Undetectable circulating tumor DNA levels correlate with low risk of recurrence/metastasis in postoperative pathologic stage I lung adenocarcinoma patients

4009 Background: The clinical utility of tracking circulating tumor DNA (ctDNA) as a non-invasive biomarker for detecting minimal residual disease (MRD) and stratifying patients based on their risk of developing relapse has been well established in colorectal cancer (CRC). This study evaluates the detection and longitudinal monitoring of ctDNA in CRC patients pre- and post-operatively, during and after adjuvant chemotherapy (ACT). Methods: The prospective, multicenter cohort study recruited patients (n = 193) diagnosed with resected stage I-III CRC. Plasma samples (n = 1052) were collected at various timepoints with a median follow up of 21.6 months (4.6-38.5 months). Individual tumors and matched germline DNA were whole-exome sequenced and somatic mutations identified. Multiplex PCR assays were designed to 16 tumor-specific single-nucleotide variants to track ctDNA in plasma samples. The study evaluated the relationship between ctDNA status and clinical outcomes including radiologic imaging. Cox regression was used to calculate recurrence-free survival (RFS) in patients stratified by ctDNA status postoperatively and post-ACT. Multivariable analysis was performed with all clinical variables. Best model was selected according to Akaike Information Criterion. Results: Pre-operatively ctDNA was detected in 90% (n = 166/185) of the patients. Post-operative ctDNA status prior to ACT was assessed in 152 patients, of which 9.2% (14/152) were identified to be MRD-positive and 78.5% (11/14) eventually relapsed. In contrast, 10.1% (14/138) of MRD-negative cases relapsed (HR: 16.53; 95% CI: 7.19-38.02; p < 0.001). Longitudinal ctDNA-positive status, post-ACT (n = 84) and post definitive therapy (n = 139) was associated with a 27.92 HR (95% CI: 9.16-85.11; p < 0.001) and a 47.52 HR (95% CI: 17.34-130.3.; p < 0.001), respectively. In the multivariable analysis, longitudinal ctDNA status was the only significant prognostic factor associated with RFS (HR: 53.19, 95% CI: 18.87-149.90; p < 0.001). Serial ctDNA analysis detected MRD up to a median of 9.08 months (0.56-16.5 months) ahead of radiologic relapse with a sensitivity of 79.1% and specificity of 99%. Conclusions: Postoperative ctDNA analyses detect patients with high-risk of recurrence, with near 100% specificity. Early detection of MRD and longitudinal monitoring of ctDNA could guide treatment decisions. Intervention trials to assess the clinical benefit of ctDNA use are underway.

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Circulating tumor DNA dynamics to predict cancer recurrence/metastasis in Chinese pathologic stage I lung adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3537 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3537-3537

Author(s):

Chao Cheng ◽

Weixiong Yang ◽

Na You ◽

Minghan Jia ◽

Sai-Ching Yeung ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Tumor Recurrence ◽

Egfr Mutation ◽

Disease Free Survival ◽

Circulating Tumor Dna ◽

Response To Therapy ◽

Stage I ◽

Dna Dynamics ◽

Mutation Status ◽

Tumor Dna

3537 Background: Pathologic(p)stage I lung adenocarcinoma (LUAD) patients exhibit high levels of genetic heterogeneity and the association between the genomic characteristics of (p)stage I LUADs and tumor recurrence remains poorly understood. Circulating tumor DNA (ctDNA) monitoring after resection represents a useful tool to predict response to therapy and tumor recurrence but its application in (p)stage I LUAD patients remains controversial. In addition, it is of great clinical interest to decipher the difference of genetic features between ground-glass opacity (GGO) and solid nodules (non-GGO) subgroups. Methods: Tumor tissues and matched post-operative plasma samples were collected from a total of 86 Chinese (p)stage I LUAD patients who were enrolled in a clinical study (NCT03172156). Comprehensive genomic profiling was performed using capture-based hybrid next generation sequencing by targeting 422 cancer relevant genes. Results: EGFR and TP53 represent commonly mutated genes in this cohort of (p)stage I lung adenocarcinoma, followed by alterations in ALK, PIK3CA, STK11and MYC. For a median follow up period of 21.54 months after surgical resection, we observed that ctDNA positivity significantly correlated with an increased probability of early tumor recurrence or metastasis ( P= 0.03, HR = 7.9), and in particular, the EGFR mutation status of ctDNA samples rather than that of primary tumor samples significantly correlated with shorter disease-free survival (DFS). Further comparison between GGO and non-GGO subgroups indicated that the frequency of TP53 mutations in non-GGO was markedly higher than that in GGO (48% vs 20%, P< 0.05). In addition, pathway analysis showed that the epigenetic regulation pathway was more frequently affected in the GGO subgroup, while impaired apoptosis/cell cycle pathway was more enriched in the non-GGO LUADs. Conclusions: Our data show that ctDNA positivity, including the EGFR mutation status, significantly correlated with early relapse or metastasis after surgery, representing a useful tool to predict treatment response and tumor relapse in (p)stage I LUAD patients. Mutated TP53 was more abundant in non-GGO comparing to GGO (p)stage I LUADs that may act as potential oncogenic driver in LUAD development and/or disease progression. Clinical trial information: NCT03172156 .

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