Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer

Herberts, Cameron; Annala, Matti; Sipola, Joonatan; Ng, Sarah W.S.; Chen, Xinyi E.; Nurminen, Anssi; Korhonen, Olga V; Munzur, Aslı D.; Beja, Kevin; Schönlau, Elena; Bernales, Cecily Q.; Ritch, Elie; Bacon, Jack V. W.; Lack, Nathan A.; Nykter, Matti; Aggarwal, Rahul; Small, Eric J.; Gleave, Martin; Quigley, David A.; Feng, Felix Y.; N., Kim; Wyatt, Alexander W.

doi:10.1038/s41586-022-04975-9

Cited by 99 publications

(102 citation statements)

References 66 publications

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“…Depending on prior treatment exposure and burden of disease, it is estimated that ctDNA fraction is below 1% in between 30-40% of patients with mCRPC ( 5 , 41 , 42 ); these patients are not amenable to tumor genotyping using ctDNA. In general, providing sufficient ctDNA% is present, ctDNA alterations from patients with mCRPC show strong concordance with matched metastatic tissue ( 19 , 71 ), and reproduce the expected mutational landscape ( 5 , 16 , 42 , 43 , 71 – 73 ). Apparent differences are explained by low ctDNA% samples, variability in assay design and presence of subclonal alterations.…”

Section: Clinical Applicationsmentioning

confidence: 85%

“…In turn, this must be balanced with the financial toxicity and substantial human capital required for successful implementation across a wide population group. While the real-world cost of shallow whole genome sequencing (0.1-5x depth) continues to fall with time, higher sequencing depth (>20-40x depth) is likely required to provide sufficient biologic insights that inform treatment decision-making ( 19 , 54 ). Factoring in the expenditure associated with data analysis, interpretation and patient counseling, the sum cost of informative whole genome analysis is likely to exceed $10,000-$20,000 per patient ( 55 ), arguably not cost-effective for routine implementation in all advanced prostate cancer patients.…”

Section: Clinical Applicationsmentioning

confidence: 99%

“…This variation in response is indicative of distinct tumor populations that have developed acquired resistance to treatment. The ability of ctDNA to sample multiple cancer populations from spatially distinct metastatic foci presents opportunities to detect evolving genomic and epigenomic determinants of acquired treatment resistance ( 19 ). Specifically, the possibility of differentiating between AR-dependent and AR-independent metastatic prostate cancer is likely to have profound implications on optimal patient management.…”

Section: Clinical Applicationsmentioning

confidence: 99%

“…The magnitude of AR amplification also appears to be relevant, with high-level amplification associated with worse outcomes ( 5 , 99 ). Notably, with repeated exposure to intensive AR-directed therapies, resistance mechanisms continue to converge upon the AR gene body and upstream enhancer, selecting for tumor populations with a greater number of AR copies ( 19 , 102 ). Mutations in the AR are concentrated in hotspot regions within the ligand binding domain.…”

Section: Clinical Applicationsmentioning

confidence: 99%

“…Critically, single lesion sampling fails to represent the diversity of competing tumor clones present between different disease sites. In a recent study employing deep whole-genome sequencing of serial plasma samples and tissue biopsies of synchronous metastases in poor-risk mCRPC patients, the contribution of any singular metastasis to the total ctDNA pool was low, providing evidence to support the long held notion that ctDNA captures tumor material from multiple metastatic foci ( 19 ). This ability to capture spatial and temporal heterogeneity between metastases have led to a number of clinical applications for ctDNA in metastatic prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

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Towards clinical implementation of circulating tumor DNA in metastatic prostate cancer: Opportunities for integration and pitfalls to interpretation

Kwan

Wyatt

2022

Front. Oncol.

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Plasma circulating tumor DNA (ctDNA) represents short fragments of tumor-derived DNA released into the bloodstream primarily from cancer cells undergoing apoptosis. In metastatic castration-resistant prostate cancer (mCRPC), characterizing genomic alterations in ctDNA identifies mutations, copy number alterations, and structural rearrangements with predictive and prognostic biomarker utility. These associations with clinical outcomes have resulted in ctDNA increasingly incorporated into routine clinical care. In this review, we summarize current and emerging applications for ctDNA analysis in metastatic prostate cancer, including outcome prediction, treatment selection, and characterization of treatment resistance. We also discuss potential pitfalls with interpreting ctDNA findings, namely false negatives arising from low tumor content and optimal assay design, including correction for clonal hematopoiesis of indeterminate potential and germline variants. Understanding the influence of these limitations on interpretation of ctDNA results is necessary to overcome barriers to clinical implementation. Nevertheless, as assay availability and technology continue to improve, recognizing both opportunities and shortcomings of ctDNA analysis will retain relevance with informing the implementation of precision-oncology initiatives for metastatic prostate cancer.

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Section: Clinical Applicationsmentioning

confidence: 85%

Section: Clinical Applicationsmentioning

confidence: 99%

Section: Clinical Applicationsmentioning

confidence: 99%

Section: Clinical Applicationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Towards clinical implementation of circulating tumor DNA in metastatic prostate cancer: Opportunities for integration and pitfalls to interpretation

Kwan

Wyatt

2022

Front. Oncol.

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Prospective clinical sequencing of 1016 Chinese prostate cancer patients: uncovering genomic characterization and race disparity

Zhou

Wang

et al. 2023

Molecular Oncology

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Although there is a well‐known disparity in prostate cancer (PC) incidence and mortality between Chinese and Western patients, the underlying genomic differences have been investigated only sparsely. This clinico‐genomic study was conducted to reveal the genomic mutations contributing to the PC disparity across ethnicities and investigate the mutational profile of Chinese PC patients. A total of 1016 Chinese PC patients were prospectively enrolled and subjected to targeted sequencing, resulting in usable sequencing data for 41 genes from 859 patients. Genomic data retrieved from The Cancer Genome Atlas (TCGA; locoregional PC), Memorial Sloan Kettering Cancer Center [MSKCC; metastatic castration‐sensitive PC (mCSPC)] and Stand Up To Cancer [SU2C; metastatic castration‐resistant PC (mCRPC)] cohorts were used as comparators representing Western men. Genomic mutations were analyzed using an integrated bioinformatic strategy. A comparison of the disease stages revealed that mutations in tumor protein 53 (TP53), androgen receptor (AR), forkhead box A1 (FOXA1) and genes involved in the cell cycle pathway were enriched in mCRPC. Mutations in adenomatous polyposis coli (APC) gene were found to be more prevalent in patients with visceral metastasis. Genomic differences between Western and Chinese men were mainly observed in castration‐sensitive PC, with tumors from Chinese men having more FOXA1 (11.4% vs 4.2%) but fewer TP53 (4.8% vs 13%) mutations in locoregional PC and harboring fewer TP53 (11% vs 29.2%), phosphatase and tensin homolog (PTEN; 2.5% vs 10.3%) and APC (1.7% vs 7.4%) mutations in the mCSPC stage than those of Western men. Patients of both ethnicities with mCRPC had similar mutational spectra. Furthermore, FOXA1 class‐2 was less common than FOXA1 class‐1 and showed no enrichment in metastasis, contrary to the findings in the Western cohort. Our study provides a valuable resource for a better understanding of PC in China and reveals the genomic alterations associated with PC disparity across races.

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Self‐Healing Electronics for Prognostic Monitoring of Methylated Circulating Tumor DNAs

Fang

Zhao

et al. 2022

Advanced Materials

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ficiently early. This highlights the great need for early cancer screening techniques, where wearable electronic devices could potentially be developed as a pointof-care (POC) alternatives. [2] Particularly, wearable electronics have evolved from simple recording of heart rate and body movements to physiological monitoring of glucose, Na + , K + , Ca 2+ , and pH, [3][4][5][6] as well as other more advanced biomarkers in different body fluids, including sweat, [7] tears, [8] saliva, [9] and interstitial fluid, [10,11] and has greatly expanded the clinician's arsenal for early disease detection.Many current tumor biomarkers are proteins or metabolites that are abundant in cancer cells and are released into the circulatory system. [12,13] Clinically, some are used to identify cancers primarily originating from different organ systems, such as α-fetoprotein for liver cancer and germ cell tumors, [14] ß-2-microglobulin for chronic lymphocytic leukemia, [15] calcitonin for medullary thyroid cancer, [16] and prostate-specific antigen for prostate cancer. [17] Despite the wide use of these biomarkers for cancer diagnostics, these protein-based tumor markers are typically detectable at the late stages of cancer progression, [18] when the efficacy of many cancer treatments is substantially compromised. Alternatively, methylated circulating DNAs (ctDNAs) Methylated circulating DNAs (ctDNAs) have recently been reported as a promising biomarker for early cancer diagnostics, but limited tools are currently available for continuous and dynamic profiling of ctDNAs and their methylation levels, especially when such assays need to be conducted in point-of-care (POC) scenarios. Here, a self-healing bioelectronic patch (iMethy) is developed that combines transdermal interstitial fluid (ISF) extraction and field effect transistor-based (FET-based) biosensing for dynamic monitoring of methylated ctDNAs as a prognostic approach for cancer risk management. The projection micro-stereolithography-based 3D patterning of an Eutectic Gallium-Indium (EGaIn) circuit with an unprecedented 10 µm resolution enables the construction of self-healing EGaIn microfluidic circuits that remain conductive under 100% strain and self-healing under severe destruction. In combination with continuous transdermal ISF sampling of methylated ctDNAs, iMethy can detect ctDNAs as low as 10 −16 m in cellular models and is capable of phenotypic analysis of tumor growth in rodent animals. As the first demonstration of a wearable device for real-time in vivo analysis of disease-indicative biomarkers, this proof-of-concept study well demonstrated the potential of the iMethy platform for cancer risk management based on dynamic transdermal surveillance of methylated ctDNAs via a painless and self-administrable procedure.

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Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer

Cited by 99 publications

References 66 publications

Towards clinical implementation of circulating tumor DNA in metastatic prostate cancer: Opportunities for integration and pitfalls to interpretation

Towards clinical implementation of circulating tumor DNA in metastatic prostate cancer: Opportunities for integration and pitfalls to interpretation

Prospective clinical sequencing of 1016 Chinese prostate cancer patients: uncovering genomic characterization and race disparity

Self‐Healing Electronics for Prognostic Monitoring of Methylated Circulating Tumor DNAs

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