Tamoxifen (TAM) is the most commonly used adjuvant endocrine drug for
hormone receptor-positive (HR+)
breast cancer patients. However, how to accurately evaluate the risk of
breast cancer recurrence and
metastasis after adjuvant TAM
therapy is still a major concern. In recent years, many studies have shown that the clinical outcomes of TAM-treated
breast cancer patients are influenced by the activity of some
cytochrome P450 (CYP)
enzymes that catalyze the formation of active TAM metabolites like
endoxifen and
4-hydroxytamoxifen. In this study, we aimed to first develop and validate an algorithm combining polymorphisms in CYP genes and clinicopathological signatures to identify a subpopulation of
breast cancer patients who might benefit most from TAM adjuvant
therapy and meanwhile evaluate major risk factors related to TAM resistance. Specifically, a total of 256 patients with invasive
breast cancer who received adjuvant endocrine
therapy were selected. The genotypes
at 10 loci from three TAM metabolism-related CYP genes were detected by time-of-flight mass spectrometry and multiplex long PCR. Combining the 10 loci with nine clinicopathological characteristics, we obtained 19 important features whose association with
cancer recurrence was assessed by importance score via random forests. After that, a logistic regression model was trained to calculate TAM risk-of-recurrence score (TAM RORs), which is adopted to assess a patient's risk of recurrence after TAM treatment. The sensitivity and specificity of the model in an independent test cohort were 86.67% and 64.56%, respectively. This study showed that
breast cancer patients with high TAM RORs were less sensitive to TAM treatment and manifested more invasive characteristics, whereas those with low TAM RORs were highly sensitive to TAM treatment, and their conditions were stable during the follow-up period. There were some risk factors that had a significant effect on the efficacy of TAM. They were tissue classification (
tumor Grade < 2 vs. Grade ≥ 2,
p = 2.2e-16), the number of
lymph node metastases (Node-Negative vs. Node < 4, p = 5.3e-07; Node < 4 vs. Node ≥ 4, p = 0.003; Node-Negative vs. Node ≥ 4, p = 7.2e-15), and the expression levels of
estrogen receptor (ER) and
progesterone receptor (PR) (ER < 50% vs. ER ≥ 50%, p = 1.3e-12; PR < 50% vs. PR ≥ 50%,
p = 2.6e-08). The really remarkable thing is that different genotypes of
CYP2D6*10(C188T) show significant differences in prediction function (
CYP2D6*10 CC vs. TT, p < 0.019;
CYP2D6*10 CT vs. TT, p < 0.037). There are more than 50% Chinese who have
CYP2D6*10 mutation. So the genotype of
CYP2D6*10(C188T) should be tested before TAM
therapy.