Study: Potential genetic basis for breast cancer survivors who develop therapy-related leukemia

IN DEPTH REVIEW OF RESEARCH

Study background:

Chemotherapy and radiation can help patients defeat their cancers, but many complications can occur during and after treatment. Breast cancer survivors are a growing population in the United States, and while they have survived their disease, they often face long-term complications and side effects. One example is developing therapy-related leukemia, a rare but potentially lethal complication of some cancer treatments.

In December 2015, Jane E. Churpek and colleagues at the University of Chicago published a study in Cancer that looked to see if inherited genetic mutations are linked to the development of therapy-related leukemia. Researchers and clinicians believe that therapy-related leukemia develops from cytotoxic therapies such as chemotherapy and radiation that cause mutations in blood cell DNA, but they do not understand why this happens to certain patients and not to others. Some breast cancer patients who are treated with surgery alone develop leukemia—this raises the possibility that some cancers that are identified as therapy-related leukemia are actually second primary cancers caused by inherited mutations in genes that are associated with increased cancer risk.

Currently, no study has looked at the possibility of increased risk for therapy-related leukemia in people who carry mutations in genes that increase cancer risk.

What researchers of this study wanted to know:

Are inherited cancer risk-increasing gene mutations involved in the development of therapy-related leukemia in breast cancer survivors?

Population(s) looked at in the study:

The study included 88 female breast cancer survivors who received cytotoxic therapy (chemotherapy and/or radiation) after their primary breast cancer diagnosis, and later developed therapy-related leukemia. Family history and/or DNA samples for genetic testing were available for patients in the study, and genetic testing was done whenever possible.

Study findings: 

1. Of the 47 breast cancer survivors who received cytotoxic therapy and developed therapy-related leukemia and had available DNA for mutation testing, about 20% had a mutation in a cancer-risk increasing gene:
   • 3 patients had mutations in BRCA1
   • 2 patients had mutations in BRCA2
   • 3 patients had mutations in TP53
   • 1 patient had a mutation in CHEK2
   • 1 patient had a mutation in PALB2
2. About 20% of the study population had an additional primary cancer and therapy-related leukemia.
3. Of the 70 patients for whom researchers had family histories, about 60% had a close relative who had breast, ovarian, or pancreatic cancer.

Limitations:

This study is relatively small, so the researchers cannot see potential differences in therapy-related leukemia between people with mutations in different genes (for example, BRCA mutation carriers compared to TP53 mutation carriers). Because the group of patients studied was small, individuals with different types of breast cancers and different treatments were grouped together, making it harder to clearly identify groups at risk. Additionally, while this study shows that about 1 in 5 women who developed treatment-related leukemia after cytotoxic therapy for breast cancer had a mutation in a gene known to increase cancer risk, this group was not compared to mutation carriers who were treated with cytotoxic therapy but did not develop therapy-related leukemia; doing so would have provided additional information.

Conclusions:

This study uncovers a potential link between having a mutation in a gene that increases cancer risk and susceptibility to developing therapy-related leukemia after receiving cytotoxic therapy for breast cancer. More work needs to be done to fully understand this, and to learn how therapy-related leukemia develops in these women. In the meantime, breast cancer survivors with mutations in BRCA or other genes that increase cancer risk should keep in mind that treatment-related leukemia is relatively rare, occurring in fewer than 1% of breast cancer survivors. Notably, 3 of the 47 patients with treatment-associated leukemia had inherited mutations in TP53, which is already associated with increased risk for leukemia. While this study raises the possibility of a link that should be explored further through larger studies, the results alone cannot conclude that mutation carriers are more likely to develop therapy-related leukemia than non-mutation carriers. People concerned about their risk of leukemia after treatment should discuss their risk with their health care provider.

Posted 1/26/15