# Molecular-progression switching beyond ESR1

Source: https://onco.cc/ideas/idea-ctdna-switch-generalised/  
OnCo record `idea-ctdna-switch-generalised` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-07
- 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.
- Proposed 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

## Sources

- ClinicalTrials.gov NCT04964934: SERENA-6: https://clinicaltrials.gov/study/NCT04964934

## Connected records

- cancers: [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- drugs: [Camizestrant](https://onco.cc/drugs/camizestrant/), [Capivasertib](https://onco.cc/drugs/capivasertib/), [Inavolisib](https://onco.cc/drugs/inavolisib/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [ESR1 mutation](https://onco.cc/terms/esr1-mutation/)
- trials: [SERENA-6](https://onco.cc/trials/serena-6/)
- key papers: ["The emerging role of capivasertib in breast cancer"](https://onco.cc/key-papers/paper-capivasertib-breast-hr-positive-breast-2022/), [Capivasertib: First Approval](https://onco.cc/key-papers/paper-capivasertib-breast-hr-positive-drugs-2024/), [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](https://onco.cc/key-papers/paper-capivasertib-breast-hr-positive-lancet-oncol-2022/), [IMvigor011: using a blood test for leftover cancer to decide who gets immunotherapy after bladder surgery](https://onco.cc/key-papers/paper-imvigor011-nejm-2025/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- ideas: [A clone report from blood at every treatment cycle](https://onco.cc/ideas/idea-bio1-ctdna-clone-report/), [Add a drug when the blood test turns, without stopping the one that works](https://onco.cc/ideas/idea-bio1-molecular-progression-add-on/), [Use a blood test at six weeks to decide whether to keep going](https://onco.cc/ideas/idea-bio2-ctdna-six-week-io-switch/)

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