409P - Biological tumor traits predicting late recurrence in premenopausal breast cancer patients: Insights from the STO-5 trial with 20-year follow-up

Background

Estrogen receptor (ER)-positive breast cancer patients have a long-term risk of distant recurrence, and premenopausal women have an increased risk. The reasons behind long-term risk are not well understood, but tumor dormancy is one suggested mechanism. Here, we aimed to identify key biological traits predicting late risk of distant recurrence.

Methods

Secondary analysis of the Stockholm tamoxifen (STO-5) randomized trial including premenopausal patients from 1990 to 1996, with 20-year complete follow-up. Gene expression data (Agilent Technologies with ∼21.5K unique genes) was used to analyze significant (p.adj.BH< 0.05) enriched MSigDB cancer hallmarks, gene ontology terms and Consensus^TME immune cells, in patients with late distant recurrence (between 10 and 20 years of primary diagnosis) compared to early recurrence (within 5 years) and no recurrence at 20 years.

Results

Besides decreased proliferation-related hallmarks (NES < -2.0), EMT was notably enriched in patients with late recurrence compared to patients with early (NES=2.51) and no recurrence (NES=2.42), suggesting the importance of cellular plasticity to leave the primary tumor and enter dormancy. Additionally, hypoxia emerged as a prominent process among late recurrence patients (NES >1.5), strongly correlating with EMT (p-cor = 0.72), indicating its potential role as an EMT driver. Moreover, late recurrence patients showed negative enrichment of immune related hallmarks and gene ontology terms (NES < -1.5), as decreased immune cell enrichment suggesting long-term immune evasion.

Conclusions

Our findings indicate that premenopausal patients with late recurrence have heightened cellular plasticity and low proliferation enabling prolonged dormancy. Increased EMT suggest enhanced potential for distant tumor cell infiltration from the primary tumor due to unfavorable conditions, such as hypoxia. Further, decreased immune activation and infiltration both indicate immune evasion, facilitating sustained quiescence. Insights into the biology driving late metastatic disease is vital to improve management of premenopausal patients with ER-positive breast cancer.

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.