ideasIdea
Molecular-progression switching beyond ESR1
SERENA-6 showed you can act on a blood test before the scan changes. The same logic could apply to PIK3CA, AKT1, or HER2 mutations emerging on treatment.
Serial ctDNA during first-line therapy could trigger the addition of a PI3K/AKT inhibitor when PIK3CA/AKT1 mutations emerge, or T-DXd when HER2 activation appears, before radiographic progression.
Hypothesis
ctDNA-triggered addition of a pathway-matched agent at molecular progression improves PFS2 and time to chemotherapy versus waiting for radiographic progression.
Rationale
Resistant clones are smaller and less heterogeneous at molecular than at radiographic progression; SERENA-6 demonstrated a 7-month PFS gain with this timing.
What would test it
A platform trial would run serial ctDNA on first-line AI + CDK4/6 and randomise at emergence of PIK3CA/AKT1 mutation to immediate capivasertib or inavolisib vs continue; primary endpoint PFS2. Address the ODAC critique with patient-reported outcomes and OS follow-up.
Maturity
early clinical