Watching Women's Health

Screening for ovarian cancer — focus on genetic risks

Most women have just over a 1% lifetime risk of developing cancer of the ovary. However, in some families, there are multiple cases of ovarian and/or breast cancer, and risks are much greater. What do we know about inherited susceptibility to ovarian cancer?

The biggest breakthrough has been the discovery of harmful mutations in the BRCA 1 and BRCA 2 genes. BRCA 1 and 2 are tumor suppressor genes located on chromosome 17 that prevent uncontrolled cell growth. With certain mutations, BRCA genes are less effective in regulating cell growth, and ovarian, breast and other cancers are more likely to occur.

A BRCA mutation can be detected through a blood test. There are well-accepted recommendations about which family cancer histories should trigger genetic counseling and possible BRCA testing. Genetic counseling is helpful, so an accurate family medical tree is constructed and appropriate candidates for BRCA testing are identified. Before getting the blood test, it is important that women fully understand the implications of both positive and negative BRCA results, and also of declining to do the test.

When possible, it makes sense first to test a family member who has been diagnosed with breast or ovarian cancer. If a BRCA mutation is found, other family members can undergo limited testing for that specific mutation.

Both females and males can inherit BRCA mutations. Men with BRCA mutations have an increased risk of breast cancer, as well as pancreatic, early-onset prostate, and possibly, testicular cancer.

Women with BRCA mutations have an increased lifetime risk of ovarian cancer ranging from 20-50%. Risks for developing breast cancer are even higher, in the 60-80% range.

If a harmful BRCA mutation is found, most physicians recommend prophylactic removal of the ovaries after childbearing is complete, in most cases by age 40. (Along with removal of the ovaries, additional steps would be taken to reduce breast cancer risk.)

Prior to completion of childbearing, BRCA positive women should be aware of ovarian cancer symptoms and have regular vaginal ultrasounds and CA-125 testing — though imperfect, these tests are the best we have for screening high risk women. We also recommend younger women use oral contraceptives when feasible. Oral contraceptives can reduce ovarian cancer risk by 50%, though the exact benefit in BRCA positive women is not known.

What if BRCA testing is negative? That means cases of ovarian and/or breast cancer in a particular family are not due to a BRCA mutation, but may be associated with other mutations that have not yet been identified. With high risk family histories, the same risk reducing strategy is appropriate.

Improving ovarian cancer screening in the future, for both high and average risk women, will almost certainly involve more accurate serum markers and better ultrasound discrimination between normal and abnormal ovarian structure.

Does recognizing symptoms lead to early diagnosis of ovarian cancer?

I wrote earlier about the difficulties of diagnosing early ovarian cancer by routinely screening asymptomatic women at average risk for this disease. But what if physicians did a better job of screening women with symptoms linked to ovarian cancer? Could we make the diagnosis at an earlier, more treatable stage?

A recently published study looked at these questions. 

813 women with ovarian cancer (including 212 diagnosed in an early stage) and 1313 otherwise similar women were interviewed about symptoms they experienced before their date of diagnosis (or comparable date for the control group).

Symptoms included early satiety, bloating, abdominal or pelvic pain and urinary changes. A woman was considered symptomatic if she had new onset of any of these symptoms in the year before diagnosis, with symptoms occurring daily for at least a week.

Women who had been diagnosed with ovarian cancer were 10 times more likely than women in the control group to report having had at least one of these symptoms. However, most women reported having symptoms for a relatively short time before diagnosis, regardless of whether their cancer was found in an early or late stage.

(One limitation of the study is that it relied on accurate recollection of symptoms. And, women with a cancer diagnosis may recall symptoms differently than the control group.)

Like other current screening approaches for ovarian cancer, the authors' symptom index had a low positive predictive value. Using their approach, 100 symptomatic women would have to be evaluated to identify one woman with early ovarian cancer.

The other 99 women would undergo ultrasounds, blood work and in some cases, unnecessary surgery, looking for a disease they did not have. At the same time, women who had early ovarian cancer but no symptoms, would not be recognized.

The editorial accompanying the article concludes

Importantly, these findings remind us that wide recognition of symptoms alone will not incrementally improve the overall survival from ovarian cancer. Rather, they highlight the urgent need to develop better molecular markers and improved imaging modalities for ovarian cancer screening. The recognition of specific symptoms associated with ovarian cancer has value. However, to truly affect the cure of ovarian cancer, we need better diagnostic tools for asymptomatic women.

Next, I'll look at what we know about inherited susceptibility to ovarian cancer.

Self and clinical breast exams not as helpful we thought

My last two posts addressed mammogram recommendations in the recent US Preventive Services Task Force (USPSTF) report on breast cancer screening. I also have some thoughts about the task force's comments on self and clinical breast exams.

For decades, physicians and breast cancer advocacy groups have recommended a monthly self breast exam (SBE) for adult women. I am not sure exactly when or from where this concept originated.

Monthly SBE apparently seemed like such an obvious good idea, it became standard medical advice without first being tested . Monthly self breast exams, yearly clinical breast exams (CBE) and regular mammograms after a certain age have been longstanding major components of breast cancer screening in the US.

Increasingly in medicine, we are trying to figure out which of our screening practices actually work. In the US, it would be very difficult to study SBE as a primary screening test, in the absence of CBE and mammograms.  So studies on the effectiveness of SBE have come from countries where other breast cancer screening is not readily available.

A major study on SBE, conducted in China, involved 266,064 women, half of whom were repeatedly instructed in SBE and reminded to do the exams. None of the women had access to CBE or mammograms.

After 10 to 11 years of followup, the women who did SBE had the same breast cancer mortality as the control group. The main difference between the two groups was the SBE group had twice as many benign breast biopsies.  A smaller study in Russia also showed no measurable SBE benefit.

On the face of it, these results seem contrary to many women's experience, as a fair number of breast cancers are found by women themselves.

Sometimes women examine their breasts because some life event made them worry in particular about breast cancer. Or, they became aware that their breast looked or felt different and then they did a self exam. Only rarely does one of my patients tell me she found a worrisome lump while doing her regular exam.

SBE every month is much too often to note meaningful change. Even if an area contains breast cancer, it is unlikely to feel different from one month to the next.  Perhaps women themselves intuitively have always known this, as the majority have never done monthly exams.

The USPSTF agrees with what most women actually don't do and recommended against SBE for women at average risk for developing breast cancer.

For women at high risk for breast cancer, SBE appears to be more helpful. At the 2009 American Society of Breast Surgeons annual meeting, a small study found high risk women doing SBE every six months were as accurate as annual mammograms and MRIs in identifying breast cancers.

Being well-trained in SBE may be particularly important for younger high risk women who have not yet begun screening with mammograms.

And what about the clinical breast exam? The USPSTF found no evidence that CBE by itself reduces breast cancer mortality.   

In the US, most women who have regular clinical breast exams also have access to mammograms. It would be difficult, probably ethically impossible, to do a large study of CBE as a stand alone screening test.

Physicians consider breast exams to be an important part of a woman's annual physical. Yet, many physicians could approach breast exams in a more thorough, systematic way. An optimal CBE takes at least one minute per side, with the entire breast being systematically evaluated. Ideally, visual inspection is also done.

If all clinicians perfomed CBE in a more structured, standardized manner, the effectiveness of CBE, though difficult to measure, would almost certainly improve.

So what are women to do? Women at high risk for breast cancer may benefit from learning to do SBE and doing an exam periodically. A six month interval seems reasonable and has a little data to back it up. Women at average risk should be aware of changes in their breasts and seek medical advice about persistent changes.

And all women who have their breasts examined by a medical professional should get the potential benefit of a thorough exam.

Reducing breast cancer risk

Last time, I wrote about using the Gail model and breast density on mammogram to estimate individual risk of developing breast cancer. Now, I'd like to address how we can reduce risk of developing breast cancer.

There are three main ways to reduce that risk — surgical intervention, medication and lifestyle modifications.

The surgical approach, prophylactic mastectomy, is a reasonable option for women at extremely high risk for breast cancer, such as those who carry a BRAC mutation. Women with a strong family history of breast cancer should consider genetic counseling to discuss testing for this mutation.

The majority of breast cancers, however, are not linked to the BRAC mutation. For women at average or moderately increased risk, other risk-reducing interventions are appropriate.

The FDA has approved two medications — tamoxifen and raloxifene — to reduce breast cancer risk in higher risk women. Both of these meds are selective estrogen receptor modulators (SERMs). They act like an estrogen in some tissues and block estrogen action in other tissues. Both act like an anti-estrogen in breast tissue.

Tamoxifen has been approved since 1998 for both pre- and postmenopausal women with a Gail model five year risk of developing breast cancer of greater than 1.7%  Tamoxifen use for five years can reduce breast cancer risk by about 40%.

Tamoxifen has not been widely prescribed for eligible women, mostly because of adverse effects. Because tamoxifen acts like an estrogen in endometrial tissue, it increases risk of endometrial cancer. It also increases hot flushes and thromboembolic events. Many primary care physicians are not personally familiar with tamoxifen and are not comfortable prescribing it.

Raloxifene, recommended for postmenopausal women only, also reduces breast cancer risk by at least 40%. Raloxifene may gain wider use, as physicians have also prescribed it for osteoporosis, and it does not increase risk of endometrial cancer. Raloxifene has other adverse effects similar to Tamoxifen.

Researchers are actively working on the next generation of SERMs, hoping to create the perfect combination of estrogenic and antiestrogenic effects. In the meantime, higher risk women and their physicians have to consider risk vs benefit in deciding whether to use one of today's SERMs.

Lifestyle changes can reduce breast cancer risk and be adopted by women at all levels of risk. Getting regular exercise, maintaining a normal weight, and minimizing alcohol intake appear to reduce risk in most studies. If you are sedentary and overweight, this is another reason to get serious about exercise and weight loss.

The Gail model is most accurate predicting risk of estrogen receptor positive (ER+) breast cancers — SERMs and lifestyle changes are effective in reducing risk of this type of cancer. The majority of breast cancers are ER+.

So far, we do not have a good model for predicting ER- breast cancer and few strategies, other than surgery, for preventing it. Understanding receptor negative breast cancer is a challenging area of  breast cancer research.

 

Predicting breast cancer risk

When women 40 and older come to clinic for an annual exam, one of the things I like to know is their risk of developing breast cancer. We use the Gail model to estimate a woman's risk of developing breast cancer over the next 5 years and during her lifetime. The model also compares individual risk to the average risk of women the same age.

While the Gail model isn't perfect, it does help us identify women at greater than average risk so we can discuss options for reducing their risk. I'll discuss those options soon — for now, I want to focus on breast cancer risk assessment.

The Gail model takes into account breast cancer in first degree relatives, as well as age of starting menstruation, current age, age at first child's birth, race and breast biopsy history.

Other factors, not included in the model, do modify breast cancer risk. Extended breastfeeding, regular exercise and abstaining from alcohol appear to reduce risk. Use of estrogen and progestin hormones postmenopausally or breast cancer in several second degree relatives, such as a grandmother or aunt, may increase risk.

Women whose family histories include several cases of breast cancer, or related ovarian and colon cancers, should consider genetic counseling. Their family may have a genetic mutation, BRAC1 or BRAC2, that significantly increases risk of developing these cancers. 

For most women, risk assessment from the Gail model gives us a starting point, and we keep other factors in mind as the model may overestimate or underestimate an individual's risk.  The Gail model predicts risk more accurately for breast cancers that are estrogen receptor positive.

A recent study suggests estimating breast cancer risk is clearly worthwhile. The researchers also confirm earlier reports that breast density on mammogram importantly affects breast cancer risk and should be included in risk assessments.

On mammograms, glandular and connective tissue appears white, or radiodense, and fatty tissue appears black, or radiolucent. When radiologists interpret a mammogram, they usually include a comment about breast density. Breasts with the least density contain less than 25% fibroglandular tissue, whereas very dense breasts have more than 75% fibroglandular tissue.

Women with very dense breasts have approximately four times the risk of developing breast cancer as women with minimal breast density.

Most women don't know what their mammographic breast density is, because that information is usually not included in letters to patients from the mammogram facility.  You can ask your doctor what the physician's report says about your breast density. 

Our biggest risks of developing breast cancer are being female and getting older. But information from models and mammograms can be used to estimate an individual's risk.

The Gail model could be improved if mammographic breast density were included in its risk assessment.Other models have been developed that include breast density, but they are not as accessible as the Gail model.

Once we have identified women at higher risk of developing breast cancer, we can take steps to reduce that risk.  I'll write about breast cancer risk reduction next time.

A little alcohol — good, bad – which is it?

Recently I wrote that moderate alcohol use, along with other habits, appears to reduce risk of stroke. Now a Washington Post article on another British study says even minimal alcohol use increases women's risk of breast, rectal, liver, esophageal and oropharynx cancer.

Between 1996 aand 2001, the Million Women Study (MWS) enrolled over 1.2 million UK women over the age of 50. Women undergoing breast screening were invited to participate. Like the Women's Health Initiative in the US, this study was designed to look at effects of postmenopausal hormone replacement.

A huge amount of questionnaire-based information has been collected, and MWS researchers are looking at how a variety of lifestyle factors influence women's health. During seven years of followup, any alcohol use — a drink a day or less — increased risk of some cancers. This study links minimal alcohol use to specific cancers more clearly than previous studies.

The link between breast cancer and alcohol is well-accepted. Drinking alcohol alters estrogen levels and about 3/4ths of breast cancers diagnosed today have estrogen receptors. It appears greater alcohol use is directly linked to greater breast cancer risk. Heavy use may increase one's risk by as much as 30%.

Similarly, the link between alcohol and liver cancer is not new. Again, heavy alcohol use has been thought to be the main risk factor.

In the MWS, greater risk of oropharynx cancer was noted only if women also smoked. Alcohol use as a cause of rectal and esophageal cancer is newer information. 

Overall, MWS estimated 13% of these cancers in women were due to drinking alcohol.

Why is it so hard to figure out exactly how alcohol affects our health? Humans are complex biological organisms and a substance that may be helpful in one organ system may be harmful in another. It is not really contradictory if alcohol is good for our hearts but bad for our livers.

Information obtained through questionnaires has limitations. People being people, some minimal alcohol users may have drunk more than they reported.

In clinic, we screen for alcohol use and it is a rare person who admits to more than an occasional drink. Probably the most reliable distinction in between people who drink any amount of alcohol and people who don't.

Living one's life simply to avoid disease seems like a joyless proposition. But when deciding how to live, most of us do want accurate information about the pros and cons of our choices. So next time, before you uncork that lovely bottle of wine, think for a moment about the results of this study.

HRT and breast cancer - relative risks vary with the progestin

One of the newer pieces of information in the HRT puzzle is that risk of invasive breast cancer varies according to the progestin used.

A progesterone or synthetic progestin protects the uterine lining from overstimulation by estrogen that can lead to endometrial cancer. Women who've had a hysterectomy can safely take estrogen alone.

In a recent editorial, Dr Robert Barbieri summarizes some of the latest scientific information that might change how we prescribe hormones for menopausal women.

Ideally, we want to protect the lining of the uterus without adding to other risks. We do not yet have that ideal agent, but it's becoming clear there are different risks with the hormones that are currently available.

Combined information from a  French study and a German study, shows progesterone use minimally affected breast cancer risk. In the US, the only progesterone currently approved for endometrial protection is Prometrium.

With medroxyprogesterone, used in PremPro and as a separate tablet, the relative risk of breast cancer was 1.48. Norethindrone had the highest relative risk — 2.11.  Norethindrone is found in FemHrt, Activella, Combipatch and as a separate tablet.

It also appears using a progestin cyclically, rather than every day, carries less breast cancer risk because less progestin is used.

Continuous hormone regimens with daily estrogen and progestin were developed so women could avoid having period-like withdrawal flow. Now, with women taking HRT for a shorter time after menopause, avoiding withdrawal flow should be less of an issue.

For various reasons, some women do stay on postmenopausal HRT for longer than the 3-4 years now recommended.  For women on HRT for an extended time, it is especially important to update HRT regimens using our best information on risks and benefits.

Up next will be the safest way for postmenopausal women to take estrogen.

When does breast cancer risk increase with postmenopausal hormone use?

Most medical experts agree menopausal women on estrogen and progestin hormones for an extended time have an increased risk of developing breast cancer. The Women's Health Initiative (WHI) clinical trial was halted in 2002 after 5.2 years because increased breast cancer risk was found.

Yet some women have severe menopausal symptoms and can benefit from being on hormone replacement, at least for a time.

How long can women take combination hormones before breast cancer risk increases? Two recent reports address this question.

A Finnish report using national registry data involved 221,551 women on combination hormones for varying periods of time. Women taking hormones all received the same estrogen — estradiol — but were on a variety of progestins.

A progestin is used so the uterine lining is not overstimulated by estrogen.

They were divided into groups based on how long they took the hormones. The incidence of breast cancer in combination hormone users was compared to that of age-matched women in the general population.

For women using combination hormones up to 3 years there was no increased risk of breast cancer. After 3 years, increasing risk was noted with longer use. Women using hormones for longer than 10 years had the highest risk. 

Risk also varied according to type of progestin and whether the progestin was taken intermittently or continuously.  I will look at this topic in a later post.

A Boston University study also looked at when breast cancer risk increases with estrogen and progestin use. This study compared 4, 515 women with breast cancer to 18,058 age-matched women who had not been diagnosed with breast cancer.

These researchers found risk with estrogen and progestin use increased after 4 years. This study also looked at estrogen and testosterone combinations and found no increased risk over time unless a progestin was also used.

After the WHI results, most physicians have advised menopausal patients to take combination hormones for less than 5 years.  It now appears we should be even more conservative, as breast cancer risk may start rising after 3 to 4 years of hormone use.

The good news is women may be able to use estrogen and progestin hormones for a few years after menopause without adding to their breast cancer risks.

Pap smears and the adolescent

Invasive cervical cancer is very rare in young women 20 and under. Why is that? Sexually active adolescents are at significant risk for exposure to the human papillomavirus (HPV) but their immune systems almost always clear the virus before an invasive cancer can occur. 

In the past, adolescents with low-grade pap smear abnormalities have been over-evaluated and over-treated.  We now know the majority of these low-grade abnormalities in young women will go away on their own. 

Age-based pap smear guidelines help gynecologists avoid treating adolescents too aggressively. In this age group, we now evaluate and potentially treat only high-grade pap smear abnormalities.  We do not evaluate low-grade abnormalities unless they persist for 2 years.  

Treatment of cervical precancer involves destruction or removal of a portion of the cervix.  Even newer treatment methods can lead to preterm delivery in subsequent pregnancies.  Because most adolescents have their reproductive lives ahead of them, it is important to treat only those young women who are at high risk for actually developing an invasive cancer. 

This post completes the series on new pap smear guidelines. (The others were on the test itself, women 30+ and women under 30.) But there is one last thing all women should know — smoking tobacco doubles the likelihood that HPV infection will lead to a significant precancer of the cervix.  So if you are a smoker, add that to the list of reasons to quit.

Pap smears for women under 30

Why don't we routinely test for high-risk HPV when doing paps on women under 30?  There are two main reasons. 

First of all, compared to women 30 and older, many younger women are not yet in a stable relationship and are more likely to be exposed to HPV.

But after HPV infection occurs, and this is the second reason, a younger woman's immune system is more likely to efficiently clear HPV. 

So younger women commonly have transient HPV infections. They may have a series of short-lived infections from different subtypes, but with routine HPV testing, they would appear to be persistently infected. (Right now, we do not do subtype-specific HPV testing, though this may be helpful in the future.)

Persistent HPV infection over several years may lead to cervical cancer. Transient HPV infection does not involve that risk. Routine HPV screening in this age group would result in unnecessary further testing for a lot of young women, significantly adding to the cost and inconvenience of the initial screening test — the pap smear.

We do ask the lab to check for HPV activity if a younger woman has a borderline pap result. If a woman has a borderline pap and tests positive for HPV, we evaluate her further for a cervical precancer. If she has a borderline pap and tests negative for HPV, we know she is at low risk for a precancer and recommend doing the next pap in one year.

Pap smears for women 30 and older

An earlier post introduced new approaches to pap smears.

We have known that the human papillomavirus (HPV) is the cause of cervical cancers and precancers for at least two decades. There are many HPV subtypes and it has taken a long time for researchers to figure out which subtypes are high risk for causing cervical cancers and precancers. Testing individuals for high-risk HPV has been used clinically only in the past 5 years or so.  

The American College of Obstetrics and Gynecology (ACOG) recently released a new practice bulletin based on consensus guidelines for Pap smear and HPV screening.

Because HPV is a common virus, women who have ever been sexually active have up to an 80% lifetime risk of acquiring it. Most women with a healthy immune system will clear HPV or suppress it to harmless levels of activity in a matter of months.

Persistent high risk HPV activity may cause cervical cancer over an average time frame of 8-12 years. Because younger women clear the virus more efficiently, a woman's age plays a role in screening guidelines. In this post I will focus on the screening recommendations for women 30 and over.

We now offer these "older" women a pap with automatic high risk HPV testing. (We don't test for low risk HPV because it does not cause cervical cancer.) If we get a double negative result — a negative Pap and a negative HPV — that individual is at extremely low risk for cervical cancer for an extended period of time. The best research suggests a three year interval before doing the next pap smear. This is still a conservative recommendation given the average length of time it takes for a cervical cancer to develop.

What if the pap is negative but the HPV test is positive?  Then we know that person has a risk of developing a cervical precancer even though the cells look normal on the pap. We do the next pap in one year.  In many cases, the immune system will have cleared HPV during that time.  If not, and HPV is still present, we do further testing for cervical precancers.

So adding an HPV test to the basic pap allows us to identify more accurately which women are at risk for cervical precancers in the next few years and which women are not.  Of course we still want to see you annually for an exam and other screening tests even if you don't need a pap every year.

Why don't we use routine HPV testing in younger women?  I'll explain in my next post.

The Pap Smear - How a good screening test keeps getting better

Most people know the pap smear is a screening test for cervical cancer that women should get done annually. In fact many patients view getting their pap smear done as a main reason to come in for an annual exam.

A new American College of Obstetrics and Gynecology practice bulletin describes how, using combined pap smear and human papillomavirus (HPV) testing, some women may safely get pap smears done every three years. Ob/Gyn physicians are now able to identify women at low risk for cervical cancer and precancer more accurately, so we can appropriately screen them less often than women at higher risk.

Both the pap and the HPV test are done from cells collected from the cervix during a speculum exam. The pap smear looks at cervical cells microscopically to see if there are abnormalities suggesting a precancer or cancer. The HPV test checks for activity of the high risk forms of the human papillomavirus that are known to cause precancers and cancers. There are low-risk forms of HPV that we don't test for as they rarely cause cervical cancer.

The American Society for Colposcopy and Cervical Cytology released detailed consensus guidelines for combined pap/HPV testing several years ago. Because these guidelines are complex and mark a departure from the annual pap "gold standard," many physicians have been slow to use them in their practice. It definitely takes some time to explain the new pap smear approach to patients and the new follow-up strategies are more complicated.

The newer guidelines describe a different approach for adolescents, women under 30 and women 30 and older. Age-based guidelines add to the complexity but benefits for women in each age group are clear.

Because this is an important topic, I will devote a series of posts to pap/HPV screening (women 30 and older, women under 30 and special considerations for adolescents). Check here or ask in clinic for information that applies to your age group and personal pap results.