While anticancer treatments, including many forms of chemotherapy and radiation, can effectively kill cancer cells, long-term use can cause mutations in healthy cells. Mutations arising in cells that undergo replication and growth promote cancer development. Thus, secondary neoplasms, cancers driven by exposure to certain cytotoxic drugs or radiotherapy used to treat cancer, result from mutations induced by anticancer treatments.
Therapy-associated secondary neoplasms, while uncommon, are a known complication of specific cancer treatments. In rare cases, tamoxifen, a hormone therapy for certain breast cancers, can lead to secondary uterine cancers. While this side effect of tamoxifen is well known, the genetic changes driving the association are not fully understood, underscoring the need for further research.
A recent publication in Nature Genetics has made a significant breakthrough by uncovering the mechanism underlying tamoxifen-driven uterine tumorigenesis. The study focused on an oncogene, PIK3CA, a gene that codes for an enzyme called phosphoinositide 3-kinase (PI3K). While PIK3CA often undergoes mutations leading to spontaneous cases of uterine cancer, genetic changes arise far less frequently in tamoxifen-associated tumors.
Using pre-clinical mouse models, the researchers found that tamoxifen directly activated signaling through the PI3K pathway in normal uterine cells. The tamoxifen-driven stimulation of this pathway bypassed the protection afforded by the low mutational burden in PIK3CA.
Tamoxifen represents a standard-of-care therapy for patients with hormone receptor positive breast cancer, and tamoxifen is also used to for breast cancer prevention in women at high-risk of developing this type of malignancy.
Oncologists prescribe tamoxifen therapy for both treating and preventing breast cancer; thus, understanding the link between its use and secondary uterine carcinogenesis has the potential to impact a lot of women. The newly uncovered mechanism by which tamoxifen induces PI3K signaling serves as a direct, non-genetic driver of uterine cancer development. This understanding paves the way for future research programs aimed at targeting the PI3K pathway in patients receiving tamoxifen.
Sources: Nat Commun, J Natl Cancer Inst, Nat Gen, ASCO Ed, Breast