Effect of Osimertinib on CTCs and ctDNA in EGFR Mutant Non-Small Cell Lung Cancer Patients: The Prognostic Relevance of Liquid Biopsy

Abstract

Introduction: Liquid biopsy is a useful tool for monitoring treatment outcome in solid tumors, including lung cancer. The relevance of monitoring CTCs and plasma ctDNA as predictors of clinical outcome was assessed in EGFR-mutant NSCLC patients treated with osimertinib. Methods: Forty-seven EGFR-mutant NSCLC patients who had progressed on prior first- or second-generation EGFR inhibitors were enrolled in the study and treated with osimertinib, irrespective of the presence of the T790M mutation in the primary tumor or the plasma. Peripheral blood was collected at baseline (n = 47), post-Cycle 1 (n = 47), and at the end of treatment (EOT; n = 39). CTCs were evaluated in 32 patients at the same time points (n = 32, n = 27, and n = 21, respectively) and phenotypic characterization was performed using triple immunofluorescence staining (CK/VIM/CD45). Results: Osimertinib resulted in an ORR of 34% (2 CR) and a DCR of 76.6%. The median PFS and OS values were 7.5 (range, 0.8–52.8) and 15.1 (range, 2.1–52.8) months, respectively. ctDNA was detected in 61.7%, 27.7%, and 61.5% of patients at baseline, post-Cycle 1, and EOT, respectively. CTCs (CK+/CD45-) were detected in 68.8%, 48.1%, and 61.9% of patients at the three time points, respectively. CTCs expressing both epithelial and mesenchymal markers (CK+/VIM+/CD45-) were detected in 56.3% and 29.6% of patients at baseline and post-Cycle 1, respectively. The detection of ctDNA at baseline and post-Cycle 1 was associated with shorter PFS and OS, whereas the ctDNA clearance post-Cycle 1 resulted in a significantly longer PFS and OS. Multivariate analysis revealed that male sex and the detection of ctDNA at baseline were independent predictors of shorter PFS (HR: 2.6, 95% C.I.: 1.2–5.5, p = 0.015 and HR: 3.0, 95% C.I.: 1.3–6.9; p = 0.009, respectively). Conclusions: The decrease in both CTCs and ctDNA occurring early during osimertinib treatment is predictive of better outcome, implying that liquid biopsy monitoring may be a valuable tool for the assessment of treatment efficacy.

PD-L1/pS6 in Circulating Tumor Cells (CTCs) during Osimertinib Treatment in Patients with Non-Small Cell Lung Cancer (NSCLC)

“…In a previous study of our group, CK + CTCs were identified by IF on ISET filters from 30 chemo-naïve stage IV NSCLC patients at baseline, before front-line chemotherapy (57% of patients), and after the third cycle of treatment (73%) [ 18 ]. In addition, in another of our studies, 69% of NSCLC patients treated with Osimertinib had CTCs isolated by ISET [ 5 ]. In the current study, 62% (26 out of 42) of patients had at least one CTC at some point in the evaluation, which is comparable to Kallergi et al (2022).…”

“…Nonetheless, CTCs’ detection and enumeration have been proven to be a useful prognostic tool for both early and advanced NSCLC, with even one CTC being an independent risk factor for recurrence and death [ 4 ]. We have recently showcased the complementarity of CTC and ctDNA analysis in NSCLC patients treated with Osimertinib, whereby both are decreased after one cycle of treatment and increased at the end of treatment (EOT), which coincided with the progression of the disease [ 5 ]. Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) [ 6 ].…”

“…Point mutations G719X, S768I, and L861Q are less frequent [ 7 , 8 ]. A previous study of our group in NSCLC patients treated with Osimertinib (a subset of these patients has been evaluated herein) identified the aforementioned EGFR mutations (with the exception of L861Q) in 62% of patients [ 5 ]. Osimertinib is effective against mutations L858R, exon 19 deletions, and T790M [ 9 ].…”

A multifunctional black phosphorus nanosheet-based immunomagnetic bio-interface for heterogeneous circulating tumor cell capture and simultaneous self-identification in gastric cancer patients

“…2 Tumor cells that are malignant, shed by solid tumors into the bloodstream, are commonly referred to as circulating tumor cells (CTCs), which are valuable in providing indicative evaluation information for therapeutic efficacy, cancer prognosis or metastases and therefore considered a prognostic biomarker for diagnosis. 3–6…”

“…2 Tumor cells that are malignant, shed by solid tumors into the bloodstream, are commonly referred to as circulating tumor cells (CTCs), which are valuable in providing indicative evaluation information for therapeutic efficacy, cancer prognosis or metastases and therefore considered a prognostic biomarker for diagnosis. [3][4][5][6] However, since the number of CTCs in blood is extremely small, how to successfully and reliably capture them from the complex blood media is a critical step for downstream analysis. [7][8][9][10][11][12] Compared with the common capture methods established according to some physical properties, such as cell size, 13 density, 14 and permittivity, 15 an affinity-based strategy is more popularly employed in CTC isolation, taking advantage of the specific interactions between the recognition ligands (antibody, 16 aptamer, 17 peptide, 18 etc.)…”