Why breast cancer therapy tamoxifen may lead to higher risk of uterine cancer

In a preclinical study, researchers found tamoxifen encourages uterine cell growth; the findings could change how some breast cancers are treated in the future

Studies show that people receiving tamoxifen, a highly effective and commonly used therapy to treat breast cancer, face a 2- to 7-fold increased risk of developing uterine cancer within 2-5 years of tamoxifen treatment compared to the general population. While this secondary cancer risk remains relatively low and tamoxifen continues to provide substantial benefit for most patients, it is important to understand even small risks to improve long-term outcomes. A new study led by researchers at Mass General Brigham, the Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute, and Berlin Institute of Health (BIH) at Charité sheds light on the mechanism underlying this link and how blocking a specific molecular pathway may offer a way to prevent uterine cancers from occurring in patients taking tamoxifen.

“Our findings suggest that tamoxifen activates a cell growth signaling pathway in cells in the uterus,” said co-corresponding author Gad Getz, PhD, Director of Bioinformatics at the Mass General Cancer Center, part of the Mass General Brigham healthcare system and an Institute Member at Broad.

“Importantly, they also point to a potential way to intervene to prevent patients with breast cancer from developing a second, serious cancer in the future,” said co-corresponding author Kirsten Kübler, MD, PhD, formerly a research fellow in Medicine at Mass General Brigham, currently an Associated Scientist at the Broad Institute and a professor at the BIH.

Researchers performed whole-exome sequencing of 21 uterine cancers that were associated with previous tamoxifen use, and compared their genetic makeup with those of non-tamoxifen-associated uterine cancers in published databases. Results, published in Nature Genetics, found only 14% of post-tamoxifen uterine cancers harbored cancer-related PIK3CA mutations, compared to 48% of uterine cancers diagnosed in women who hadn’t taken tamoxifen. This finding of lower rates of PIK3CA mutations, a key component of the PI3K pathway, in tamoxifen-exposed patients was validated in three independent cohorts.

To see how tamoxifen might induce cancer without inducing genetic changes, the researchers exposed mice to estrogen, tamoxifen, or no treatment. Compared to the other groups, mice exposed to tamoxifen had greater activity in the P13K-AKT pathway, which regulates uterine cell growth, in part through insulin-like growth factor 1 (IGF1), a hormone that encourages cell growth.

Researchers then exposed mice to both tamoxifen and alpelisib, a drug that blocks the P13K pathway and is also used in the treatment of breast cancer. The addition of alpelisib significantly decreased PI3K-AKT signaling, IGF1 receptor activation, and cell proliferation.

Importantly, the study suggests that blocking the PIK3 pathway could reduce the low but concerning risk of tamoxifen-associated uterine cancer.

“Future clinical research can confirm whether combining non-mutant selective PI3K inhibitors with tamoxifen reduces the risk of uterine cancer and ultimately saves lives,” said co-corresponding author Rinath Jeselsohn, Associate Professor of Medicine at DFCI and an Associate Member of the Broad Institute.

Authorship: Authors include Gad Getz, Kirsten Kübler; Agostina Nardone; Shankara Anand; Daniel Gurevich; Jianjiong Gao; Marjolein Droog; Francisco Hermida-Prado; Tara Akhshi; Ariel Feiglin; Avery S. Feit; Gabriella Cohen Feit; Gwen Dackus; Matthew Pun; Yanan Kuang; Justin Cha; Mendy Miller; Sebastian Gregoricchio; Mirthe Lanfermeijer; Sten Cornelissen; William J. Gibson; Cloud P. Paweletz; Eliezer M. Van Allen; Flora E. van Leeuwen; Petra M. Nederlof; Quang-Dé Nguyen; Marian J. E. Mourits; Milan Radovich; Ignaty Leshchiner; Chip Stewart; Ursula A. Matulonis; Wilbert Zwart; Yosef E. Maruvka; and Rinath Jeselsohn

Disclosures: Getz receives research funding from IBM, Pharmacyclics/Abbvie, Bayer, Genentech, Calico, Ultima Genomics, Inocras, Google, Kite and Novartis and is an inventor on patent applications filed by the Broad Institute. He is a founder, consultant, and equity holder in Scorpion Therapeutics, PreDICTA Biosciences and Antares Therapeutics, and has consulted for Merck. Additional author disclosures can be found in the paper.

Funding: This study was funded in part by the Susan F. Smith Center for Women’s Cancers at Dana Farber Cancer Institute, the National Cancer Institute (5R01CA237414-05), the Claudia Adams Barr Program, Pink Ribbon, the KWF Dutch Cancer Society, startup funds from Massachusetts General Hospital, the CDMRP (W81XWH-17-1-0084), the Private Excellence Initiative Johanna Quandt of the Stiftung Charité, the Paul C. Zamecnik Chair in Oncology at the Massachusetts General Hospital Cancer Center, and the Dana-Farber/Harvard Cancer Center Ovarian Cancer SPORE grant (P50CA240243), the Breast Cancer Research Foundation.

Paper cited: Kübler K, Nardone A et al. “Tamoxifen Induces PI3K Activation in Uterine Cancer” Nature Genetics DOI: 10.1038/s41588-025-02308-w

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