Circulating tumor DNA (ctDNA) analysis predicts recurrence following surgery in patients with stage I-IIIA non-small-cell lung cancer (NSCLC): Results of GASTO1035 and GASTO1018.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9023-9023
Author(s):  
Si-Yu Wang ◽  
Ning Li ◽  
Wei Ou ◽  
Chao Cheng ◽  
Peng-Peng Kuang ◽  
...  
Keyword(s):  
High Risk ◽  
Early Stage ◽  
Disease Recurrence ◽  
Circulating Tumor Dna ◽  
Stage I ◽  
Disease Stage ◽  
Tissue Samples ◽  
Ctdna Analysis ◽  
Personalized Cancer ◽  
Tumor Dna

9023 Background: Circulating tumor DNA can be detected in the plasma and serum of patients with solid tumors and has emerged as a noninvasive biomarker for dynamically monitoring tumor. Postsurgical ctDNA analysis of early-stage NSCLC may identify patients at high risk of recurrence and facilitate early intervention and personalized cancer therapy. Methods: These studies recruited 123 patients with newly diagnosed resectable stage I-IIIA NSCLC. Preoperative and postoperative plasma and postoperative tissue samples were subjected to next-generation sequencing (Nanjing Shihe Jiyin Biotechnology Inc.) using a 425 cancer-related genes panel. Peripheral blood samples were collected before surgery, postoperatively within 1 month, and every 3-6 months for up to 3 years. Plasma samples with at least 1 variants detected in tissue samples were defined as ctDNA positive. Results: After 4 exclusions, 119 eligible patients were enrolled from June 2016 to February 2019. Presurgical ctDNA was detectable in 31 of 117 (26.5%) patients and was associated with inferior recurrence-free survival (HR, 3.90, 95% CI, 1.44-10.58, P = 0.004). Similarly, ctDNA was detected in 13 of 116 (11.2%) of the first postsurgical samples and was associated with shorter RFS (HR, 3.54, 95% CI, 1.22-10.23, P = 0.002). During surveillance after surgery, ctDNA-positive patients (38/119, 31.9%) were more than 9 times more likely to experience disease recurrence than ctDNA-negative patients (HR, 9.17, 95% CI, 2.60-32.42, P <0.001). Serial ctDNA detection preceded radiologic disease recurrence by a median lead time of 4.23 months (95% CI, 0.91-7.54 months). We also observed a positive correlation between the ctDNA detection rate and the disease stage. Conclusions: These results suggest that detection of ctDNA before and after surgery is associated with the identification of a high risk of disease recurrence of resectable NSCLC. Perioperative ctDNA analyses identify disease recurrence earlier than standard-of-care radiologic imaging, and thus could facilitate personalized cancer treatment at early time points. Clinical trial information: NCT03465241 and NCT03172156.

A plasma-only integrated genomic and epigenomic circulating tumor DNA (ctDNA) assay to inform recurrence risk in colorectal cancer (CRC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3602-3602 ◽  
Author(s):  
Aparna Raj Parikh ◽  
Emily E. Van Seventer ◽  
Genevieve Marie Boland ◽  
Anna Hartwig ◽  
Ariel Jaimovich ◽  
...  
Keyword(s):  
High Risk ◽  
Standard Therapy ◽  
Residual Disease ◽  
Early Stage ◽  
Recurrence Risk ◽  
Disease Recurrence ◽  
Circulating Tumor Dna ◽  
Entire Cohort ◽  
Therapy Decision ◽  
Therapy Completion

3602 Background: ctDNA identifies patients (pts) at high risk for disease recurrence post CRC resection (post-op). Current ctDNA residual disease detection approaches assess only genomic alterations (alts) and rely on tissue sequencing to identify tumor-derived alts. We evaluated a plasma-only ctDNA assay to identify high risk pts. Methods: 72 CRC pts (surgery only = 42; adjuvant therapy (adj) = 30) had post-op and/or post-adj plasma samples (3-4mL). Extracted cfDNA (median 27 ng) was analyzed using a single-sample NGS test validated in early stage CRC that integrates assessment of genomic alts with epigenomic cancer signature (Guardant Health, CA). A variant classifier was applied to differentiate tumor-derived from non-tumor derived alts in a tumor tissue-uninformed approach. Results: In the surgery cohort, samples were collected a median of 31 days (d) post-op. 7/8 pts with post-op ctDNA detected (ctDNA+) recurred (PPV 88%; median time to recurrence (mTTR) 248d). The recurrence-free pt has < 180d follow-up. 7/34 pts without ctDNA detected (ctDNA-) recurred (NPV 79%; mTTR 333d). 1/1 Stage 0-II ctDNA+ pt recurred (PPV 100%; TTR 440d) while 1/20 ctDNA- recurred (NPV 95%; TTR 440d). 27 pts in the adj cohort had samples collected a median of 37d post-adj. 6/6 ctDNA+ pts recurred (PPV 100%, mTTR 239d). 4/21 ctDNA- pts recurred (NPV 81%, mTTR 466d). 2/2 ctDNA+ and 0/11 ctDNA- Stage III pts recurred (PPV, NPV 100%, mTTR 420d). All 3 post-op ctDNA+/post-adj ctDNA+ (ctDNA persistence) pts recurred. 1/2 post-op ctDNA+/post-adj ctDNA- (ctDNA clearance) pts is recurrence free (306d). 2 post-op ctDNA-/post-adj ctDNA+ pts recurred. In the entire cohort, ctDNA+ after standard therapy completion had a recurrence PPV 93%, NPV 80%, HR 11.29 (p < 0.0001). Conclusions: In post-op CRC, ctDNA detection utilizing a tumor-uninformed integrated genomic and epigenomic assay has high recurrence PPV and NPV following standard therapy completion. ctDNA identifies pts who may benefit from post-op adj therapy or additional/modified post-adj therapy. These findings demonstrate that ctDNA detection from a single post-op/post-adj plasma sample stratifies high/low risk pts and informs therapy decision making.

Circulating tumor DNA (ctDNA) mutation and epigenomic patterns in early-stage lung cancer patients and its utility in identifying patients at high risk for early recurrence.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14557-e14557
Author(s):  
Jong Ho Cho ◽  
Il-Jin Kim ◽  
Junghee Lee ◽  
Hong Kwan Kim ◽  
Jinseon Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Somatic Mutations ◽  
Early Stage ◽  
Circulating Tumor Dna ◽  
Stage I ◽  
Early Stage Lung Cancer ◽  
Lung Cancer Patients ◽  
Tumor Dna ◽  
Stage Lung Cancer

e14557 Background: Circulating tumor DNA (ctDNA) analysis has been successfully applied to therapy selection and treatment monitoring in advanced cancer patients. However, it is not yet established whether ctDNA can be used clinically for early cancer detection or predicting tumor recurrence in early stage lung cancer patients. Methods: We analyzed pre-operative plasma samples from 55 early stage NSCLC patients (stages I-IIIA) using next-generation sequencing to detect somatic mutations and differential epigenomics patterns, including methylation signatures. Results: Using somatic mutation analysis alone, ctDNA was detected in 42% (23/55) of patients, whereas combined mutational and epigenomic analysis detected ctDNA in 71%. ctDNA detection rate also varied markedly between lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC);using combined analysis of somatic mutations and epigenomic patterns, ctDNA was detected in all SCC patients, while only 55% of ADC (12/22) were ctDNA-positive (p= 0.006). Within the ADC subgroup, ctDNA detection rates using the combined approach were dependent on disease stage: 47% (8/17) in stage I, 100% (2/2) in stage II, and 100% (2/2) in stage IIIA. Importantly, pre-operative ctDNA status was correlated with tumor recurrence post-resection; three of eight (38%) ctDNA-positive stage I ADC patients recurred within 2 years of resection, while only one of nine (11%) ctDNA-negative stage I ADC patients recurred (p= 0.29). Conclusions: Taken together, we show that the combination of somatic mutation detection and epigenomic analysis outperforms each individual biomarker in the detection of ctDNA in early stage lung cancer. Importantly, we also demonstrate that pre-operative ctDNA detection may identify a high-risk population of early stage lung cancer patients that may benefit from (neo)adjuvant therapy.

Circulating tumor DNA to detect minimal residual disease, response to adjuvant therapy, and identify patients at high risk of recurrence in patients with stage I-III CRC.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4009-4009
Author(s):  
Noelia Tarazona ◽  
Tenna V Henriksen ◽  
Juan Antonio Carbonell-Asins ◽  
Thomas Reinert ◽  
Shruti Sharma ◽  
...  
Keyword(s):  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Multivariable Analysis ◽  
Circulating Tumor Dna ◽  
Stage I ◽  
Plasma Samples ◽  
Risk Of Recurrence ◽  
Tumor Dna ◽  
Minimal Residual

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.

A blood-based assay for diagnosis of early-stage pancreatic cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 234-234
Author(s):  
Thomas Jens Ettrich ◽  
Andreas Wolfgang Berger ◽  
Daniel Schwerdel ◽  
Anke C. Reinacher-Schick ◽  
Waldemar Uhl ◽  
...  
Keyword(s):  
Early Stage ◽  
Circulating Tumor Dna ◽  
Pancreatic Disease ◽  
Stage I ◽  
Ductal Adenocarcinoma ◽  
C Statistic ◽  
Dismal Prognosis ◽  
Marker Combination ◽  
Droplet Pcr ◽  
Ctdna Analysis

234 Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Biomarker are needed to facilitate early and preferably noninvasive detection of PDAC, which directly may influence patients’ prognosis. Here we aimed to test a new biomarker combination for early PDAC, consisting of thrombospondin-2 (THBS2), CA19-9 and circulating tumor DNA (ctDNA) analysis. Methods: Thirty-nine patients with histologically proven and clearly resectable PDAC (recruited from the NEONAX trial, NCT02047513) were enrolled. Fifteen patients with benign pancreatic disease (intraductal papillary-mucinous neoplasms, IPMN) served as controls. Blood samples were collected prior treatment. KRAS genotyping was performed after isolation of ctDNA from plasma (QIAamp MinElute ccfDNA Kit, Qiagen) by digital droplet PCR ( KRAS Screening Multiplex Kit; QX200 system, both: Bio-Rad). Clinical data and CA 19-9 levels were assessed by ELISA (Roche); THBS2 values were determined by Quantikine ELISA Human Thrombospondin-2 (R&D Systems). Statistical analyses were done by using GraphPad Prism Version 7.00, GraphPad Software, Inc. Results: THBS2 had a c-statistic of 0.73 for all PDAC stages which was comparable to that of CA 19-9 (0.78). The c-statistic was improved to 0.94 by combining CA 19-9, THBS2 and total cfDNA amount. This marker combination performed best for all stages. C-statistics of defined PDAC stages was 0.93, 1.00 and 0.92 for stage I, stage II and stage III, respectively. Of note, the biggest improvement in sensitivity and specificity was seen for stage I PDAC. Here, c-statistic improved from 0.69 or 0.85 for CA 19-9 alone or the combination of CA 19-9 and THBS2, respectively, to 0.93 for the three-marker combination. Conclusions: These data underscore that CA 19-9, THBS2 and cfDNA marker combination constitutes a composite liquid biomarker for non-invasive diagnosis of early-stage PDAC with a remarkable specificity. Larger studies are needed to examine the power of this approach.

Clinical outcomes in patients with BRAFV600 mutant melanoma and undetectable circulating tumor DNA treated with dabrafenib and trametinib.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10059-10059
Author(s):  
Alain Patrick Algazi ◽  
Megan Othus ◽  
Benjamin Newell Voorhies ◽  
Kari Lynn Kendra ◽  
Shaker R. Dakhil ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Circulating Tumor Dna ◽  
Disease Stage ◽  
Rank Test ◽  
Continuous Therapy ◽  
Blood Samples ◽  
Phase 2 Clinical Trial ◽  
Pre Treatment ◽  
Ctdna Analysis ◽  
Tumor Dna

10059 Background: Circulating tumor DNA (ctDNA) analysis has been promoted as a less-invasive surrogate assay for tumor-tissue based tumor oncogene analysis. Here, we associate detection of BRAF mutant ctDNA with PFS and OS in patients with tissue-confirmed BRAFV600 mutant melanoma enrolled in S1320, a randomized phase 2 clinical trial of continuous versus intermittent dosing of dabrafenib and trametinib. Methods: Patients with BRAFV600 melanoma received continuous therapy with dabrafenib and trametinib for 8 weeks after which patients were randomized 1:1 to proceed with intermittent treatment on a 3-week-off, 5-week-on schedule or to continue with continuous therapy. Pre-treatment blood samples were interrogated using the Guardant 360 ctDNA assay for all exons of 30 known oncogenes including BRAF and for all exons with known oncogenic mutations in the COSMIC database in 40 additional oncogenes. Clinical responses were assessed at 8-week intervals by RECIST v1.1 and PFS and OS estimates were compared using log-rank test in patients with detectable versus undetectable BRAFV600 mutant ctDNA,. Results: Somatic BRAFV600E or BRAFV600K ctDNA was detected in 34 of 50 patients with baseline (before lead-in cycle 1) blood samples available for analysis including 16 of 23 (70%) patients randomized to continuous dosing, 15 of 21 (71%) randomized to intermittent dosing, and 3 of 6 (50%) who were not randomized due to disease progression at 8 weeks or other factors. Four additional patients had other detectable somatic mutations but no detectable BRAFV600 ctDNA at baseline, and 12 patients had no detectable somatic ctDNA mutations at baseline. Detection of BRAFV600 ctDNA was associated with baseline disease stage (p = 0.008). There was no difference in the overall response rate based on baseline ctDNA detection. Detection of ctDNA at baseline was associated with worse PFS (median BRAFV600 ctDNA positive = 5.8; 95% CI: 4.2-9.6 months, BRAFV600 ctDNA negative = 21.4 mos; 95% CI 10.4-NA; measured from registration to lead-in cycle 1, p = 0.001) and OS (BRAFV600 ctDNA positive = 17.8 mos; 95% CI 9.76-NA, BRAFV600 ctDNA negative = not reached; 95% CI NA-NA, p = 0.0021). Conclusions: The absence of detectable BRAFV600 ctDNA at baseline is associated with improved PFS and OS in patients receiving treatment with dabrafenib and trametinib. Clinical trial information: NCT02196181.

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