Tamoxifen is part of standard treatment for estrogen receptor-positive breast cancer. While research has shown how effective it can be in reducing recurrence risk, it’s also linked with a two to seven times higher risk of developing uterine cancer within two to five years of use. New research may have uncovered why.

A multi-institution team of researchers recently compared 21 cases of tamoxifen-linked uterine cancer with cases in women who had not taken the drug. The goal was to uncover the link between tamoxifen and uterine cancer. The findings, published in Nature Genetics, showed that 14% of the tamoxifen group had cancer-related mutations in the PIK3CA gene, a component in the PI3K signaling pathway, which regulates uterine cell growth and is linked with uterine cancer. However, 48% of the non-tamoxifen group had mutations. This led the team to investigate how the drug can raise the risk of uterine cancer if it’s not causing genetic changes.

To answer that, the researchers exposed mice to either estrogen, tamoxifen, or no treatment at all and found that the tamoxifen group had more activity in the PI3K-AKT pathway. When tamoxifen and PI3K pathway blocker alpelisib - another breast cancer treatment - were combined, PI3K-AKT signaling decreased, as did IGF1 activation, which encourages cell growth. There was also less cell proliferation.

Researchers say the findings suggest PI3K pathway blockers may help eliminate tamoxifen’s increased risk of uterine cancer, helping improve outcomes for breast cancer patients.

Dr. Rinath Jeselsohn, co-author and Director for ER+ Translational Discovery Research at Dana-Farber Cancer Institute, says, “Future clinical research can confirm whether combining non-mutant selective PI3K inhibitors with tamoxifen reduces the risk of uterine cancer and ultimately saves lives. From a clinical perspective, it is also important to emphasize that tamoxifen does not cause mutagenesis in the uterus, and this mechanism of tumor genesis is consistent with the fact that the risk of uterine cancer occurs during and shortly after tamoxifen and is not a lifetime risk.”

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