PI3K Pathway Activation May Underlie Tamoxifen-Associated Uterine Cancer

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Even though it is infrequent, uterine cancer can develop in patients treated with tamoxifen. A study presented at the 2021 San Antonio Breast Cancer Symposium (SABCS) suggests that the mechanism by which uterine cancers develop is tamoxifen-induced PI3K pathway activation.1 Patients treated with tamoxifen who developed uterine cancer had fewer PI3K pathway mutations than patients who developed de novo uterine cancers not associated with tamoxifen use. In mouse models, the PI3K inhibitor abemaciclib given with tamoxifen appeared to mitigate PI3K pathway activation, as demonstrated by decreased markers of PI3K staining.

Kirsten Kübler, PhD, MD

Kirsten Kübler, PhD, MD

“We want to make sure people understand that tamoxifen is safe to use, and tamoxifen-associated uterine cancer is infrequent,” explained presenting author Kirsten Kübler, PhD, MD, associate scientist at the Broad Institute of MIT and Harvard, research staff at Massachusetts General Hospital, and Instructor in Medicine at Harvard Medical School. Dr. Kübler recently joined the faculty of the Berlin Institute of Health at Charite in Berlin. “We wanted to understand the mechanism behind this uncommon event to potentially help patients who are at an increased risk of uterine cancer due to additional-risk cancers.”


Tamoxifen is the first hormonal treatment of estrogen receptor–positive breast cancer, and it used worldwide to improve overall survival. Although tamoxifen blocks estrogen activity in the breast, it can activate estrogen receptors in other tissue, including the uterus. Although tamoxifen improves relapse-free and overall survival in women with estrogen receptor–positive breast cancer, it also increases the risk of uterine cancer two- to sevenfold after 2 to 5 years of treatment. “At 10 years, there is a twofold further increase in uterine cancer compared with 5 years,” Dr. Kübler noted.

“To date, the mechanism of tamoxifen-driven tumorigenesis is not well understood, and preventive approaches are lacking,” Dr. Kübler said. “We sought to molecularly characterize tamoxifen-associated uterine cancers and gain insights into their unique evolution using whole-exome sequencing.”

Dr. Kübler explained that cancer treatments can select for mutations that cause uncontrolled growth in other tissues, leading to second cancers. “The model for how secondary cancers occur after chemotherapy, for example, is that cells acquire 

driver mutations that lead to clonal outgrowth. Our study results extend that view in the sense that a drug could directly activate a signaling pathway instead of creating mutations that activate that pathway.”

Study Details

To develop a model of therapy-related tumorigenesis, the research team explored the genomic mutation landscape of uterine cancer by whole-exome sequencing on 21 pairs of tamoxifen-associated uterine cancer samples from the TAMARISK study, which evaluated the occurrence of secondary cancers in patients taking tamoxifen. These results were compared with results from The Cancer Genome Atlas of de novo uterine cancers that developed without tamoxifen use. They found that most genomic alterations associated with uterine cancer occurred at similar rates in the two groups of samples, with a key exception.

The key exception was a significant decrease in mutations associated with the PI3K pathway in patients with tamoxifen-associated uterine cancer. An independent validation set of 40 pairs of independent samples from patients who developed tamoxifen-associated uterine cancer enrolled in the TAMARISK trial; the investigators compared the data set with a cohort of de novo uterine cancers from AACR Project Genie. Again, the frequency of PI3K mutations was significantly lower compared with de novo uterine cancer: 7.5% vs 21%, respectively.

“Together, our genomic analysis revealed a decrease in PI3K mutations in tamoxifen-associated uterine cancer,” Dr. Kübler stated.

Then, the researchers wanted to explore the mechanisms of decreased PI3K pathway mutations in the uterine tissue of tamoxifen-treated mice. In these experiments, tamoxifen increased the expression of KI67, a marker of cell proliferation. They found that markers of PIK3 pathway activation were increased in the tamoxifen-treated mice compared with the controls. 

“We think tamoxifen might be a substitute for crosstalk between estrogen receptor and PI3K, thereby stimulating uterine cancer development,” she commented.

The next step was to see whether a PI3K inhibitor might mitigate this mechanism. In a series of mouse experiments, tamoxifen increased activation of the PI3K pathway, which was abrogated by the PI3K inhibitor abemaciclib.

“We found a new mechanistic explanation for the development of therapy-related tumors that, to our knowledge, has not been previously described,” Dr. Kübler said. “As an early event, tamoxifen can indeed substitute for the mutant-driven activation of the PI3K pathway. These results suggest it may be possible for women at high risk of uterine cancer on tamoxifen to take a PI3K inhibitor as a prevention strategy, but this is a very preliminary result.”

One limitation of the study is the small number of patient samples available for a relatively uncommon disease such as uterine cancer. 

Other Points of Interest

William J. Gradishar, MD, FACP, FASCO

William J. Gradishar, MD, FACP, FASCO

During the discussion session following this presentation, session moderator William J. Gradishar, MD, FACP, FASCO, the Betsy Bramsen Professor of Breast Oncology and Chief of Hematology/Oncology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, raised several questions.

In response to these questions, Dr. Kübler noted that some data from a different study found a lower frequency of PIK3 mutations in tamoxifen-associated uterine cancer samples. In the TAMARISK trial, the median age of patients was around 70 in both the whole-exome sequencing and validation sets. In addition, the distribution of different types of uterine cancers was similar in both tamoxifen-associated and de novo uterine cancers.

“No histologic subtype popped out,” she said. The data will continue to be analyzed further. 

DISCLOSURE: Dr. Kübler reported no conflicts of interest.  


1. Kubler K, Nardone A, Anand S, et al: Tamoxifen instigates uterine cancer development by activating PI3K signaling and supersedes PIK3CA driver mutations. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-09. Presented December 8, 2021.


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