Evaluation of a Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) Cartridge Assay for Predicting Early Disease Progression and Survival: TBCRC 005 Prospective Trial

Visvanathan, Kala; Cope, Leslie; Fackler, Mary Jo; Considine, Michael; Sokoll, Lori J.; Carey, Lisa A.; Forero-Torres, Andres; Ingle, James N.; Lin, Nancy U.; Nanda, Rita; Storniolo, Anna Maria; Tulac, Suzana; Venkatesan, Neesha; Wu, Natalie C.; Marla, Sudhakar; Campbell, Scott; Bates, Michael; Umbricht, Christopher B.; Wolff, Antonio C.; Sukumar, Saraswati

doi:10.1158/1078-0432.ccr-22-2128

Cited by 7 publications

(7 citation statements)

References 18 publications

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“…The QM-MSP assay could be a valuable triaging tool for further clinical intervention and for risk stratification in developed countries and could provide higher sensitivity and specificity for detection of cervical neoplasia. The test could be automated and modified for high throughput as demonstrated by our studies using GeneXpert cartridges for detection of tumor-specific methylated DNA in fine needle aspirates of the breast lesion for distinguishing between benign and malignant growths and to assess changes in tumor load in circulating DNA in patients undergoing chemotherapy [ 26 , 60 – 62 ]. We are currently developing a cartridge-based liquid biopsy-methylated marker assay for colon cancer detection [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Discovery and technical validation of high-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries

Fackler,

Pleas,

et al. 2024

Clin Epigenet

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Background Cervical cancer remains a leading cause of death, particularly in developing countries. WHO screening guidelines recommend human papilloma virus (HPV) detection as a means to identify women at risk of developing cervical cancer. While HPV testing identifies those at risk, it does not specifically distinguish individuals with neoplasia. We investigated whether a quantitative molecular test that measures methylated DNA markers could identify high-risk lesions in the cervix with accuracy. Results Marker discovery was performed in TCGA-CESC Infinium Methylation 450 K Array database and verified in three other public datasets. The panel was technically validated using Quantitative Multiplex-Methylation-Specific PCR in tissue sections (N = 252) and cervical smears (N = 244) from the USA, South Africa, and Vietnam. The gene panel consisted of FMN2, EDNRB, ZNF671, TBXT, and MOS. Cervical tissue samples from all three countries showed highly significant differential methylation in squamous cell carcinoma (SCC) with a sensitivity of 100% [95% CI 74.12–100.00], and specificity of 91% [95% CI 62.26–99.53] to 96% [95% CI 79.01–99.78], and receiver operating characteristic area under the curve (ROC AUC) = 1.000 [95% CI 1.00–1.00] compared to benign cervical tissue, and cervical intraepithelial neoplasia 2/3 with sensitivity of 55% [95% CI 37.77–70.84] to 89% [95% CI 67.20–98.03], specificity of 93% [95% CI 84.07–97.38] to 96% [95% CI 79.01–99.78], and a ROC AUC ranging from 0.793 [95% CI 0.68–0.89] to 0.99 [95% CI 0.97–1.00] compared to CIN1. In cervical smears, the marker panel detected SCC with a sensitivity of 87% [95% CI 77.45–92.69], specificity 95% [95% CI 88.64–98.18], and ROC AUC = 0.925 [95% CI 0.878–0.974] compared to normal, and high-grade squamous intraepithelial lesion (HSIL) at a sensitivity of 70% (95% CI 58.11–80.44), specificity of 94% (95% CI 88.30–97.40), and ROC AUC = 0.884 (95% CI 0.822–0.945) compared to low-grade intraepithelial lesion (LSIL)/normal in an analysis of pooled data from the three countries. Similar to HPV-positive, HPV-negative cervical carcinomas were frequently hypermethylated for these markers. Conclusions This 5-marker panel detected SCC and HSIL in cervical smears with a high level of sensitivity and specificity. Molecular tests with the ability to rapidly detect high-risk HSIL will lead to timely treatment for those in need and prevent unnecessary procedures in women with low-risk lesions throughout the world. Validation of these markers in prospectively collected cervical smear cells followed by the development of a hypermethylated marker-based cervical cancer detection test is warranted.

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Section: Discussionmentioning

confidence: 99%

Discovery and technical validation of high-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries

Fackler,

Pleas,

et al. 2024

Clin Epigenet

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“…The QM-MSP assay could be a valuable triaging tool for further clinical intervention, for risk strati cation, and along with HPV testing, could provide a higher sensitivity and speci city for detection of cervical neoplasia. The test could be automated and modi ed for high throughput as demonstrated in our studies using GeneXpert cartridges for early detection of breast cancer in ne needle aspirates of the breast lesion, and validated in cell-free DNA in blood for monitoring disease in patients undergoing chemotherapy [9,[50][51][52]. A liquid biopsy assay for colon cancer detection is also under development [53].…”

Section: Discussionmentioning

confidence: 99%

High-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries

Fackler,

Pleas,

et al. 2023

Preprint

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Background Cervical cancer remains a leading cause of death, particularly in developing countries. WHO screening guidelines recommend Human Papilloma Virus (HPV) detection as a means to identify women at risk of developing cervical cancer. While HPV testing identifies those at risk, it does not specifically recognize individuals with neoplasia. We investigated whether a molecular test that quantitatively measures methylated DNA markers could identify high-risk lesions in the cervix with accuracy. Results Marker discovery was performed in TCGA-CESC Infinium Methylation 450K Array database, and the selected 5-gene panel was verified in three other public datasets. The panel was technically validated using Quantitative Multiplex-Methylation Specific PCR (QM-MSP) in tissue sections (N = 293) and cervical smears (N = 244) from the U. S., S. Africa, and Vietnam. The gene panel consisted of FMN2, EDNRB, ZNF671, TBXT, and MOS. Cervical tissue samples from U.S., South Africa, and Vietnam showed highly significant differential methylation in squamous cell carcinoma (SCC) with 100% sensitivity, 91–93% specificity, and a Receiver Operating Characteristic Area under the curve (ROC AUC) = 1.000 [CI 1.000 to 1.000], and cervical intraepithelial neoplasia 2/3 (CIN2/3) with 55–100% sensitivity, 91–96% specificity, and a ROC AUC ranging from 0.793 [CI 0.681 to 0.905] to 1.000 [CI 1.000 to 1.000] compared to normal. In cervical smears, the marker panel detected SCC at 87% sensitivity, 95% specificity, and ROC AUC = 0.925 [CI 0.878 to 0.974], and high-grade intraepithelial lesion (HSIL) at 74% sensitivity, 95% specificity, and a ROC AUC = 0.907 [CI 0.851 to 0.964] in an analysis of pooled data from the three countries. Similar to HPV-positive, HPV-negative cervical carcinomas were frequently hypermethylated for these markers. Conclusions This 5-marker panel detected SCC and CIN2/3 in cervical smears with a high level of sensitivity and specificity. Molecular tests with the ability to rapidly detect high-risk CIN3 + lesions will lead to timely treatment for those in need while preventing unnecessary procedures in women with low-risk lesions throughout the world. Validation of these markers in prospectively collected cervical smear cells followed by the development of a hypermethylated marker-based cervical cancer detection test is warranted.

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“… 68 Additionally, blood‐based liquid biopsy plays a pivotal role in metastatic breast cancer by monitoring disease progression and assisting in therapeutic decision‐making, as shown in the Translational Breast Cancer Research Consortium (TBCRC) 005 trial. 69 Furthermore, the realm of prenatal diagnostics has been transformed by noninvasive prenatal sequencing (NIPS), which leverages ctDNA for the early detection of genetic disorders, demonstrating the wide‐ranging applicability of blood‐based biomarkers in both oncological and nononcological contexts. 70 …”

Section: Clinical Applications and Case Studies In Diverse Fluidsmentioning

confidence: 99%

Beyond blood: Advancing the frontiers of liquid biopsy in oncology and personalized medicine

Bao,

Zhang,

Guo

et al. 2024

Cancer Science

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Liquid biopsy is emerging as a pivotal tool in precision oncology, offering a noninvasive and comprehensive approach to cancer diagnostics and management. By harnessing biofluids such as blood, urine, saliva, cerebrospinal fluid, and pleural effusions, this technique profiles key biomarkers including circulating tumor DNA, circulating tumor cells, microRNAs, and extracellular vesicles. This review discusses the extended scope of liquid biopsy, highlighting its indispensable role in enhancing patient outcomes through early detection, continuous monitoring, and tailored therapy. While the advantages are notable, we also address the challenges, emphasizing the necessity for precision, cost‐effectiveness, and standardized methodologies in its broader application. The future trajectory of liquid biopsy is set to expand its reach in personalized medicine, fueled by technological advancements and collaborative research.

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Evaluation of a Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) Cartridge Assay for Predicting Early Disease Progression and Survival: TBCRC 005 Prospective Trial

Cited by 7 publications

References 18 publications

Discovery and technical validation of high-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries

Discovery and technical validation of high-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries

High-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries

Beyond blood: Advancing the frontiers of liquid biopsy in oncology and personalized medicine

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