for up to 13 years. Over that time period, ovarian cancer rates in the screened group were 5.7 per 10,000 person-years vs 4.7 per 10,000 persons-years in the usual care group, with 3.1 deaths vs 2.6 deaths per 10,000 person years, respectively. Over 3000 women had false positive screening results, a third of whom had surgery and 15% of those operated on had a complications from their surgery. Deaths from other causes did not differ between the groups.

The investigators concluded that annual screening for ovarian cancer does not reduce mortality, and in fact caused harms among women with fals positive abnormal results.

This is not the first study that failed to find efficacy for ultrasound and ca125 in reducing mortality from ovarian cancer, but it is certainly among (if not ) the largest.

Whether or not more frequent sonogram screening, combining ca125 with other serum markers, or trending ca125 levels over time (rather than just looking for “abnormal” results) will prove to be effective ovarian cancer screening has yet to be determined. Studies continue to be done, although preliminary results to date on these have not been encouraging.

What I do in My Practice

I tell my asymptomatic, low-risk patients who ask me for ovarian cancer screening that annual sonograms are like kissing the Blarney Stone. It makes us all feel lucky for awhile, but actually does nothing to reduce ovarian cancer mortality.

Still, I have not refused occasional screening for anxious women (Often women who have had a friend recently diagnosed with ovarian cancer0), so long as they understand the limitations of screening, but seem to need that negative sonogram to sleep at night. I do respect their anxiety, and if that means an occasional scan in the office and a reassured patient, I don’t see much harm, and they are told up front that their insurance may not cover the scan. I also happen to refer to a great radiologist who does not overcall abnormals, so if I see anything of concern, I refer straight to him. Now that we have this data regarding adverse outcomes due to over-screening, I will share that with my patients, and may be able to stand a bit more firmly in refusing to order ineffective screening to asymptomatic but anxious women.

For women at increased risk (family history of ovarian cancer, BRCA gene mutation carriers), I do offer vaginal sonogram and ca125 screening, but at minimum of twice a year, and urge these women to instead enroll on one of the several ovarian cancer screening trials currently in progress.

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Prophylactic Oophorectomy in BRCA Carriers Reduces Mortality

September 8, 2010

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).

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

Screening for Ovarian Cancer Based on Symptoms – Not Good Enough

February 4, 2010

Thanks to Toni Brayer for pointing out this new study on ovarian cancer symptoms published in the Journal of the National Cancer Institute.

This study confirms previous studies which found that ovarian cancer, long thought to be a silent disease in its early stages, does indeed have symptoms. The problem is that those symptoms – bloating, urinary frequency, pelvic pain, early satiety – are common, non-specific and, according to this new study, 99% of the time not due to an underlying ovarian cancer.

That’s good news, of course, for women with these symptoms. But bad news for those hoping for a means of early detection for ovarian cancer, since early symptom recognition is neither sensitive nor specific enough to be useful as a screening test on a population basis.

This is extremely important for women to understand. Each new screening test gets over-hyped and sets women up with unrealistic expectations about just what it is we docs can do to diagnose this disease. (The latest hope comes from a study that found elevated serum markers in women with ovarian cancer up to three years before their cancer was diagnosed. Unfortunately, the test were not useful in discriminating normals from abnormals until shortly before diagnosis.)

I don’t know if the results of this new symptom screening study will lead to changes in the current recommendations for ovarian cancer screening, so for now I will just reiterate them here –

If you have any of the following symptoms almost daily for more than a few week and these symptoms represent a change from normal for you, see your doctor, preferably a gynecologist.

Bloating
Pelvic or abdominal pain
Urinary urgency or frequency
Difficulty eating or feeling full quickly

Prompt medical evaluation may lead to detection at the earliest possible stage of the disease. Remember, though, that these symptoms are almost always caused by something other than ovarian cancer.

Wouldn’t it be great if we had a pill to prevent ovarian cancer?

Wait a minute – we already do! It’s call the Birth Control Pill. According to the National Cancer Institute, use of the pill for even as little as a year lowers ovarian cancer risk by 10-12%, and there is a 50% risk reduction after 5 years of use. Other studies show even higher risk reduction with longer term use.

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Those ovarian cancer awareness wristbands up there are sold to raise funds for the Lynne Cohen Ovarian Cancer Research Foundation. The Susan Komen Foundation sells them too. The Ovarian Cancer Research Fund has a whole store!

More info on ovarian cancer screening from The National Cancer Institute.

Ovaries – If they’re Normal, Leave them Alone

May 12, 2009

That’s what I’ve been telling my patients for years. And I will continue to say it after reading the results of a recent study comparing long term health outcomes in women whose ovaries were removed at time of hysterectomy for benign disease to those whose ovaries were left in place. The study found that women who had oophorectomy (removal of the ovaries) had an increased risk for death from cardiovascular disease. How high?

With an approximate 35-year life span after surgery, one additional death would be expected for every nine oophorectomies performed.

That’s a significant risk, I’d say.

As expected, women whose ovaries were removed had a lower risk of ovarian cancer, probably the most common reason some doctors give for removing normal ovaries at the time of hysterectomy. But this benefit was far outweighed by the cardiovascular risks conferred by removing the ovaries.

A surprising new finding in this study was an increased risk of lung cancer in women whose ovaries were removed. There is not obvious biologic reason for this, so it remains unexplained (and could be a statistical aberration).

The overall study findings were not surprising

Previous studies have found that removal of the ovaries confers increased risk of death from cardiovascular disease, which also occurs more frequently in women who undergo premature menopause. A decision analysis published in 2005 using data available at that time suggested age 65 as the cutoff for leaving the ovaries in place, since after that age, there was no added benefit. This more recent study suggests there should be no upper age limit.

What I found interesting in this study was that removal of the ovaries at the time of hysterectomy for benign disease did not appear to confer protection against future ovarian in women with a family history of ovarian cancer. This stands in direct contrast to well done prospective randomized data showing a clear benefit to prophylactic oophorectomy in this group. The authors suggest that their findings support a benefit from hysterectomy alone in preventing ovarian cancers, perhaps from a disruption of the influx path for potential carcinogens or changes in hormonal or triggering pathways. This would suggest that a randomized trial of hysterectomy without oophorectomy in women at high risk for ovarian cancer might be in order. (Currently, when prophylactic oophorectomies are done, the uterus is frequently kept in place.) It’s an interesting idea, but one that would need to be well-studied before suggesting anything other than current practice for these women.

Is there ever a reason to remove the ovaries?

Absolutely. If a woman has cancer of the ovary, the risk for death far, far outweighs any benefit to leaving the ovaries. (The exception is the young women with very early stage unilateral or borderline ovarian cancer – more limited surgery is generally offered to these women.)

Uterine cancer is also an indication for oophorectomy. Again, exceptions are often made in premenopausal women with early stage uterine cancers, and some of these women are being treated hormonally rather than with surgery. It will be interesting to see if anyone uses these study findings to recommend against removal of the ovaries in older women with very early stage uterine cancer.

I find the more difficult women to counsel are those having a hysterectomy for endometriosis with ovarian involvement, or for pelvic abscess or adhesions trapping a normal ovary and causing severe pain. For these women, the risk of continued pain and stress related to it, as well as the potential risks for additional surgery needs to be weighed against their risks for cardiovascular disease. The stress associated with chronic pain should not be minimized. For some of these women, removal of the ovaries may continue to be appropriate.

What if you’ve had your ovaries out?

It’s important to remember that oophorectomy is not the only modifiable risk factor for heart disease – diet, exercise, and treatment for underlying conditions such as hypertension and elevated cholesterol are just as important (and may be even more so). There is still an awful lot you can do to be sure you maximize your odds of beating heart disease as you age.

Oophorectomy is not the same as a hysterectomy

Hysterectomy is removal of the uterus. Oophorectomy is removal of the ovaries. Other than the risks associated with having surgery itself, hysterectomy alone does not confer an increase risk of mortality, and, unlike oophorectomy, does not increase long term heart disease risks. For many women, hysterectomy remains an important option for treatment of benign conditions such as uterine fibroids.
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Image from Wikpedia Commons

Ovarian Cancer and Obesity – Weighing the Risks

January 18, 2009

A recent research study reports an increased risk of ovarian cancer among obese women.

Since every woman I know thinks she is fat, this report is sure to raise anxiety levels across the board. So let’s see if I can calm things down a bit by placing the data in perspective.

First off, you need to know your BMI. Go here and calculate it , then come back. For those of you who are too lazy to click the link, you can think of it this way – your BMI is 30 if you are 5’2″ and 150 lbs, 5’5″ and 180 lbs or 5’8″ and 200 lbs.

Got your BMI? Okay. Here’s the data –

Women with a BMI of 30 or more had a relative risk of 1.6 for ovarian cancer compared to women whose BMI is < 25. That means for every 1 case of ovarian cancer in the thin women, there were 1.6 cases among the obese women. Almost double the rate. Sounds pretty bad, right?

Well, that depends on how risky ovarian cancer is to start with. Turns out ovarian cancer is not that common, whether you are thin or fat. The risk in this study was less than 1% over the 7 years of the study.

Here’s how it looks visually – There are 1000 dots in each group, representing 1000 women. The red dots represent the women who got ovarian cancer in the 7 years of the study.

What about the risk among HRT users? Well, in that group, obese women’s risk for ovarian cancer was no higher than thinner women’s risk, because thinner women on HRT have a higher risk of ovarian cancer than their thin counterparts who don’t use HRT. How high? For every 1000 women on HRT there were 3-4 cases of ovarian cancer. Same as with obese women.

Bottom Line

Obesity increases your risk for ovarian cancer. Fortunately, that risk is still quite low – certainly not high enough to warrant anything other than routine screening.

But add it to the increased risks of diabetes, hypertension, hyperlipidemia, heart disease and breast cancer associated with obesity, and maybe it’s enough to get you thinking more seriously about losing weight. Not to mention the improvement in your quality of like when you can sleep without snoring or apnea, exercise comfortably, wear the clothes you love and just plain feel better.

Total Inhibin – A New Ovarian Cancer Screening Test?

July 9, 2007

If researchers in Siena, Italy, are right, measurement of Inhibin, a hormone molecule produced by the ovary, could be an effective ovarian cancer screening test.

In a study published this month in The Journal of Clinical Endocrinology and Metabolism, the researchers measured total Inhibin levels using an Elisa-based assay, comparing results in women with ovarian cancers to those of normals and those with benign ovarian tumors and other cancers. Total Inhibin levels were highly sensitive and specific in detecting ovarian cancers. When combined with Ca125 levels, the results were superior to either test alone. (See graph above).

The percentage of cancers detected at 95% specificity varied according to the histological subtype but was always improved by the combination of total inhibin and CA-125. In detail, the detection rate of all tumors raised from 84–87% with single markers to 99% with combined markers (P < .05). The addition of total inhibin increased the CA-125 detection rate for mucinous tumors from 14 of 17 (82%) to 17 of 17 cases (100%) without loosing specificity (95%). Remarkably, the detection rate of clear cell adenocarcinomas increased from 59–68% with single markers to 96% with combined markers (P < .05)

The next step is a large multicenter trial.

Inhibin has been on the radar as a potential ovarian cancer marker for some years now. The problem has been that there are various Inhibin molecules, and the different kinds of ovarian cancers make one or more of these in any combination. Most Inhibin assays are specific to one or more of the subtypes, which limits them in detecting all ovarian cancers. It seems that the total Inhibin assay used in this study may have worked so well because of its lack of specificity, making it more useful as a screening test.

What I found most exciting is that the inhibin assay used is one that is already commercially available, meaning that, if these results hold true, then we won’t have to wait very long to implement screening.

Stay tuned…

Ovarian Cancer Symptoms

June 14, 2007

Gilda Radner, who died of ovarian cancer at the age of 42,

had symptoms for months before her cancer was finally diagnosed.

The American Cancer Society and the Society for Gynecologic Oncologists have issued a consensus opinion outlining the symptoms of ovarian cancer, and more importantly, urging women and their doctors to consider ovarian cancer in the differential diagnosis when these symptoms present.

What are the symptoms? They are vague and all too common – bloating, pelvic or abdominal pain, early satiety, and urinary sympotms such as urgency and frequency. But, when present and persistent for more than 2 weeks and less than 1 year (or in the case of urinary symptoms, persistent after treatment for a UTI), one must consider ovarian cancer in the differential. And consider it early, because this is one cancer that won’t wait around while you exclude everything else.

For almost 2 decades now, this is exactly how I have been practicing. As I’ve said before, I don’t hesistate a second before performing a pelvic ultrasound in women with any of the symptoms listed in the consensus statement. I happen to be pretty good with a vaginal ultrasound probe, and I have an amazing gynecologic radiologist to whom I can refer.

Despite this, in all these years, after performing or referring for thousands of sonograms (and not a few ca125 tests) in what I believe is an optimally aggressive screening approach for ovarian cancer in symptomatic women, I have yet to diagnose a single case of early ovarian cancer. Of the 5 or so cases (it is, after all, not a common cancer), all but one presented to me at stage 3 or more. That early tumor was a borderline cancer, and she would have done well no matter what I had done.

I wish I could say my aggressive management of symptoms has impacted ovarian cancer mortality. It’s certainly reassured a lot of frightened women and found quite a bit of benign disease. But ultimately, I just don’t think it has made a difference in terms of ovarian cancer outcomes.

Maybe it is because my patients with ovarian cancer ignored their symptoms for too long before coming in to see me. If so, then publicizing this consensus statement may make a difference. I certainly hope that it does. And despite my reservations about my practice’s efficacy, I’m not changing what I do, because at this point, there is nothing else I can do. It’s what I have to do, and what my patients deserve.

What we really need is a good early ovarian cancer screening test for asymptomatic women. (No, it’s not the Ca125 test.)

Or better yet, how about a pill to prevent ovarian cancer? Oh, wait a minute – we already have that. It’s called the Birth Control Pill.

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Here’s the Consensus Statement:

Historically ovarian cancer was called the “silent killer” because symptoms were not thought to develop until the chance of cure was poor. However, recent studies have shown this term is untrue and that the following symptoms are much more likely to occur in women with ovarian cancer than women in the general population. These symptoms include:

Bloating
Pelvic or abdominal pain
Difficulty eating or feeling full quickly
Urinary symptoms (urgency or frequency)

Women with ovarian cancer report that symptoms are persistent and represent a change from normal for their bodies. The frequency and/or number of such symptoms are key factors in the diagnosis of ovarian cancer. Several studies show that even early stage ovarian cancer can produce these symptoms.

Women who have these symptoms almost daily for more than a few weeks should see their doctor, preferably a gynecologist. Prompt medical evaluation may lead to detection at the earliest possible stage of the disease. Early stage diagnosis is associated with an improved prognosis.

Several other symptoms have been commonly reported by women with ovarian cancer. These symptoms include fatigue, indigestion, back pain, pain with intercourse, constipation and menstrual irregularities. However, these other symptoms are not as useful in identifying ovarian cancer because they are also found in equal frequency in women in the general population who do not have ovarian cancer.

Ovarian Cancer Screening – Telling It Like It Is

January 30, 2006

A very well-written article in USA Today honestly tells readers why an Ovarian Cancer Test Remains Elusive.

I spend a lot of time discussing ovarian cancer screening with my patients who come in anxious about the disease. Most of that time is spent explaining that, unfortunately, we still don’t have a good screening test for ovarian cancer.

I aggressively screen with ultrasound and CA 125 in women with a family history or personal risks factors for ovarian cancer. And I don’t hesitate a second to get a pelvic ultrasound in any woman complaining of the vague, non-specific symptoms associated with this cancer – bloating, early satiety, abdominal pain. (I don’t wait for other tests to be negative before ordering an ultrasound, because even though ovarian cancer is not common, it is usually rapidly growing, and won’t wait for me to finish my workup.)

But for low risk women without any complaints, I really have no screening test to offer, and this article does a nice job explaining why.

Unfortunately, what the writer does not tell women is that there is something they can do that will actually lower their risk of getting ovarian cancer in the first place. What’s that? Go on birth control pills. As little as 3 months of use imparts protection, and long term users can expect up to an 80% reduction in risk. Now that’s something to write about.

If you want more information about ovarian cancer screening and prevention, see these great web sites:
National Cancer Institute
The OvarianCancer Coalition
Contraception Online
Johns Hopkins Pathology

Category Archives: Ovarian Cancer