# Look for the resistant sub-population before the first dose

Source: https://onco.cc/ideas/idea-bio1-baseline-ultradeep-resistant-clones/  
OnCo record `idea-bio1-baseline-ultradeep-resistant-clones` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Resistance mutations often exist in a tiny fraction of cells before treatment starts. Error-corrected sequencing that detects variants below 0.01 percent allele fraction could find them at diagnosis and prompt a mechanism-matched combination from day one.

## Summary

Duplex or error-corrected sequencing detects variants below 0.01 percent allele fraction. Pre-existing resistance clones (EGFR T790M before first-generation TKIs, KRAS in colorectal cancer before anti-EGFR, ESR1 in breast cancer) predict early failure. The proposal is a baseline ultra-deep panel of known resistance alleles for every patient starting a targeted drug, with a pre-specified rule to add the mechanism-matched second agent if a clone is found.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Hypothesis: Ultra-deep baseline detection of a resistance allele predicts progression within six months on monotherapy, and patients with detectable pre-existing clones who receive an upfront combination have progression-free survival matching those without such clones.
- Rationale: Pre-existing resistance was shown for T790M and for KRAS in colorectal cancer; assays have improved by two orders of magnitude since those studies.
- Proposed test: Prospective observational study in 300 patients starting osimertinib or an anti-EGFR antibody: ultra-deep baseline plasma and tissue, blinded, correlated with time to progression; if predictive, a randomised combination trial in the clone-positive group.
- Maturity: preclinical-evidence
- Actor: research

## Sources

- Bottleneck evidence (Tumour heterogeneity and clonal evolution): Gerlinger et al., Intratumor heterogeneity and branched evolution (NEJM 2012): https://doi.org/10.1056/NEJMoa1113205

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [Estrogen receptor (ERα)](https://onco.cc/targets/estrogen-receptor/), [KRAS](https://onco.cc/targets/kras/)
- terms: [Variant allele frequency (VAF)](https://onco.cc/terms/vaf/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- key papers: [Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial](https://onco.cc/key-papers/paper-egfr-nsclc-lancet-oncol-2012/), [FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-flaura-nejm-2018/), [Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR](https://onco.cc/key-papers/paper-egfr-nsclc-n-engl-j-med-2010/)

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