Matthew Kurian, Executive Committee Member at KYSCO, shared on LinkedIn:
“One of the toughest decisions in metastatic HR+/HER2- breast cancer? ESR1 + PIK3CA co-mutations. Interestingly, there’s already a disconnect.
Ask an AI platform like OpenEvidence which pathway to target first, and it often leans toward PIK3CA-directed therapy. Ask many academic breast oncologists, and you’ll often hear the opposite: target ESR1 first.
But is that even a fair comparison?
The strongest evidence supporting oral SERDs (EMERALD, EMBER-3, evERA, VERITAC-2) specifically studied ESR1-mutant disease, with several analyses including patients harboring concurrent PI3K pathway alterations.
In contrast, the landmark trials for inavolisib (INAVO120), gedatolisib (VIKTORIA-1), and capivasertib (CAPItello-291) have not reported dedicated efficacy analyses focused specifically on ESR1/PIK3CA co-mutated tumors, making sequencing decisions difficult.
Maybe the better question isn’t which pathway should we target first? It’s which evidence best matches the patient sitting in front of us? Trials like ELEVATE I think are quite important in answering these questions. A combination strategy ESR1 + PIK3CA is likely the answer in my mind, but the toxicity will be the key in my mind.
Check out my biomarker review on Breast Cancers Today, where I dive deeper into this evolving topic and the practical challenges of biomarker-driven treatment selection:”
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