BRCA & Fertility: Implications of Angelina’s Choice

Thank you Angelina.

Angelina JolieLike most people, I just learned that Angelina Jolie has undergone an elective double mastectomy because she is a carrier for the breast cancer gene BRCA1. As a carrier, she had an 87 percent chance of developing breast cancer.

She noted that part of her decision to undergo surgery was to increase the chances that she would be alive for her children and her grandchildren. Jolie’s mother died at a relatively young age and did not have much time with her grandchildren.

Jolie is fortunate. She had valuable information which helped her make a decision that may benefit both her and her children.

BRCA mutations increase the risk of multiple cancers including breast and ovarian cancer. In the general population, 1 in 8 women will develop breast cancer during their life. Meanwhile, 1.5 percent of women will develop ovarian cancer.

BRCA genes can dramatically increase the odds of cancer. Different mutations of these genes carry different risks, but some BRCA mutations carry up to a 40 percent chance of ovarian cancer.

So why is an REI writing about this? Well, there are important reproductive implications and questions:

  1. What can REIs and Ob/Gyns do to decrease the risk of cancer in patients?
  2. What can be done to decrease the chances a mom passes these genes to her children?
  3. Should these women do something to preserve their fertility?
  4. Does fertility treatment pose an increased cancer risk to women with these mutations?
Concerned what a BRCA diagnosis means for your fertility?
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What can we do to decrease the risk of cancer in these patients?

The short answer is: lots of things that are beyond the scope of this blog post. To mention just a few, in addition to mastectomy, BRCA carriers can decrease their breast and ovarian cancer risks in a number of ways. Bilateral ovarian oophorectomy (removal of both ovaries) can decrease the risk of both ovarian and breast cancer. Tubal ligation or removal of the tubes can decrease the chance of ovarian cancer. Birth control pills are thought to decrease the risk of ovarian cancer, as well.

Whether or not to remove breasts or ovaries is highly individualized. A woman who has not had children may want to get pregnant first. A woman who has not had children or who wants to store eggs for future use has the option to do that, as well (see below).

What can be done to decrease the chances a mom passes these genes to her children?

The surest way not to pass on this gene is to not have genetic offspring. For many reasons, this is not always possible or desirable.

Women can use donor eggs (eggs from another woman) from a donor with no family history of breast or ovarian cancer. An egg donor can be tested for the gene, but this is not a gene that is routinely tested for in egg donor situations, so there can be extra cost with this testing.

Women who carry a BRCA mutation (or many other unwanted gene mutations) can undergo in vitro fertilization with preimplantation genetic diagnosis (IVF-PGD). With IVF-PGD, a woman undergoes ovarian stimulation to get her ovaries to produce multiple eggs at the same time. The eggs are fertilized with the husband’s sperm (or donor sperm) and then grown in the lab for several days before they are each biopsied and tested to see which embryos carry the gene mutation(s). Only embryos that test negative for the gene mutation(s) are placed back into the uterus.

Of course, PGD has ethical implications. Each patient and/or family must decide what to do with embryos that have gene mutations; whether to discard them, use them, or donate them to research.

Should these women do something to preserve their fertility?

Again, this is highly individualized. A lot depends on the patient’s age, the importance to her of having children, her family history and the particular mutation she has. For example, if she has had multiple family members develop cancers at a young age, or if she is approaching her later 30s and does not have a partner, or if she has a new diagnosis of cancer, a woman may elect to undergo egg or embryo freezing.

Egg and embryo freezing are accomplished in a manner just like IVF. A woman takes medications to induce her ovaries to produce multiple eggs. If a woman has a male partner, or is willing to use donor sperm, she can fertilize her eggs and freeze embryos. Most IVF clinics have the ability to freeze embryos, so this treatment is not too difficult for people who live near an IVF center to do.

Egg freezing is newer and more challenging. Because of their high water content and because water expands when it freezes, eggs have proven more difficult to freeze. Recent advancements in research have enabled some clinics, including TRM, to freeze and thaw eggs with much increased efficiency and with high clinical pregnancy rates — in line with traditional unfrozen donor egg success rates. Egg freezing is an option for women who do not have a male partner and who do not want to use donor sperm. Once frozen, eggs can be stored for years.

When a woman is ready to conceive, the eggs are thawed, fertilized, the embryos are grown (and tested for BRCA mutation(s), if desired) and then transferred to the uterus. If a woman freezes her eggs at age 29 and then uses them years later, her chances of conception are essentially what they were when she was 29 years old.

Does fertility treatment pose an increased cancer risk to women with these mutations?

This has been a long-standing question and the short answer is that we don’t know. To date, there is simply not enough data to reliably say that there if there is an increased risk or not.

We know that a full term pregnancy decreases the risk of ovarian cancer, but this is much less protective in women with BRCA gene mutation(s). The most comprehensive data we have on fertility treatments comes from the Netherlands. In the Netherlands, IVF is paid for and there are unified medical records, so it’s easier to track IVF patients over time.

In a large study of fertility patients, there was no detected increased risk of ovarian cancer in women who took the drugs used to stimulate the ovaries in IVF. These drugs are gonadotropins (FSH, LH, hCG) and in the United States include: Follistim, Gonal F, Menopur, Repronex, Novarel and others. In other words, simply stimulating the ovaries with medications did not seem to increase the risk of cancer.

However, compared to women who took gonadotropin medications for treatments other than IVF, IVF patients did have a small increased risk of cancer. When comparing the two groups of women, there were several differences in the first group (who received gonadotropins but did not undergo IVF) and the IVF group, including:

  1. IVF patients received higher doses of the drugs.
  2. As a result, IVF patient’s had more robust ovarian stimulation and response.
  3.  Patients who got pregnant using drugs alone did not do IVF, and may have had beneficial effects of pregnancy.
    4. If patients failed drug only therapy, many of them then did IVF, which further increases the number of times their ovaries were stimulated and the amount of drug they received.
    5. But perhaps most importantly, and this is just my theory, the IVF patients had a needle placed in their ovary, while the drug only group did not.

Now you might rightly ask: how could a needle cause cancer? By itself, it probably does not. However, there is a biologic plausibility that puncturing the ovary with a needle could increase the risk of cancer, especially in biologically susceptible individuals.

To understand this, let’s revisit what I said earlier about tying the fallopian tubes in BRCA mutation patients and the effect on ovarian cancer. Remember, tying the tubes decreases the risk of cancer in these patients.

The female abdomen and pelvis are open to the external environment. Environmental agents, perhaps carried by bacteria or menstrual flow, can theoretically track up through the vagina, into the uterus, out the tubes and reach the ovaries. It is possible that one or more of these agents could increase the risk of ovarian cancer. It stands to reason that tying the tubes prevents “something” from migrating from the vagina, to the ovaries.

Similarly, it stands to reason that a needle could bring something from the vagina directly to the ovaries that increases the risk of cancer. This is completely speculative, but it stands to reason that women with BRCA mutations might be more susceptible to these external agents than women without a mutation.

OK — so is there an ovarian malignancy risk with IVF? Maybe, but if so the risk is likely small. To know for sure, we need more data.

Overall, in the Netherlands the increased risk was small for IVF patients, compared to the general population. In fact, in more than 10,000 IVF patients, there were fewer than 80 malignant ovarian tumors and a high percentage of these were not actual cancer, but tumors of low malignant potential, and there was no increased risk of death in the IVF group.

There was no detectable increased risk of ovarian cancer for the group as a whole. But for the relatively small number of IVF patients who had been followed for 15 years, there was an increase in ovarian cancer. What we don’t know is if this bump in this one group represents statistical noise and as more patients reach that mark, the bump will disappear, or if the 15 year mark is the beginning of a trend, and cancer risk increases after that.

In this study, the farthest anyone has been tracked is 15 years from her first IVF stimulation. In the coming years, as researchers revisit the Netherlands’ database, we will have data on patients 20, 25, 30 years and more after IVF.

Perhaps they will also be able to determine if there is a disproportionate number of BRCA mutation carriers in the malignancy groups. In other words, if there is an increased risk, is it isolated to a high risk group? Right now, we just don’t know.

For patient safety, I’m going to assume the worst. The good news is, if the Netherlands data is true, the excess risk of needle puncture is still quite small and well more than 1000 women need to go through IVF to get one additional cancer than would have occurred spontaneously.

For my patients with BRCA mutation(s) who are considering IVF, I tell them that we really don’t know if IVF will increase their risk of ovarian malignancy or any other malignancy; however, I would err on the side of caution and consider the risk. I also tell them that many of them will benefit from having their ovaries removed once child-bearing or egg harvesting is complete.

Final thoughts

This is a big topic. I am grateful that Angelina Jolie shared this information. She may save a few lives by doing so … including the lives of those who have not yet been born.

This blog post is by no means exhaustive on the subject, but hopefully you find it useful.

Please feel free to send your comments to us, or make an appointment to discuss further.

Learn more about BRCA.