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Observational Study
. 2025 Feb 14;23(1):90.
doi: 10.1186/s12916-025-03929-y.

Prospective validation study: a non-invasive circulating tumor DNA-based assay for simultaneous early detection of multiple cancers in asymptomatic adults

Luu Hong Dang Nguyen #  1 , Thi Hue Hanh Nguyen #  1 , Van Hoi Le  2 , Vinh Quang Bui  3 , Lan Hieu Nguyen  4 , Nhu Hiep Pham  5 , Thanh Hai Phan  6 , Huu Thinh Nguyen  7 , Van Song Tran  8 , Chi Viet Bui  9 , Van Kha Vo  10 , Pham Thanh Nhan Nguyen  11 , Ha Huu Phuoc Dang  12 , Van Dung Pham  13 , Van Thinh Cao  14 , Ngoc Minh Phan  1 , Ba Linh Tieu  1 , Giang Thi Huong Nguyen  1 , Dac Ho Vo  1 , Trung Hieu Tran  1 , Thanh Dat Nguyen  1 , Van Thien Chi Nguyen  1 , Trong Hieu Nguyen  1 , Vu Uyen Tran  1 , Minh Phong Le  1 , Thi Minh Thu Tran  1 , Minh Nguyen Nguyen  1 , Thi Tuong Vi Van  1 , Anh Nhu Nguyen  1 , Thi Thanh Nguyen  1 , Nhu Nhat Tan Doan  1 , Hoang Tan Nguyen  1 , Phuoc Loc Doan  1 , Le Anh Khoa Huynh  1 , Tien Anh Nguyen  1 , Huu Tam Phuc Nguyen  1 , Y-Thanh Lu  1 , Chi Thuy Tien Cao  1 , Van Tung Nguyen  2 , Thi Le Quyen Le  3 , Thi Lan-Anh Luong  4 , Thi Kim Phuong Doan  4 , Thi Trang Dao  4 , Canh Duy Phan  5 , Thanh Xuan Nguyen  5 , Nguyen Tuong Pham  5 , Bao Toan Nguyen  6 , Thi Thu Thuy Pham  6 , Huu Linh Le  6 , Cong Thanh Truong  6 , Thanh Xuan Jasmine  6 , Minh Chi Le  7 , Van Bau Phan  8 , Quang Binh Truong  7 , Thi Huong Ly Tran  10 , Minh Thien Huynh  10 , Tu Quy Tran  11 , Si Tuan Nguyen  13 , Vu Tran  13 , Van Khanh Tran  14 , Huu Nguyen Nguyen  1   15 , Duy Sinh Nguyen  1   15 , Thi Van Phan  1 , Thi Thanh-Thuy Do  1 , Dinh Kiet Truong  1 , Hung Sang Tang  1 , Hoa Giang  1   15 , Hoai-Nghia Nguyen  1   15 , Minh-Duy Phan  16   17 , Le Son Tran  18   19
Affiliations
Observational Study

Prospective validation study: a non-invasive circulating tumor DNA-based assay for simultaneous early detection of multiple cancers in asymptomatic adults

Luu Hong Dang Nguyen et al. BMC Med. .

Abstract

Background: Non-invasive multi-cancer early detection (MCED) tests have shown promise in enhancing early cancer detection. However, their clinical utility across diverse populations remains underexplored, limiting their routine implementation. This study aims to validate the clinical utility of a multimodal non-invasive circulating tumor DNA (ctDNA)-based MCED test, SPOT-MAS (Screening for the Presence Of Tumor by DNA Methylation And Size).

Methods: We conducted a multicenter prospective study, K-DETEK (ClinicalTrials.gov identifier: NCT05227261), involving 9057 asymptomatic individuals aged 40 years or older across 75 major hospitals and one research institute in Vietnam. Participants were followed for 12 months.

Results: Of the 9024 eligible participants, 43 (0.48%) tested positive for ctDNA. Among these, 17 were confirmed with malignant lesions in various primary organs through standard-of-care (SOC) imaging and biopsy, with 9 cases matching our tissue of origin (TOO) predictions. This resulted in a positive predictive value of 39.53% (95%CI 26.37-54.42) and a TOO accuracy of 52.94% (95%CI 30.96-73.83). Among the 8981 participants (99.52%) who tested negative, 8974 were confirmed cancer-free during a 12-month period after testing, yielding a negative predictive value of 99.92% (95% CI 99.84-99.96). The test demonstrated an overall sensitivity of 70.83% (95%CI 50.83-85.09) and a specificity of 99.71% (95% CI 99.58-99.80) for detecting various cancer types, including those without SOC screening options.

Conclusions: This study presents a prospective validation of a multi-cancer early detection (MCED) test conducted in a lower middle-income country, demonstrating the potential of SPOT-MAS for early cancer detection. Our findings indicate that MCED tests could be valuable additions to national cancer screening programs, particularly in regions where such initiatives are currently limited.

Trial registration: ClinicalTrials.gov ID: NCT05227261. Date of registration: 07/02/2022.

Keywords: Clinical validation; Liquid biopsy; Multicancer early detection; Multimodal analysis; Tissue of origin.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This research received approval from the Ethics Committee of the University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam (approval number: 192/HĐĐĐ-ĐHYD). Each participant provided written informed consent, adhering to the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors including LST, HNN, HG, MDP, HHN and DSN hold equity in Gene Solutions. NHN, HG, MDP and LST are inventors on the patent application (USPTO 17930705). LHDN, THHN, NMP, BLT, GTHN, DHV, THT, TDN, VTCN, THN, VUT, MPL, TMTT, MNN, TTVV, ANN, TTN, NNTD, HTN, PLD, LAKH, TAN, HTPN, YTL, CTTC, TVP, TTTD, DKT, and HST received salaries from the project funded by the Medical Genetics Institute, Ho Chi Minh City, Vietnam. We confirm that this does not alter our adherence to journal policies on sharing data and materials. VHL, VQB, LHN, NHP, THP, HTN, VST, CVB, VKV, PTNN, HHPD, VDP, VTC, BLT, TTN, HTPN, CTTC, VTN, TLQL, TLAL, TKPD, TTD, CDP, TXN, NTP, BTN, TTTP, HLL, CTT, TXJ, MCL, VBP, QBT, THLT, MTH, TQT, STN, VT, VKT declare that they have no competing interests. VHL, VQB, LHN, NHP, THP, HTN, VST, CVB, VKV, PTNN, HHPD, VDP, VTC, BLT, TTN, HTPN, CTTC, VTN, TLQL, TLAL, TKPD, TTD, CDP, TXN, NTP, BTN, TTTP, HLL, CTT, TXJ, MCL, VBP, QBT, THLT, MTH, TQT, STN, VT, and VKT declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
K-DETEK study design. K-DETEK is a prospective study involving the recruitment of 9057 asymptomatic participants aged 40 or older from 75 hospitals and one research institute in Vietnam. Plasma cell-free DNA (cfDNA) was extracted from 10 ml of blood collected from eligible participants and analyzed using the SPOT-MAS assay. SPOT-MAS assay provides two possible results: “ctDNA signal detected” or “ctDNA signal not detected,” along with the predicted TOO. Participants with a “ctDNA signal detected” result were consulted by physicians and underwent further confirmation through diagnostic imaging tests based on the TOO probability values. All participants were followed up at 6 and 12 months to collect information on possible cancer diagnoses
Fig. 2
Fig. 2
The flow chart of recruiting and following up participants in the K-DETEK study
Fig. 3
Fig. 3
The analysis of diagnostic results of 17 participants with a true positive result. Colored squares indicate the lesion-specific origin, while circles and triangles denote the first and second predicted TOO by SPOT-MAS assay. Colors represent the cancer diagnostic outcomes: metastatic cancer (blue), locally advanced cancer (purple), localized cancer (red). Intersections between colored squares and circles or triangles signify correct TOO predictions by SPOT-MAS. The bar charts display the observed time from the receipt of positive ctDNA results to final diagnosis confirmation. Unclassified group including cancers outside the scope of SPOT-MAS: Prostate cancer (K6348), Bile duct cancer (K6583), Endometrial cancer (K6642), Lymphoma (K9024), Cervical cancer (K4101), Thyroid cancer (K9012)
Fig. 4
Fig. 4
The distribution of cancer types detected in the 17 true-positive participants. SPOT-MAS test can detect a wide range of cancers, including those with standard-of-care (SOC) screens and those lacking SOC screens
Fig. 5
Fig. 5
Positive predictive value (PPV), negative predictive value (NPV), sensitivity and specificity of SPOT-MAS test in different demographic groups
See this image and copyright information in PMC

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