This single-patient case report presents an integrated timeline of diagnosis, systemic therapy, longitudinal circulating tumor DNA (ctDNA) monitoring, radiologic assessment, clinical course, and death. The figures provided map treatment start and stop dates, serial ddPCR quantification of KRAS G12C in plasma (copies/mL, log scale), and targeted ctDNA NGS variant allele frequencies at baseline and at molecular progression. Imaging by CT and MRI was assessed using RECIST 1.1 criteria.
The patient was a 66-year-old woman with lung adenocarcinoma harboring KRAS G12C together with co-occurring STK11 C132W and KEAP1 A159S alterations. She received second-line adagrasib following progression on prior chemo-immunotherapy. Baseline plasma quantification of the KRAS G12C alteration was reported at 6205.3 copies/mL.
Serial plasma monitoring combined droplet digital PCR (ddPCR) for quantification and targeted next-generation sequencing (NGS) for broader variant detection. After starting adagrasib, ddPCR showed a rapid and dramatic reduction of KRAS G12C copies to 3.2 copies/mL at 7 weeks, reflective of an initial molecular response. Subsequently, ctDNA levels rose to 21.1 copies/mL at month 4 and increased further to 315.2 copies/mL at month 6, indicating molecular recurrence prior to radiographic progression.
At the time of molecular progression (month 6), targeted ctDNA NGS detected three emergent secondary KRAS mutations: G12D, G13D, and Q61H. These secondary variants were absent at baseline testing. The simultaneous presence of multiple distinct secondary KRAS mutations defines a pattern of polyclonal resistance, with at least three resistant subclones inferred to have arisen under the selective pressure of adagrasib.
Throughout the interval in which ctDNA fell then rebounded and secondary KRAS mutations emerged, CT and MRI imaging remained stable by RECIST 1.1 criteria. Clinical deterioration requiring prolonged hospitalization occurred approximately 8 weeks after the initial rise in ctDNA. The patient died about 2 months after detection of the acquired resistance mutations. The report highlights a temporal dissociation between molecular relapse detected in plasma and radiographic stability.
FIGURE 1 integrates the treatment timeline, ddPCR quantification of KRAS G12C (log-scale copies/mL), and variant allele frequencies from targeted ctDNA NGS at baseline and molecular progression. The ddPCR trace shows the sharp reduction after adagrasib initiation, then a rebound beginning about 7 weeks after starting therapy with continued rise through month 6.
FIGURE 2 schematically illustrates the inferred tumor evolutionary dynamics: a dominant clone bearing KRAS G12C with STK11 and KEAP1 co-mutations undergoes therapeutic selection pressure and gives rise to multiple resistant subclones, each carrying a different secondary KRAS mutation (G12D, G13D, Q61H), consistent with polyclonal evolution under adagrasib.
This case demonstrates that longitudinal ctDNA monitoring can identify acquired resistance to a KRAS G12C inhibitor earlier than conventional imaging, detecting both quantitative rises in mutant allele copies and qualitatively new resistance-associated variants. The detection of multiple distinct secondary KRAS mutations in plasma supports the concept of polyclonal resistance developing under targeted therapy pressure.
Limitations include that this report describes a single patient; no cohort-level sensitivity, specificity, or standardized lead-time between ctDNA detection and radiographic progression are reported. Details on subsequent therapeutic interventions after molecular progression, tumor tissue confirmation of the secondary mutations, and broader clinical management decisions were not reported in the source article. The authors declare no conflicts of interest.
In a patient with KRAS G12C-mutant NSCLC treated with adagrasib, combined ddPCR and targeted ctDNA NGS identified an early molecular response followed by a rise in ctDNA and the emergence of three distinct secondary KRAS mutations during a period of radiographic stability. The timeline ended with clinical decline and death within weeks of molecular progression. The case supports the clinical utility of longitudinal liquid biopsy to reveal emerging polyclonal resistance in KRAS-targeted therapy, while underscoring that further data are required to define how such molecular findings should modify clinical management.