Diagnostic validation and interpretation of longitudinal circulating biomarkers using a biomarker response characteristic plot

Moritz, R.; Muller, Mirte; Korse, Catharina M.; Broek, Daan van den; Baas, Paul; Noort, Vincent van den; Hoeve, Jelle J. ten; Heuvel, Michel M. van den; Rossum, Huub H. van

doi:10.1016/j.cca.2018.09.015

Cited by 17 publications

(15 citation statements)

References 19 publications

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“…In our study, it was shown that smaller tumor diameter (<20 mm: HR: 2.437, 95% CI: 1.245-4.770, P=0.009) had a significant effect on stage I LUAD survival (AUC =0.592), which is consistent with a few previous studies (5,(43)(44)(45). Moreover, we found that postoperative CEA grouping (NN vs. NH, NN vs. HH; both P<0.001) had a considerable (31)(32)(33)(34)(35)(36). In these latter combination studies, a universal cutoff value or the reference value of the kit was used.…”

Section: Discussionsupporting

confidence: 91%

“…The expression of CEA also increases in patients with lung cancer, especially those with LUAD, and has higher diagnostic value than do the other types (28)(29)(30). Most relevant current studies have focused on either the predictive effect of the preoperative serum CEA level on the prognosis of patients or on combining serum CEA with other markers for diagnosis (31)(32)(33)(34)(35)(36). These reports are only the results of a one-time preoperative CEA test.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic significance of postoperative longitudinal change of serum carcinoembryonic antigen level in patients with stage I lung adenocarcinoma completely resected by single-port video-assisted thoracic surgery: a retrospective study

Chen

Jiang

Jia

et al. 2021

Transl Lung Cancer Res

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Background: Patients with stage I lung adenocarcinoma (LUAD) have varying postoperative prognosis. This study aimed to investigate the prognostic significance of postoperative longitudinal change of serum carcinoembryonic antigen (CEA) level in patients with stage I LUAD. Methods: The study cohort comprised 241 patients with stage I LUAD completely resected with singleport video-assisted thoracic surgery (VATS). The patients were categorized into 4 groups according to the postoperative longitudinal change of serum CEA levels measured in the third and sixth months after surgery: the NN group (continuously normal), HN group (increase first and then decrease), NH group (decrease first and then increase), and HH group (continuously high). Recurrence-free survival (RFS) was analyzed by the Kaplan-Meier method and compared by log-rank test. A nomogram was developed to predict recurrence in the stage I LUAD patients. Results: In univariate analysis, differentiation (P<0.001), visceral pleural invasion (VPI) (P=0.025), tumor diameter (P<0.001), tumor-node-metastasis (TNM) stage (P=0.008), preoperative CEA levels (≥10.0 vs. <10.0 ng/mL, P<0.001), and postoperative CEA grouping (NH/HH vs. NN/HN, P<0.001) were significant prognostic factors for stage I LUAD patients. Multivariate analysis showed that tumor diameter (P=0.009) and postoperative CEA grouping (P<0.001) were considered to be independent prognostic factors of postoperative recurrence of stage I LUAD. Tumor diameter (≥20 mm) and postoperative CEA (NH/HH vs. NN/HN) were associated with worse RFS. Receiver operating characteristic (ROC) curve analysis showed that postoperative CEA (NH/HH vs. NN/HN) have high sensitivity (64.7%) and specificity (83.2%) for early prediction of postoperative recurrence of stage I LUAD. The area under curve (AUC) value was 0.745. The nomogram based on multivariate Cox regression had a concordance index (value of 0.789). The calibration plot showed that the predicted probabilities closely matched the observed probabilities. ^ ORCID: 0000-0002-6127-8773. Conclusions: Longitudinal change in serum CEA level after surgery was found to be an independent unfavorable prognostic factor in completely resected stage I LUAD patients. The NH group and HH group were significantly associated with worse RFS. A nomogram was established to predict the postoperative recurrence of patients with stage I LUAD.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Prognostic significance of postoperative longitudinal change of serum carcinoembryonic antigen level in patients with stage I lung adenocarcinoma completely resected by single-port video-assisted thoracic surgery: a retrospective study

Chen

Jiang

Jia

et al. 2021

Transl Lung Cancer Res

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“…The correlation to clinical response was visualized in Biomarker Response Characteristic plots (BReC plots) (Fig. S1) [14].…”

Section: Design Of Tumor Marker Testmentioning

confidence: 99%

“…Recently, a method and software package, called ReMarker, was developed to assess the applicability of tumor marker changes after start of treatment in the response assessment [14]. We used this application to design and validate biomarker-response based tests that allow an accurate and early detection of non-responsiveness to immunotherapy for patients with NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Validation of a clinical blood-based decision aid to guide immunotherapy treatment in patients with non-small cell lung cancer

Muller

Hoogendoorn

Moritz

et al. 2021

TUB

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BACKGROUND: The widespread introduction of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) has led to durable responses but still many patients fail and are treated beyond progression. OBJECTIVE: This study investigated whether readily available blood-based tumor biomarkers allow accurate detection of early non-responsiveness, allowing a timely switch of therapy and cost reduction. METHODS: In a prospective, observational study in patients with NSCLC treated with nivolumab or pembrolizumab, five serum tumor markers were measured at baseline and every other week. Six months disease control as determined by RECIST was used as a measure of clinical response. Patients with a disease control < 6 months were deemed non-responsive. For every separate tumor marker a criterion for predicting of non-response was developed. Each marker test was defined as positive (predictive of non-response) if the value of that tumor marker increased at least 50% from the value at baseline and above a marker dependent minimum value to be determined. Also, tests based on combination of multiple markers were designed. Specificity and sensitivity for predicting non-response was calculated and results were validated in an independent cohort. The target specificity of the test for detecting non-response was set at > 95%, in order to allow its safe use for treatment decisions. RESULTS: A total of 376 patients (training cohort: 180, validation cohort: 196) were included in our analysis. Results for the specificity of the single marker tests in the validation set were CEA: 98·3% (95% CI: 90·9–100%), NSE: 96·5% (95% CI: 87·9–99·6%), SCC: 96·5% (95% CI: 88·1–99·6%), Cyfra21·1 : 91.8% (95% CI: 81·9–97·3%), and CA125 : 86·0% (95% CI: 74·2–93·7%). A test based on the combination of Cyfra21.1, CEA and NSE accurately predicted non-response in 32.3% (95% CI 22.6–43.1%) of patients 6 weeks after start of immunotherapy. Survival analysis showed a significant difference between predicted responders (Median PFS: 237 days (95% CI 184–289 days)) and non-responders (Median PFS: 58 days (95% CI 46–70 days)) (p < 0.001). CONCLUSIONS: Serum tumor marker based tests can be used for accurate detection of non-response in NSCLC, thereby allowing early and safe discontinuation of immunotherapy in a significant subset of patients.

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“…However, such examinations are expensive, but not fast, and need the judgment of radiologists, and moreover, some local hospitals lack the relevant equipment [13,14]. Some traditional tumor biomarkers are used in clinical postoperative recurrence monitoring and the efficacy evaluation of malignant tumor patients, but their sensitivity and specificity are insufficient [15,16]. Therefore, it is urgent to find novel and accurate tumor biomarkers for the diagnosis, curative effect verification, recurrence monitoring and prognosis evaluation of malignant tumors.…”

Section: Introductionmentioning

confidence: 99%

Diagnostic and Prognostic Characteristics of Circulating Free DNA Methylation Detected by the Electrochemical Method in Malignant Tumors

Sun¹,

Du²,

Liu

et al. 2021

Cancers

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Prior research has established an electrochemical method based on the differential adsorption capacity of gold surfaces with different methylated DNA degrees and found that this method might be valuable for cancer diagnosis by detecting circulating free DNA methylation. However, further investigation on the underlying mechanism and validation of its diagnostic and prognostic values in a large cohort of malignant tumors was limited. We found that DNA with different methylation levels formed particles of diverse sizes on the gold surface. Hydrophobic bonds played a significant role in the binding process of methylated DNA to the gold surface. The detection condition of an adsorption time of 10 min and temperature of 20 °C was optimal. In a large cohort of plasma samples from the patients with different malignant tumors, as well as normal individuals, we found that the electrochemical detection method based on the differential adsorption capacity of methylated DNA degree on a gold surface could be used as a noninvasive tool for malignant tumor diagnosis and prognostic evaluation. The diagnostic efficiency of this method in malignant tumors was even slightly better than that of the current tumor biomarkers widely used in routine clinical practice (circulating free DNA (cfDNA) vs. carcinoembryonic antigen (CEA), 0.8131 vs. 0.7191 and cfDNA vs. CA19-9, 0.7687 vs. 0.6693).

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Diagnostic validation and interpretation of longitudinal circulating biomarkers using a biomarker response characteristic plot

Cited by 17 publications

References 19 publications

Prognostic significance of postoperative longitudinal change of serum carcinoembryonic antigen level in patients with stage I lung adenocarcinoma completely resected by single-port video-assisted thoracic surgery: a retrospective study

Prognostic significance of postoperative longitudinal change of serum carcinoembryonic antigen level in patients with stage I lung adenocarcinoma completely resected by single-port video-assisted thoracic surgery: a retrospective study

Validation of a clinical blood-based decision aid to guide immunotherapy treatment in patients with non-small cell lung cancer

Diagnostic and Prognostic Characteristics of Circulating Free DNA Methylation Detected by the Electrochemical Method in Malignant Tumors

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