Women With Inherited KRAS-Variant Mutation May Be at Increased Breast Cancer Risk Due to Acute Estrogen Withdrawal


Key Points

  • Up to 45% of breast cancer patients with the KRAS-variant went on to develop a second independent breast cancer, a rate 12 times that of those with no such mutation.
  • KRAS-variant–positive patients are also at an increased risk for ovarian cancer.
  • The investigators believe that KRAS-variant–positive women may benefit from continued or tapered estrogen therapy.

Researchers at UCLA Jonsson Comprehensive Cancer Center 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. These findings were published by McVeigh et al in Cell Cycle.

Study Findings

In a 2-year study led by Joanne Weidhaas, MD, PhD, UCLA Jonsson Comprehensive Cancer Center member and Director of Translational Research at the David Geffen School of Medicine, data were analyzed from a group of more than 1,700 breast cancer patients who 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 biologic 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 biologic models used in the study. Furthermore, Dr. Weidhaas' team found that up to 45% 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.

New Explanation for a Common Mutation

Prior research has shown the KRAS-variant, found in 1 of 17 people, or 6% of the world's population, predicts an increased risk of various cancers including breast and is found in up to 20% 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 cancers.

“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 Dr. Weidhaas, who is also 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 the treatment appropriately,” said Dr. 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 research was supported by the National Cancer Institute, and the work was done in collaboration with MiraKind, a nonprofit organization.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.