Top Line: Advanced, HR+/HER2- breast cancer can acquire resistance to aromatase inhibition (AI) through activating mutations in ESR1.
The Study: ESR1 encodes the gene for the most common estrogen receptor isoform. Up to 40% of patients who progress on an AI have mutations in ESR1 that can be detected in circulating tumor DNA. While resistant to AI therapy, these mutated estrogen receptors may still be sensitive to degradation by fulvestrant. So, what should happen when such mutations are detected that forecast likely disease progression? Patience you must have. PADA-1 was a randomized phase 3 trial where 1017 women with advanced HR+ breast cancer were monitored for rising ESR1 mutations in the blood (bESR1mut) while on first line AI and palbociclib. Of these, 17% (172) had a rising bESR1mut without clinical progression and were randomized to either continue AI plus palbociclib or to switch to fulvestrant plus palbociclib. Overall, 27% had a rising bESR1mut, but some were excluded due to synchronous disease progression. Median progression-free survival was more than doubled after switching to fulvestrant from 5.7 months to 11.9 months.
TBL: In patients with HR+/HER2- breast cancer receiving an AI and palbociclib, switching from the AI to fulvestrant upon a rising bESR1mut prolongs progression-free survival.
- Bidard, Lancet Oncol 2022