68P - Neratinib in combination with fulvestrant and or palbociclib can overcome endocrine resistance in HER2-low/ ER+ breast cancer

Background

Luminal A (ER+/ HER2-low) is the most common breast cancer subtype and hormonal therapy is the preferred first-line treatment. However, most patients (>50%) develop resistance, leading to disease recurrence and limited clinical benefit, even with the addition of a combination regimen. Therefore, treatment optimization is required urgently. Furthermore, studies have indicated that the tumours with low HER2 and ER levels evade ER blockade via the upregulation of EGFR/HER2 signalling. Therefore, this study will aim to assess the effects of anti-HER2 in combination with hormone treatment in ER+/HER2-low breast cancer.

Methods

A panel of patient-derived organoids ( n=31) was successfully established and characterized using immunohistochemical and confocal imaging. Through the drug sensitivity test, the drug combination efficacy of the anti-HER2 drug (neratinib), hormone treatment (fulvestrant), and CDK4/6 inhibitor (palbociclib) was tested in HER2-low breast cancer patient-derived organoids. The underlying molecular mechanisms were investigated using immunofluorescence, western blot analysis, immunohistochemical staining, and cell cycle analysis.

Results

We found that neratinib combined with palbociclib and or fulvestrant showed better efficacy than palbociclib and fulvestrant combination in HER2-low breast cancer, resulting in the deactivation of HER2-EGFR signalling pathway, decreased transcriptional activation of ER and cycle proteins. Furthermore, the dual or triple combination of neratinib, palbociclib, and fulvestrant could decrease the nuclear translocation of ER. This may be the underlying mechanism by which the addition of palbociclib and/or fulvestrant to neratinib was more beneficial than the combination of palbociclib plus fulvestrant.

Conclusions

Our study provides the rationale for combining neratinib with fulvestrant and or palbociclib for the treatment of ER+/HER2-low breast cancer and indicates that the dual or triple combination treatment may be a better strategy to overcome resistance to hormone treatment. Moreover, future translational research will investigate the potential biomarkers indicating the responsiveness to the treatment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The author.

Funding

Puma biotechnology.

Disclosure

The author has declared no conflicts of interest.