Predictive modeling of the probability of gynecological complications of tamoxifen therapy: A prospective study

Background. It is well known that adjuvant therapy for breast cancer (BC) with tamoxifen is associated with an increased risk of endometrial hyperplasia (EH). Currently, the problem of hyperplastic processes and endometrial cancer during long-term tamoxifen therapy is particularly relevant since the incidence of endometrial disorders has a direct correlation with the duration of tamoxifen therapy. Follow-up by a gynecologist should be tailored to consider the risk of endometrial cancer in women who survived BC to improve the early detection of endometrial cancer and avoid unnecessary invasive procedures.

Aim. To predict adverse drug reactions (ADRs) of tamoxifen, including EH, endometrial polyps, and abnormal uterine bleeding, based on mathematical modeling in relation to the carriage of polymorphic variants of cytochrome P450 enzyme genes and drug transporter proteins.

Materials and methods. A prospective pharmacogenetic study of 120 women with stage I–III luminal BC receiving tamoxifen was conducted. The polymerase chain reaction method was used to detect the presence of polymorphisms of cytochrome P450 genes, followed by an assessment of their associations with ADRs of tamoxifen, namely with local gynecological symptoms.

Results. Predictive models of ADR occurrence based on the logistic regression function have been created and validated by ROC analysis. We have developed a prognostic model to estimate the probability of developing a composite endpoint (polyp, EH, abnormal uterine bleeding) based on history and genetic risk factors. It was found that the predictors of the combination of local gynecological ADRs (EH, endometrial polyp, and abnormal uterine bleeding) include such factors as weight loss, the presence of asthenia, an increase in the number of births, carriage of the TT genotype of the ABCB1 3435 polymorphic variant and the GG genotype of the CYP2D6*4 polymorphic variant, GG of the CYP3A5 polymorphic variant. The relatively high incidence (43.3%) of local gynecological symptoms requires regular monitoring by obstetrician-gynecologists using instrumental methods (transvaginal ultrasound).

Conclusion. This prognostic model has demonstrated high diagnostic effectiveness, which allows it to be implemented in the routine clinical practice of an obstetrician-gynecologist.