Women with inherited mutation may be at increased breast cancer risk

Study shows those with KRAS-variant mutation also have higher possibility of devloping second breast cancer
Dr. Joanne Weidhaas in her lab

UCLA researchers have discovered that for women with a relatively common inherited mutation, known as the KRAS-variant, abrupt lowering of estrogen may increase their breast cancer risk and impact breast cancer biology. Scientists also found that women with the KRAS-variant are more likely to develop a second primary breast cancer independent of a first breast cancer.

In a two-year study led by Dr. Joanne Weidhaas, UCLA Jonsson Comprehensive Cancer Center member and director of translational research at the David Geffen School of Medicine, data was analyzed from a group of more than 1,700 breast cancer patients who all submitted DNA samples to be tested for the inherited KRAS-variant. The study also included a group of women with the KRAS-variant who were cancer-free, as well as biological models to scientifically confirm the clinical findings.

Results showed that acute estrogen withdrawal, as experienced after ovary removal, or with hormone replacement therapy discontinuation, and/or a low estrogen state were associated with breast cancer in women with the KRAS-variant. Acute estrogen withdrawal also triggered breast cancer formation in KRAS-variant biological models used in the study.

Weidhaas' team further found that up to 45 percent of breast cancer patients with the KRAS-variant went on to develop a second independent breast cancer, representing a 12-fold increased risk over breast cancer patients without the KRAS-variant.

Prior research has shown the KRAS-variant, found in 1 out of 17 people, or 6 percent of the world's population, predicts an increased risk of various cancers, including breast cancer, and is found in up to 20 percent of newly diagnosed cancer patients. Additionally, a previous study found that women with the KRAS-variant are significantly more likely to develop both breast and ovarian cancer.

"Although we had evidence that the KRAS-variant was a stronger predictor of cancer risk for women than men, we did not previously have a scientific explanation for this observation," said Weidhaas, a professor of radiation oncology. "This study's findings, showing that estrogen withdrawal can influence cancer risk for women with the KRAS-variant, begins to provide some answers."

Though the findings run contrary to some past research suggesting that women on combination hormone replacement therapy are more likely to develop breast cancer, they are in agreement with follow-up studies that found estrogen alone may actually protect women from breast cancer.

"The KRAS-variant may be a genetic difference that could actually help identify women who could benefit from continuing estrogen, or at a minimum, at least tapering it appropriately," said Weidhaas. "We hope that there are real opportunities to personalize risk reducing strategies for these women, through further defining the most protective estrogen management approaches, as well as by understanding the impact of different treatment alternatives at the time of a woman's first breast cancer diagnosis."

The study was published in Cell Cycle on May 11, 2015.

The research was supported by the National Cancer Institute and the work was done in collaboration with Mirakind, a non-profit organization.