{"entity":{"id":"idea-bio1-baseline-ultradeep-resistant-clones","kind":"idea","name":"Look for the resistant sub-population before the first dose","aka":[],"tldr":"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.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Tumour heterogeneity and clonal evolution): Gerlinger et al., Intratumor heterogeneity and branched evolution (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1113205"}],"tags":[],"related":[],"cancers":["nsclc","colorectal","breast-hr-positive"],"sections":[],"technologies":["liquid-biopsy","cgp"],"targets":["egfr","kras","estrogen-receptor"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["vaf"],"trials":[],"people":[],"bottlenecks":["b-tumor-heterogeneity","b-resistance"],"keyPapers":["paper-flaura-nejm-2018","paper-egfr-nsclc-lancet-oncol-2012","paper-egfr-nsclc-n-engl-j-med-2010"],"journals":[],"dependsOn":[],"notes":[],"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.","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","cost":"medium","horizonYears":3},"route":"/ideas/idea-bio1-baseline-ultradeep-resistant-clones/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"estrogen-receptor","kind":"target","name":"Estrogen receptor (ERα)","route":"/targets/estrogen-receptor/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"term":[{"id":"vaf","kind":"term","name":"Variant allele frequency (VAF)","route":"/terms/vaf/"}],"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/"}],"paper":[{"id":"paper-egfr-nsclc-lancet-oncol-2012","kind":"paper","name":"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","route":"/key-papers/paper-egfr-nsclc-lancet-oncol-2012/"},{"id":"paper-flaura-nejm-2018","kind":"paper","name":"FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer","route":"/key-papers/paper-flaura-nejm-2018/"},{"id":"paper-egfr-nsclc-n-engl-j-med-2010","kind":"paper","name":"Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR","route":"/key-papers/paper-egfr-nsclc-n-engl-j-med-2010/"}]}}