Circulating Tumor Cells with Aberrant ALK Copy Number Predict Progression-Free Survival during Crizotinib Treatment in ALK-Rearranged Non–Small Cell Lung Cancer Patients

Abstract

The duration and magnitude of clinical response are unpredictable in ALK-rearranged non-small cell lung cancer (NSCLC) patients treated with crizotinib, although all patients invariably develop resistance. Here, we evaluated whether circulating tumor cells (CTC) with aberrant ALK-FISH patterns [ALK-rearrangement, ALK-copy number gain (ALK-CNG)] monitored on crizotinib could predict progression-free survival (PFS) in a cohort of ALK-rearranged patients. Thirty-nine ALK-rearranged NSCLC patients treated with crizotinib as first ALK inhibitor were recruited prospectively. Blood samples were collected at baseline and at an early time-point (2 months) on crizotinib. Aberrant ALK-FISH patterns were examined in CTCs using immunofluorescence staining combined with filter-adapted FISH after filtration enrichment. CTCs were classified into distinct subsets according to the presence of ALK-rearrangement and/or ALK-CNG signals. No significant association between baseline numbers of ALK-rearranged or ALK-CNG CTCs and PFS was observed. However, we observed a significant association between the decrease in CTC number with ALK-CNG on crizotinib and a longer PFS (likelihood ratio test, P ¼ 0.025). In multivariate analysis, the dynamic change of CTC with ALK-CNG was the strongest factor associated with PFS (HR, 4.485; 95% confidence interval, 1.543-13.030, P ¼ 0.006). Although not dominant, ALK-CNG has been reported to be one of the mechanisms of acquired resistance to crizotinib in tumor biopsies. Our results suggest that the dynamic change in the numbers of CTCs with ALK-CNG may be a predictive biomarker for crizotinib efficacy in ALK-rearranged NSCLC patients. Serial molecular analysis of CTC shows promise for realtime patient monitoring and clinical outcome prediction in this population. Cancer Res; 77(9); 2222-30. Ó2017 AACR.

Single tube liquid biopsy for advanced non‐small cell lung cancer

“…Due to the low efficiency to retrieve high CTC numbers (30% of the patients have 1 or more CTC; 8% with >5 CTC per 7.5 mL blood) and elevated plasma DNA tumor fractions all fall short when it comes to a broad patient coverage. 33,[40][41][42] In our study we detected one of the biomarkers in 45% of the patients, whereas each individual biomarker was detected in 15-27% of the patients. A potential solution to increase these percentages even further is To separate between favorable and unfavorable groups, the threshold for CTC was 2, for tdEV 18, and for ctDNA 10% mutant alleles (z-score of 5).…”

“…A variety of different liquid biopsy approaches have been evaluated for their clinical potential in NSCLC. Due to the low efficiency to retrieve high CTC numbers (30% of the patients have 1 or more CTC; 8% with >5 CTC per 7.5 mL blood) and elevated plasma DNA tumor fractions all fall short when it comes to a broad patient coverage . In our study we detected one of the biomarkers in 45% of the patients, whereas each individual biomarker was detected in 15–27% of the patients.…”

Real-World Treatment Patterns, Survival, and Prediction of CNS Progression in ALK-Positive Non-Small-Cell Lung Cancer Patients Treated with First-Line Crizotinib in Latin America Oncology Practices

“…A study conducted by Pailler et al [31] looked at circulating tumor cells with aberrant ALK-FISH patterns in patients treat ed with crizotinib. Although an association between the baseline number of circulating cells and ALK rearrangements was not found, the decrease in the number of these cells while on treatment seems to be an indicator of maintained PFS.…”

Critical issues in the clinical application of liquid biopsy in non-small cell lung cancer

“…Although this study highlights the potential use of dynamic changes of ALK-CNG CTC number for monitoring treatment efficacy in ALK-positive NSCLC, its results still apply to a small cohort of patients, and reflect the lack of a consensus on CTC definition (i.e., no epithelial/mesenchymal additional marker for CTC detection by ISET ® ). Moreover, the parallel CellSearch ® analyses revealed a median CTC number of 0/7.5 mL detected both at baseline and during treatment (range 0-713 and 0-544, respectively), thus the EpCAM-positive CTC fraction, that so far has been demonstrated to correlate with NSCLC patient outcome, was not further associated to clinical data in this study (55). Notably, EMT CTCs and CTM could be only two of the factors affecting CTC detection: in fact, CTCs expressing a different CK-pattern from the most commonly detected in epithelial-dependent assays (CKs 4-6, 8, 10, 13, 18, 19) have been documented in lung cancer (53).…”