Jolie news highlights changing nature of mastectomy

Breast cancer cells

The world pays extra attention to diseases when celebrities have them, so it dominated the news this week when actress Angelina Jolie revealed that she recently had a double mastectomy. Tests had revealed she has the BRCA1 genetic variation known to drastically increase breast cancer risk. A sad detail in her case was her mother's death from the disease, which points to the interplay between genetic tests and family history when assessing risk.

The media did a good job of explaining that each case is different, and that women should make decisions with respect to breast cancer surgery in partnership with their doctors and genetic counselors. Included in the coverage was a fine piece by The Associated Press that described how women who make the same decision as Ms. Jolie now benefit from new approaches and technologies.

The nature of mastectomies has changed in recent years to save more of the breast, reduce scarring and pain and, in some cases, to enable breast reconstruction during the same surgery that removes the cancer. About 220,000 women are diagnosed with breast cancer each year in the United States, and 40,000 die.

We asked Helen Krontiras, M.D., co-director of UAB Breast Health Center and scientist at the UAB Comprehensive Cancer Center, for her take on the news and emerging trends in breast cancer surgery, which is her specialty.

Making it easier

Women who had double mastectomies in years past likely faced the removal of their entire breasts, including nipples and good deal of skin. They then faced a series of surgeries required to rebuild the breast with skin taken from the belly, construct a nipple and tattoo a ring around it.

Today, most women chose to have some degree of reconstruction done during the same surgery as their mastectomy, said Dr. Krontiras. For reconstruction requiring implant, surgeons must still, in many cases, put in expanders to stretch the skin for a time before a second surgery to put the implant in. Some patients go straight to implant at the time of mastectomy. According to the AP article, about 25 to 30 percent of women nationally get immediate reconstruction.

Despite a growing focus on the cosmetic aspects of breast reconstruction, Dr. Krontiras emphasized that the first goal is obviously to remove all the cancer. Second to that, but still important, is the effort to preserve cosmetic outcome. In some patients, she starts with chemotherapy first to try to shrink the tumor to the point that patients become candidates for skin saving techniques. One factor making this possible is the increasing sophistication of chemotherapy against breast cancer based on the realization that breast cancer can be one of several cancers, with treatment now tailored for each patient's genetic make-up.

In addition, new approaches to mastectomy that save original nipples are gaining in popularity. Many studies now show that the rate of local breast cancer recurrence in patients that retain their nipple and areola are low and on par with older procedures that remove them, Dr. Krontiras said. Injections of body fat are used in some cases to fill in defects that may occur as a results of removing breast tissue.

Looking forward, women may one day benefit from an experimental out-patient technique called cryoablation. A liquid-nitrogen-cooled probe freezes bits of cancer to death, with the dead cancer tissue removed by normal bodily processes. The technique is currently being tested in clinical trials.

Talk it over

Jolie made the decision to have the double mastectomy because counseling revealed she had the BRCA1 gene, and because her mother had died of breast cancer. It has been reported that her health team told her she had an 87 percent chance of getting breast cancer.  Of course, such numbers are the opposite of universal, and vary greatly form patient to patient.

Dr. Krontiras recommends that women diagnosed with the BRCA 1 or 2 gene start with a discussion of options with their doctor and genetic counselor. Each patient’s risk for cancer will be managed by varying combinations of surveillance, chemoprevention and prophylactic surgery of breasts and/or the ovary. There is no once-size-fits-all approach.

She added that she hopes the widespread attention generated by Jolie’s announcement does not lead to a whole-sale increase in requests for mastectomy. Genetic predisposition for breast cancer affects less than 10 percent of all women diagnosed with breast cancer.

However, women who do carry such a gene can have an up to 85 percent lifetime risk for breast cancer. Therefore, asking questions about family history are important, and patients need to learn about risk on both their mother’s and father’s sides of the family.

While the BRCA genes are important predictors of breast cancer risk, they are likely to be the first of many as yet undiscovered genetic and familial factors that contribute to risk, Dr. Krontiras said. Even those with negative BRCA tests should be watched closely if family members have developed breast cancer.
     
Women and family members interested in genetic counseling with respect to breast cancer can visit the UAB Cancer Genetics Clinic site. There is a website offered by The National Society of Genetic Counselors that has information about family history, as well as another by the National Cancer Institute on preventive mastectomies.  More commentary is available in this UAB news story and in this article and video from Medpage Today.

Obesity, exercise and epigenetics: no excuses

No excuses. It's the mantra of many a fitness boot camp and weight room. But what if your genes make you more likely to store fat on your body or less likely to lose weight when you exercise?

In the experience of Molly Bray, Ph.D., professor of epidemiology and genetics at UAB, the many obese people she has worked with do not see genetic barriers to weight loss as excuses. To the contrary, learning that their genes are making it harder to lose weight is empowering. New enthusiasm and harder workouts replace the frustration of doing everything your doctor tells you and getting nowhere.

Along with counseling people about genetic components of obesity risk, Bray leads a research effort to understand the mechanisms behind them. As she explained in her presentation at a recent UAB Epigenetics Symposium, some people have versions of genes that contribute to obesity. Risk may be influenced further by epigenetic chemical reactions that determine when genes that control energy use are turned on or off.

To recap for this third podcast in our epigenetics series, the human genetic system is composed of more than genes, the long stretches of DNA that encode instructions for the building of proteins. Proteins are the workhorse molecules that comprise the body's structures and carry its signals. We inherit genes and proteins from our parents largely unchanged, because changes often cause disease or death, even though they are necessary if we are to evolve.

While genes form the basic instructions for human life, they are not very good at changing quickly as our surroundings change. In fact, you and many like you may have to die (say during a plague) before the gene pool gets around to favoring those who happen to have the mutations (slow, random changes in genes) that make some better adapted to survive.

That may explain why we have epigenetic mechanisms: quick, reversible chemical reactions that turn genes on and off, often in response to environmental cues. Research has revealed that many genes are turned on and off epigenetically based on whether or not we eat good food, breathe clean air and exercise, and these changes have consequences for our risk of developing many diseases, including obesity.



Show notes for the podcast:

1:50 Epigenetic changes proceed very rapidly, some believe within 24 hours, said Bray.

2:23 The Human Genome Project, for all it has revealed about the DNA sequence of our genes, could not account for the variation in risk for many diseases going from person to person. Differences in the mechanisms that regulate genes may explain more about this disease risk variability than differences in genes themselves.

3:29 Methylation, the attachment of a methyl group (one carbon plus three hydrogens) to certain spots in the DNA chain, is recognized as a major epigenetic mechanism. It enables other proteins to assemble there in a way that silences or turns off the surrounding gene. Researchers once thought that such methylation marks were made in the womb and persisted throughout life, an idea which gave rise to theories about the fetal origins of adult disease. Then came the discovery of enzymes called demethylases, which remove methyl groups. The field now understands that methylation is an active process, with epigenetic changes occurring throughout life, some of them in response to our diet and excercise patterns.

4:18 One reason that epigenetic changes may be important for each person's obesity risk has to do with a gene called FTO (fat mass and obesity related transcript), said Bray.  Certain versions of this gene are more closely associated with obesity risk than any other gene, with the effect consistently shown in several studies across multiple populations and in people of all ages.

4:55 Researchers theorize that the protein built according to the instructions encoded in the FTO gene may act as a demethylase. Its not known why FTO continues to be associated with obesity, but it could be that an FTO demethylase is turning on or off genes that govern energy balance (e.g. how we burn calories in response to exercise).

5:40 Importantly, regular exercise largely erases the increased risk for obesity associated with the versions of the FTO gene. No one then is doomed by their genes, said Bray, because behavior can change them. A recent, small study showed that a single exercise session changes the methylation status of many genes.

7:24 Bray's lab is currently studying how people respond to exercise. Lack of response to an exercise program can be extremely frustrating, but the answer may be straightforward: work out harder.  Her data shows that clinicians can safely increase exercise intensity for many of these patients, and that current treatment guidelines in this regard may need to change.  People can tolerate harder workouts if that's what it takes, said Bray.

8:06 Genes may influence several aspects of a person's response to exercise, including the tough combination of making you need higher intensity workouts to get results and less able to tolerate them. Exercise for some may not "feel good."

8:22 Generally when people find out that a genetic or epigenetic variation may be affecting their response to exercise, they don't see it as an excuse. They benefit greatly from the insight, and realize they're not "just lazy," Bray said.

9:55 Obesity is associated with inflammation, the out-of-place triggering of the immune response.  Inflammation has been established as one link between obesity and several complex diseases, including cardiovascular disease, diabetes and cancer.  Excercise has been shown to counter inflammation. At the intersection of these processes, many of the methylation changes related to exercise and obesity are happening on genes that govern immune responses and inflammation.