In a groundbreaking preclinical study, researchers have discovered that tamoxifen, a widely used therapy for breast cancer, may significantly increase the risk of uterine cancer. The study, conducted by experts from Mass General Brigham, the Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute, and the Berlin Institute of Health (BIH) at Charité, reveals that tamoxifen encourages uterine cell growth, potentially altering future breast cancer treatment protocols.
According to the study, individuals undergoing tamoxifen treatment face a two- to seven-fold increased risk of developing uterine cancer within two to five years compared to the general population. Despite this elevated risk, the overall incidence remains relatively low, and tamoxifen continues to offer substantial benefits for many patients. However, understanding even minor risks is crucial for improving long-term patient outcomes.
Unveiling the Mechanism: How Tamoxifen Affects Uterine Cells
The research team conducted whole-exome sequencing on 21 uterine cancers linked to prior tamoxifen use, comparing their genetic profiles with those of non-tamoxifen-associated uterine cancers from existing databases. The findings, published in Nature Genetics, indicate that only 14% of post-tamoxifen uterine cancers had cancer-related PIK3CA mutations, compared to 48% in women who had not taken tamoxifen.
Dr. Gad Getz, co-corresponding author and Director of Bioinformatics at the Mass General Cancer Center, explained,
“Our findings suggest that tamoxifen activates a cell growth signaling pathway in cells in the uterus.”
This pathway, known as the PI3K-AKT pathway, is crucial in regulating uterine cell growth, partly through the hormone insulin-like growth factor 1 (IGF1).
Potential Interventions: Blocking the PI3K Pathway
To explore how tamoxifen might induce cancer without genetic changes, researchers conducted experiments on mice, exposing them to estrogen, tamoxifen, or no treatment. The tamoxifen-treated mice showed increased activity in the PI3K-AKT pathway. Subsequently, the team administered both tamoxifen and alpelisib, a drug that inhibits the PI3K pathway, to another group of mice. The combination significantly reduced PI3K-AKT signaling, IGF1 receptor activation, and cell proliferation.
Dr. Kirsten Kübler, co-corresponding author, emphasized the potential of these findings, stating,
“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.”
Implications for Future Research and Treatment
The study suggests that blocking the PI3K pathway could mitigate the risk of tamoxifen-associated uterine cancer. Dr. Rinath Jeselsohn, another co-corresponding author, noted,
“Future clinical research can confirm whether combining non-mutant selective PI3K inhibitors with tamoxifen reduces the risk of uterine cancer and ultimately saves lives.”
This development follows a growing body of research aimed at understanding the side effects of cancer treatments and improving patient safety. The potential for combining tamoxifen with PI3K inhibitors could revolutionize treatment protocols, offering a dual approach to managing breast cancer while minimizing secondary cancer risks.
Funding and Disclosures
The research was supported by various institutions, including the Susan F. Smith Center for Women’s Cancers at Dana Farber Cancer Institute, the National Cancer Institute, and the Breast Cancer Research Foundation. Disclosures reveal that Dr. Gad Getz receives research funding from multiple pharmaceutical companies and holds positions in various biotech firms.
The study’s comprehensive approach and collaboration among leading cancer research institutions underscore the importance of multidisciplinary efforts in advancing cancer treatment. As the medical community continues to explore these findings, the hope is that they will lead to safer and more effective therapeutic strategies for breast cancer patients worldwide.
