{"entity":{"id":"idea-ctdna-switch-generalised","kind":"idea","name":"Molecular-progression switching beyond ESR1","aka":[],"tldr":"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.","summary":"This idea generalises SERENA-6: run serial ctDNA during first-line aromatase inhibitor plus CDK4/6 therapy for HR-positive breast cancer and, when a PIK3CA or AKT1 mutation emerges, add capivasertib or inavolisib before the scan changes, with T-DXd the analogous move for HER2 activation. Resistant clones are smaller and less heterogeneous at molecular than at radiographic progression, and SERENA-6 showed that acting at this earlier point lengthens disease control. The test is a platform trial randomising at mutation emergence to an immediate pathway-matched drug versus continuation, with PFS2 as primary endpoint and patient-reported outcomes to answer the ODAC critique. At an early clinical stage, it addresses the tumour-heterogeneity and acquired-resistance bottlenecks.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT04964934: SERENA-6","url":"https://clinicaltrials.gov/study/NCT04964934"}],"tags":[],"related":[],"cancers":["breast-hr-positive"],"sections":[],"technologies":["liquid-biopsy"],"targets":[],"drugs":["camizestrant","capivasertib","inavolisib"],"companies":[],"institutions":[],"pathways":[],"terms":["esr1-mutation","ctdna"],"trials":["serena-6"],"people":[],"bottlenecks":[],"keyPapers":["paper-capivasertib-breast-hr-positive-lancet-oncol-2022","paper-capivasertib-breast-hr-positive-breast-2022","paper-capivasertib-breast-hr-positive-drugs-2024"],"journals":[],"dependsOn":[],"notes":[],"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.","test":"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"},"route":"/ideas/idea-ctdna-switch-generalised/","neighbours":{"cancer":[{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"}],"drug":[{"id":"camizestrant","kind":"drug","name":"Camizestrant","route":"/drugs/camizestrant/"},{"id":"capivasertib","kind":"drug","name":"Capivasertib","route":"/drugs/capivasertib/"},{"id":"inavolisib","kind":"drug","name":"Inavolisib","route":"/drugs/inavolisib/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"esr1-mutation","kind":"term","name":"ESR1 mutation","route":"/terms/esr1-mutation/"}],"trial":[{"id":"serena-6","kind":"trial","name":"SERENA-6","route":"/trials/serena-6/"}],"paper":[{"id":"paper-capivasertib-breast-hr-positive-breast-2022","kind":"paper","name":"\"The emerging role of capivasertib in breast cancer\"","route":"/key-papers/paper-capivasertib-breast-hr-positive-breast-2022/"},{"id":"paper-capivasertib-breast-hr-positive-drugs-2024","kind":"paper","name":"Capivasertib: First Approval","route":"/key-papers/paper-capivasertib-breast-hr-positive-drugs-2024/"},{"id":"paper-capivasertib-breast-hr-positive-lancet-oncol-2022","kind":"paper","name":"Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial","route":"/key-papers/paper-capivasertib-breast-hr-positive-lancet-oncol-2022/"},{"id":"paper-imvigor011-nejm-2025","kind":"paper","name":"IMvigor011: using a blood test for leftover cancer to decide who gets immunotherapy after bladder surgery","route":"/key-papers/paper-imvigor011-nejm-2025/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}],"idea":[{"id":"idea-bio1-ctdna-clone-report","kind":"idea","name":"A clone report from blood at every treatment cycle","route":"/ideas/idea-bio1-ctdna-clone-report/"},{"id":"idea-bio1-molecular-progression-add-on","kind":"idea","name":"Add a drug when the blood test turns, without stopping the one that works","route":"/ideas/idea-bio1-molecular-progression-add-on/"},{"id":"idea-bio2-ctdna-six-week-io-switch","kind":"idea","name":"Use a blood test at six weeks to decide whether to keep going","route":"/ideas/idea-bio2-ctdna-six-week-io-switch/"}]}}