Source/Disclosures
Disclosures: Oktay reports serving as the co-chair of the ASCO fertility preservation guidelines committee since 2005.
July 27, 2020
3 min read
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Women with BRCA mutations may be at higher risk for infertility after chemotherapy

Source/Disclosures
Disclosures: Oktay reports serving as the co-chair of the ASCO fertility preservation guidelines committee since 2005.
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Chemotherapy is known to increase a woman’s risk for infertility, and women with BRCA mutations have lower ovarian reserves and higher risk for developing breast cancer.

Now, researchers have found that women who harbor BRCA mutations face increased risk for infertility after undergoing chemotherapy for breast cancer.

“The emerging opinion is that because of the BRCA mutations, the ovaries of women carrying these mutations age faster and, as a result, have lower ovarian reserves to being with,” Kutluk Oktay, MD, PhD, FACOG, professor of obstetrics, gynecology and reproductive and director of the Laboratory of Molecular Reproduction and Fertility Preservation at Yale School of Medicine, and medical director of Innovation Institute of Fertility Preservation, said in an interview with Healio. “On top of that, they are more sensitive to chemotherapy. These patients should be more aggressively counseled about preserving their fertility before these treatments.”

Kutluk Oktay, MD, PhD, FACOG
Kutluk Oktay

In a longitudinal cohort study — funded by the NIH and published in Fertility and Sterility — Oktay and colleagues evaluated 177 women who were undergoing chemotherapy for the treatment of breast cancer. Fourteen of the women carried a BRCA mutation. The researchers assessed the women during chemotherapy and at 12, 18 and 24 months after therapy, measuring their levels of antimüllerian hormone, which is indicative of a woman’s ovarian reserves. They found that after chemotherapy, women with BRCA mutations had significantly lower rates of antimüllerian hormone recovery than women without these mutations.

Oktay spoke with Healio about the findings, what they mean for women with BRCA mutations, and how they might be applied to other mutations.

Question: Can you describe the state of the ovarian reserves of a BRCA mutation carrier prior to developing cancer?

Answer: Women with BRCA mutations, particularly those with BRCA1 as opposed to BRCA2, have a faster decline of egg reserve compared with women without the mutations. Additionally, because BRCA genes are DNA repair genes, women who have mutations in these genes tend to have more DNA damage in their eggs. That’s why we thought chemotherapy might harm them further, because we also have found that DNA damage is the main mechanism of how chemotherapy affects fertility. It does the same kind of DNA damage to eggs that it does to cancer cells. Since the eggs of a woman with a BRCA mutation inefficiently repair DNA damage, we thought there might be a double whammy here.

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As they age, every woman’s eggs repair DNA damage less efficiently, and as a result, there is an accumulation of DNA damage. Women with these mutations are losing more eggs because the eggs are more sensitive to environmental damage; the body eliminates them. On top of that, we’re adding a supercharged environmental stress: chemotherapy.

Q: What did your study show about the post-chemotherapy ovarian reserves of women with BRCA mutations vs. those without?

A: We compared women with BRCA mutations with those who tested negative for mutations and those who were not tested because they were at low risk for having these mutations. In the end, we found that if you compare the ovarian reserve, there was a threefold difference after chemotherapy. For women who did not have mutations or were at low risk for mutations, there was about 6% of the reserve remaining. In the BRCA mutation group, however, it was about 1.5% to 2%. Antimüllerian hormone measures can determine, for example, a woman’s likelihood of success with in vitro fertilization procedures and when a woman will start menopause. It does not necessarily determine how fertile you are, but you can infer that if you go into menopause years earlier than normal, you’ll have that much less time to be able to reproduce.

Q: You also conducted a related analysis on mouse models. What did you find?

A: In mouse models, we knocked out the BRCA1 gene in the oocyte and exposed them in a petri dish to the same kind of chemotherapy that these women receive. We found that those eggs tended to die at quite higher rates, so we confirmed our clinical findings in a biological fashion.

Q: How should women with BRCA mutations be counseled?

A: Several factors go into this, such as the age of the woman and how many children she wants. Overall, though, if the patient has one or more of these mutations, she should be carefully counseled in terms of preserving fertility. If the woman is pursuing embryo freezing, we have the option now of testing the embryo genetically for the presence or absence of these mutations, so they don’t have to pass this on.

Q: What is the next step for research?

A: Other mutations are being discovered to be associated with breast cancer or ovarian cancer that are in the same family of genes as BRCA, like ATM and CHEK2 mutations. We think these may be linked to many of the same issues in terms of fertility as the BRCA mutations. That’s our current research, and it may turn out that this may be about much more than just the BRCA mutations.

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For more information:

Kutluk Oktay, MD, PhD, FACOG, can be reached at 7 West 51st St., 5th Floor, New York, NY 10019; website: www.fertilitypreservation.org; email: info@fertilitypreservation.org.