Elsevier

Clinical Lung Cancer

Volume 20, Issue 2, March 2019, Pages 124-133.e2
Clinical Lung Cancer

Original Study
Dynamic Monitoring and Predictive Value of Circulating Tumor Cells in EGFR-Mutated Advanced Non–Small-Cell Lung Cancer Patients Treated With First-Line EGFR Tyrosine Kinase Inhibitors

Presented in part as a poster at the 17th World Conference on Lung Cancer (WCLC), 2016, Vienna, Austria.
https://doi.org/10.1016/j.cllc.2018.11.014Get rights and content

Abstract

Background

There is an urgent need to develop a convenient and less invasive technique to monitor the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated non–small-cell lung cancer (NSCLC). We proposed folate receptor–based assay to count circulating tumor cells (CTCs) to predict and dynamically monitor the therapeutic response to first-line EGFR-TKIs in patients with EGFR-mutated NSCLC.

Patients and Methods

Eligible patients were enrolled, and 3 mL of blood was obtained before initial treatment, 1 month after treatment, and every 2 months thereafter. CTCs were isolated on the basis of negative enrichment by immunomagnetic beads and detected by a ligand-targeted PCR method.

Results

A total of 232 patients with EGFR-mutated NSCLC and treated with first-line EGFR-TKIs were included. Patients with low baseline CTC count had a markedly longer progression-free survival (hazard ratio = 0.48; P < .001) and overall survival (hazard ratio = 0.52; P = .002) than those with high count. This difference remained significant in multivariate analysis. Dynamic change of CTC count was significantly associated with partial response (P = .042) and stable disease/progressive disease (P = .032). Notably, dynamic monitoring of CTC provided evidence of resistance to EGFR-TKIs before computed tomographic scanning with a median lead time of 113 days (range, 45-169 days).

Conclusion

The current evidence suggests that folate receptor–positive CTC counts can be used for both the dynamic monitoring and prediction of outcome in EGFR-mutated NSCLC patients treated with EGFR-TKIs, which could serve as an alternative or supplement to computed tomographic scanning.

Introduction

Lung cancer is the most common cancer and the leading cause of cancer-related death both in China and worldwide.1, 2 Non–small-cell lung cancer (NSCLC) accounts for 80% to 85% of all cases of lung cancer.3, 4 The discovery of mutations of several driver genes such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1 protooncogene receptor tyrosine kinase (ROS1), and serine/threonine–protein kinase v-Raf murine sarcoma viral oncogene homolog B (BRAF) in NSCLC has increased the treatment options for these patients.5, 6 Patients with EGFR-active mutations could significantly benefit from therapy with EGFR tyrosine kinase inhibitors (TKIs).7, 8, 9, 10 However, acquired resistance is inevitable in the majority of patients after 10 to 12 months of initial therapy.11

To overcome drug resistance, several third-generation EGFR-TKIs based on the resistance molecular mechanism, such as osimertinib, have been developed and have demonstrated remarkable response in both preclinical and clinical settings.12, 13 Despite the superior efficacy of different generations EGFR-TKIs, it is still important to monitor recurrence and disease progression (PD) because NSCLC may relapse as a result of acquired resistance or other unknown events. Unfortunately, there is a lack of validated biomarkers for tracking the disease burden of patients with EGFR-mutant NSCLC. Currently radiologic assessment such as computed tomographic (CT) scan remains the standard method to interpret the therapeutic response of targeted therapy. Therefore, there is a need to develop a convenient and less invasive technique to monitor the efficacy of EGFR-TKIs in patients with EGFR-mutant NSCLC.

Circulating tumor cells (CTCs) could be an alternative marker of response. CTCs are shed from the primary or metastatic tumor mass and migrate into the circulating system.14 Through a simple blood test, CTCs can be captured and analyzed for dynamic monitoring of cancer response. CTC count has been shown to be useful in predicting prognosis of metastatic breast cancer, colorectal cancer, cutaneous melanoma, gastric cancer, NSCLC, and prostate cancer.15, 16, 17, 18, 19, 20 Several studies have shown that baseline CTC count was an independent predictive factor of progression-free survival (PFS) and overall survival (OS) of advanced NSCLC patients treated with chemotherapy, yet the significance of CTCs in advanced NSCLC remains controversial.19, 21, 22, 23 A recent prospective phase 2 study investigated the association between the efficacy of EGFR-TKIs and CTC count in patients with advanced NSCLC.24 Their results showed that low CTC count was associated with the significantly better objective response rate and longer PFS than those with high CTC count. Although this study revealed the potential value of CTC counts in predicting EGFR-TKI activity in patients with EGFR-mutant NSCLC, it enrolled only a small number of participants, and its conclusions require further validation. Furthermore, there are no data on the dynamic monitoring value of CTC count in EGFR-mutant NSCLC patients treated with first-line EGFR-TKIs.

We previously showed that folate receptor (FR)-positive CTCs have a high sensitivity (72%-76%) and specificity (82%-88%) for the diagnosis of lung cancer, thus supporting the clinical significance of FR-positive CTCs with a cutoff point of 8.7 FR units (FU)/3 mL.25 Thus, it has recently been approved by the Chinese Food and Drug Administration for clinical application for differential diagnosis of lung cancer. To further investigate the predictive and dynamic monitoring significance of FR-positive CTC counts in patients with EGFR-mutant NSCLC treated with EGFR-TKIs, we conducted this study to prospectively collect peripheral blood from included patients. CTC counts were analyzed on the basis of FR expression and were detected by the ligand-targeted (LT) PCR method as described previously.25, 26, 27 We aimed to explore the association between the efficacy of EGFR-TKIs and CTC count in patients with EGFR-mutant NSCLC.

Section snippets

Study Design

This was a prospective single-institution clinical study conducted at the Shanghai Pulmonary Hospital (registration ChiCTR-DDT-15006040, http://www.chictr.org.cn/showprojen.aspx?proj=10511). Patients aged ≥ 18 years with treatment-naive, histologically or cytologically confirmed advanced NSCLC with EGFR mutations were enrolled. Peripheral blood samples (3 mL) were collected for CTC analysis within 1 day before receiving treatment (defined as the baseline), 1 month after treatment commenced, and

Patient Characteristics

A total of 488 consecutive patients with NSCLC were enrolled onto the study between September 2014 and May 2016. Among them, 445 patients received an EGFR mutation test, and 232 of them had EGFR activating mutations. Of these, 217 patients were eligible for and had data evaluable for RECIST assessment (Figure 1). A total of 164 patients (75.6%) had a positive CTC count at baseline based on our previous findings.25, 31, 32 Demographic features of included patients are listed in Table 1. There

Discussion

Prediction and dynamic monitoring of EGFR-TKI treatment efficacy and assessment of treatment resistance in real time were valuable to identify the optimal populations of patients who would obtain maximal clinical benefit, and then to optimize therapeutic strategies in due course. We conducted this prospective study aiming to validate the predictive and dynamic monitoring value of CTC counts, an noninvasive approach, in EGFR-mutant NSCLC patients treated with first-line EGFR-TKIs. The current

Conclusion

Our study demonstrated that baseline FR-positive CTC counts and dynamic change in CTC count were potential predictors for the prognosis in EGFR-mutant NSCLC treated with EGFR-TKI. CTC counts could play a critical role in monitoring the effect of targeted therapy in patients with NSCLC, and the value of this measure warrants further validation in a larger, strictly designed prospective study.

Disclosure

The authors have stated that they have no conflict of interest.

Acknowledgments

Supported in part by part by grants from the National Natural Science Foundation of China (81672286, 81772467, and 81874036) and the Chronic Diseases Program of Shanghai Shen Kang Pharmaceutical Development Co Ltd (SHDC 12015314).

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      In addition, certain CTC phenotypes can predict treatment efficacy. For example, folate-receptor-positive CTC counts can be used to predict the outcome of NSCLC patients who are treated with EGFR-TKIs and can be used as an alternative or supplement to computed tomographic scanning.65 The T790M mutation in EGFR is acquired in some cases of NSCLC as tumor cells become resistant to selective TKIs.66

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    T.J. and J.Z. contributed equally to this work as first authors.

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