Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer

Authors

Jee J

Lupinacci L

Li BT

Doi

10.1038/s41591-022-02047-z

PMID: 36357680 · DOI: 10.1038/s41591-022-02047-z · Journal: Nature Medicine (2022)

TL;DR

This prospective international cohort study of 1,127 patients with advanced non-small-cell lung cancer (NSCLC) demonstrates that circulating tumor DNA (ctDNA) sequencing can effectively guide targeted therapy and is strongly associated with overall survival. The study found that ctDNA detection is a prognostic marker for shorter survival, while matching patients to targeted therapies based on ctDNA findings significantly improves outcomes. Notably, ctDNA captured heterogeneous subclonal drivers of resistance, such as RICTOR and PIK3CA alterations, that were often missed by time-matched tissue sequencing.

Cohort & data

Key findings

  • Prognostic Value of ctDNA: Detection of ctDNA was associated with significantly shorter overall survival (HR 2.05; 95% CI 1.74–2.42; P < 0.001), independent of clinicopathologic features and metabolic tumor volume PMID:36357680.
  • Clinical Utility: Among patients with detectable ctDNA (64%), those matched to targeted therapy via ctDNA sequencing (23%) had significantly longer survival than those not receiving targeted therapy (HR 0.63; 95% CI 0.52–0.76; P < 0.001) PMID:36357680.
  • Plasma-Tissue Divergence: ctDNA-only alterations (not found in time-matched tissue) were present in 25% of patients. These alterations often represented subclonal drivers of resistance and were associated with poor prognosis PMID:36357680.
  • Operational Advantages: ctDNA sequencing had lower failure rates (2%) and faster turnaround times compared to tissue sequencing (13% failure rate) PMID:36357680.

Genes & alterations

  • RICTOR & PIK3CA: These alterations were disproportionately found in ctDNA only (subclonal) and were associated with resistance to therapy and shorter survival PMID:36357680.
  • EGFR & KRAS: Common drivers identified in both tissue and plasma, used for matching to targeted therapies PMID:36357680.
  • TP53: Frequently detected alteration in the cohort PMID:36357680.

Clinical implications

  • Prognosis: ctDNA detection serves as a robust, independent prognostic biomarker in advanced NSCLC PMID:36357680.
  • Therapy Selection: Liquid biopsies can expand access to life-prolonging targeted therapies, especially when tissue is unavailable or sequencing fails PMID:36357680.
  • Resistance Monitoring: ctDNA is superior to single-site tissue biopsy for capturing spatial heterogeneity and subclonal resistance mechanisms PMID:36357680.

Limitations & open questions

  • The study focused on advanced/metastatic disease; the utility in early-stage NSCLC requires further validation.
  • While ctDNA-guided therapy improved survival, the optimal integration of plasma and tissue sequencing in clinical workflows remains to be standardized.
  • The impact of clonal hematopoiesis (CH) on ctDNA interpretation was addressed but remains a potential confounder in community settings without matched WBC sequencing.

Citations from this paper used in the wiki

  • “Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52–0.76; P < 0.001).”
  • “Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival.”
  • “ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74–2.42; P < 0.001) independently of clinicopathologic features and metabolic tumor volume.”

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