300P - Gene expression landscape of the long-term tamoxifen resistance in premenopausal ER+ breast cancer patients in the STO-5 controlled randomized clinical trial with >20-year follow-up

Background

Tamoxifen is a cornerstone treatment for estrogen receptor positive (ER+) breast cancer (BC). Long-term risk of recurrence is a distinguishing trait of ER+ BC, especially in premenopausal patients. Mechanisms behind late ER+ BC recurrences despite tamoxifen treatment are poorly understood.

Methods

Secondary analysis of 406 premenopausal ER+, HER2- invasive BCs randomized to 2 years of tamoxifen treatment or control in the Stockholm Tamoxifen 5 (STO-5) trial, with 20 years complete follow-up. Tumor expression of ∼21.5K unique genes (Agilent Technologies) was analyzed in relation to DRFI in Cox proportional hazards models restricted to 10-20 years post-diagnosis. Genes with a tamoxifen-interaction term p value (p _i)<.01 were further analyzed. Gene sets identified by k-means clustering were subjected to GO enrichment analyses with Benjamini-Hochberg adjustment to generate q-values. Correlations were evaluated using Pearson correlation.

Results

With a cutoff at p _i<.01, 188 genes were associated with tamoxifen effect on late recurrences: 58 with benefit, 130 with resistance. These genes did not include ESR1 or any gene strongly correlated to ESR1 expression (correlation >|.5| and p<.01), and only 50% were previously described in BC. Clustering the 188 genes in a heatmap, benefit and resistance genes were separately co-expressed, suggesting distinct treatment benefit vs. treatment resistance phenotypes. Functionally, the clusters represented a wide range of GO-terms (q<.05); resistance-related enrichment terms included e.g. export from the nucleus, while benefit-related functions included e.g. regulation of transcription and translation.

Conclusions

Among the genes related to long-term tamoxifen benefit in this patient subset, co-expression patterns indicated distinct phenotypes for benefit and resistance. The lack of predictive indication of ESR1 suggests that in this setting, tamoxifen resistance may be attributed to indirect tamoxifen effects rather than tumor ER. Our data support the need and feasibility of a novel gene expression-based resistance panel for clinical utilization.

Clinical trial identification

The trial was approved and initiated before the practice of trial registration in Sweden.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

This work was supported by the Swedish Research Council [Vetenskapsrådet, grant number 2020-02466 and 2023-03009 to L.S.L.]; the Swedish Cancer Society [Cancerfonden, grant number 222216 to O.S., 232670 to N.P.T., and 222081 and 220552SIA to L.S.L.]; Stockholm Cancer Society [Cancerföreningen iStockholm, grant number 181093 to T.F., 224112 to N.P.T., and 221233 and 201212 to L.S.L.].

Disclosure

All authors have declared no conflicts of interest.