Background

SERDs are a common 2L treatment for pts with HR+ mBC following progression on CDK4/6 inhibitors + endocrine therapy. However, many pts do not benefit from SERDs, and even among those who benefit, the majority of responders progress in < 6 months (mo). Here, we analyzed genomic and transcriptomic differences between pts who progressed on 2L SERDS in < 6 mo vs > 6 mo to elucidate the biological mechanisms contributing to a durable benefit from to SERDs.

Methods

We selected mBC pts from the Tempus database (HR+, HR+/HER2-, or HER2-) who underwent Tempus xF or xT/xR next-generation DNA and RNA seq. Pts were filtered to those that received 1L palbociclib, abemaciclib, or ribociclib mono- or combination therapy, followed by 2L elacestrant or fulvestrant mono- or combination therapy (commercially approved SERDs), whose sample was collected < 6 mo pre- or post- 2L therapy initiation. Patients were stratified based on timing of progression on 2L therapy into early (< 6 mo, n=114) vs late (≥ 6 mo, n=32). Significance (p<0.05) was assessed using X²/Fisher’s exact or Wilcoxon rank sum tests, as applicable and corrected for multiple testing using false discovery rate.

Results

78% of pts progressed in <6 mo, while 22% progressed ≥6 mo after starting 2L therapy. The most frequent 2L therapy for early progressors was fulvestrant (26%), vs. alpelisib + fulvestrant for late progressors (25%). No significant differences in somatic mutation prevalence were observed between groups for any of the genes analyzed, including ESR1, PIK3CA, and TP53. RNA-seq data were available for 82 patients without durable benefit and 20 with durable benefit. Those progressing within 6 mo had lower median gene expression of ESR1 (6.27 vs 7.32, p=0.01), BAG1 (6.01 vs 6.36, p=0.03), and PGR (1.02 vs 1.98, p=0.02) compared to those with durable benefit.

Conclusions

Higher expression of ESR1, PGR, and BAG1 was observed in pts who had durable clinical benefit for at least 6 mo on SERDs. These findings should be further validated to determine whether increased expression of these genes may contribute to an improved duration of response to SERDs to help us predict who may be the best patient for these therapies.

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