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  • 1
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    Abstract 3401: Whole genome cell-free tumor DNA mutational signatures for noninvasive monitoring of pediatric brain cancers
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3401-3401
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3401-3401
    Abstract: Introduction: Liquid biopsy offers a noninvasive approach to monitor cancer burden during therapy and surveillance period. However, in pediatric brain cancers, liquid biopsy methods from the blood have been unsuccessful due to a low tumor burden and low number of mutations in coding regions. We hypothesized that a whole genome sequencing (WGS)-derived patient specific mutational signature from a matched tumor-normal WGS can provide a sensitive and specific approach to detect mutations in circulating cell free tumor DNA (ctDNA) and provide blood-based monitoring in pediatric patients with brain tumor. Methods: All tumors were analyzed and molecularly subclassified using whole genome DNA methylation profiling and machine learning classifier. Tumor DNA was extracted from pathology tissue and normal germline DNA from the white blood cells, while ctDNA was extracted from 1-2 mL of post-surgery or follow-up plasma samples, WGS was applied to sequence DNA from matched tumor-normal and plasma samples. WGS coverage was 40x for matched tumor-normal DNA and 20x for ctDNA. Using the C2i assay, we derived a personalized mutational pattern for each tumor and used an AI-based error suppression model for quantification and ultra-sensitive detection of ctDNA in plasma samples. A patient-specific personalized genome-wide compendium of somatic mutations was established and ctDNA tested at 1 to 3 available time points during the therapy or surveillance period. An AI-based error suppression model was implemented to filter out the noise in the cell free DNA (cfDNA) while the personalized mutational signature was used to detect the ctDNA in the cfDNA and to amplify the somatic signal contained in it. The ctDNA Tumor Fraction (TF) was compared to the clinical status and MR-based imaging. Results: We profiled 7 pediatric brain tumors, including 2 medulloblastomas (one Group 3, one Group 4), 3 pediatric glioblastomas IDH wild-type, 1 ependymoma PFA subtype and one low grade ganglioglioma. Tumor specific signatures were identified and detected in the plasma of 5 patients with clinical disease with a TF range 0.02-0.0005 but not in 2 patients with no tumor at the time of blood collection. In two children with a medulloblastoma and glioblastoma, the decrease of tumor fraction in ctDNA over 2 (TF: 0.002 to 0.0009) and 3 time points (TF: 0.0005 to undetectable), respectively, correlated with response to therapy based on imaging. Conclusions: Patient-specific WGS tumor signature in ctDNA from blood can be used for sensitive monitoring of children with brain tumors. Citation Format: Ivy Tran, Kristyn Galbraith, Guisheng Zhao, Robyn Borsuk, Joyce Varkey, Sharon Gardner, Jeffrey Allen, David Harter, Jeffrey Wisoff, Eveline T. Hidalgo, Sunil Deochand, Dillon Maloney, Danielle Afterman, Tomer Lauterman, Noah Friedman, Imane Bourzgui, Nidhi Ramaraj, Zohar Donenhirsh, Ronel Veksler, Jonathan Rosenfeld, Ravi Kandasamy, Iman Tavassoly, Boris Oklander, G. Praveen Raju, Theodore Nicolaides, Asaf Zviran, Matija Snuderl. Whole genome cell-free tumor DNA mutational signatures for noninvasive monitoring of pediatric brain cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3401.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-3401
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    Ultrasensitive detection and monitoring of central nervous system tumors from plasma using personalized whole-genome ctDNA profiling.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 2064-2064
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2064-2064
    Abstract: 2064 Background: Patients with the central nervous system (CNS) tumors are largely followed up by imaging. Current plasma-based liquid biopsy techniques have limited utility in neuro-oncology due to a low circulating cell-free tumor DNA (ctDNA) burden, blood-brain barrier, and low number of mutations in coding regions. Whole genome sequencing (WGS)-derived patient specific mutational signature from a matched tumor-normal WGS can provide a personalized, highly sensitive and specific approach to detect mutations in ctDNA and provide blood-based monitoring in brain tumor patients. Furthermore, it can be performed on lower amount of peripheral blood since WGS requires less sequencing depth compared to targeted ctDNA panels. Methods: We have profiled a cohort of 28 extra- and intra-axial adult and pediatric brain tumors including adult and pediatric low- and high-grade glioma (9), meningiomas (11), medulloblastomas (5), ependymomas (2), neurocytoma (1). Tumor DNA was extracted from archival pathology tissue, normal DNA from unsorted white blood cells, and ctDNA from 1-2 mL of post-surgery plasma. WGS was performed with 40x coverage for Tumor-Normal DNA and 20x for ctDNA. Using WGS of matched Tumor-Normal and plasma samples, we derived a personalized mutational pattern using SNVs, indels, and copy numbers for quantification and ultra-sensitive detection of ctDNA in plasma samples. An AI-based error suppression model was implemented to filter out the noise in the cell-free DNA (cfDNA) while the personalized mutational signature was used to detect the ctDNA in the cfDNA and to amplify the somatic signal to determine the Tumor Fraction at the time of diagnosis, during the therapy or surveillance period. The ctDNA Tumor Fraction (TF) was compared to the clinical status and MRI-based imaging. Results: All subtypes of brain tumors contained enough mutations to derive personalized mutational signatures. Most mutations were distributed in the noncoding DNA. TF correlated with clinical status and with the disease course on imaging at given time points reaching a 10 -4 minimal residual disease detection sensitivity. We were able to detect ctDNA across all WHO grades ranging from WHO 1 meningioma to WHO 4 glioblastoma and medulloblastoma. Furthermore, we were able to detect tumor-specific copy number aberrations such as MYCN amplification in plasma samples and mutational signatures. Conclusions: Here we demonstrate that patient-specific WGS tumor signature in ctDNA from plasma can be used for sensitive monitoring of adults and children with primary low- and high-grade CNS tumors.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.2064
    RVK:
    XA 52760
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 3
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    Accuracy of genome-wide mutational analysis for tumor-informed ctDNA-guided MRD monitoring in bladder cancer.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4589-4589
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4589-4589
    Abstract: 4589 Background: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard management of localized muscle-invasive bladder cancer (MIBC). However, about 45% of patients develop metastases within 2 years after RC. Biomarkers for treatment efficacy evaluation and early detection of minimal residual disease (MRD) are needed for earlier treatment initiation and monitoring of treatment response. Tumor-informed detection of mutations in cell-free DNA (cfDNA) has shown promising results to monitor MRD. However, the low tumor fraction after surgery and limited input material obtained from a typical plasma sample limits the probability of detecting low metastatic burden scenarios. Here we implemented and applied a whole-genome sequencing (WGS) approach to monitor circulating tumor DNA (ctDNA) for sensitive ctDNA detection. Methods: 110 MIBC patients undergoing NAC and RC were enrolled. cfDNA was extracted from ~1mL plasma (n=978) and procured from longitudinal plasma sampling during NAC and pre-RC and post-RC. WGS of tumor/germline pairs (30x/20x) and plasma cfDNA ( 〉 20x) was performed, facilitating detection of genome-wide genomic alterations and quantification of ctDNA using the C2inform method. Results: For each patient we developed a tumor-informed WGS model by integrating genome-wide mutation and copy number variation data coupled with advanced signal processing and AI-based error suppression. Patient-specific somatic variant patterns were used for detection and measuring ctDNA levels in low-input blood samples by WGS. Post-RC ctDNA analysis identified patients with recurrence with 78% sensitivity and 95% specificity and with a median lead time over radiographic imaging of 118 days (full follow-up included). When restricting follow-up time to 12 months following the latest ctDNA test, a sensitivity of 86% and specificity of 94% was achieved. ctDNA status was associated with recurrence-free (p 〈 0.0001) and overall survival (p 〈 0.0001). Furthermore, ctDNA clearance during NAC was also associated with recurrence-free survival (p=0.0051). The APOBEC associated signatures SBS2 and SBS13 were identified as the primary contributors to the mutational landscape of the primary tumors and TP53, KMT2D, PIK3CA, RB1 and KDM6A were the main affected driver genes. Half of the tumors displayed whole genome doubling. Moreover, our analysis of plasma samples after treatment showed the presence of chemotherapy-induced mutational signatures not present in the primary tumor, along with increases in copy numbers on chromosomes 19q and 20, and a focal amplification of the FGFR3 gene on chromosome 4. Conclusions: Our results highlight the clinical potential of personalized genome-wide mutation integration as an ultra-sensitive, non-invasive method for MRD detection and treatment response monitoring.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4589
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 4
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    Genome-wide circulating tumor DNA monitoring for bladder cancer treatment management and organ preservation.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. e16527-e16527
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e16527-e16527
    Abstract: e16527 Background: Bladder cancer (BC) is the 9th most commonly diagnosed cancer worldwide and each year responsible for 165,000 deaths. Neoadjuvant combination chemotherapy, followed by radical cystectomy, is used for the management of localized muscle-invasive bladder cancer. One of the critical challenges in this therapeutic regimen is monitoring the tumor load to assess therapeutic efficacy – this is typically performed by assessing pathological downstaging in the cystectomy specimen. A high frequency of patients presents with T0N0 at cystectomy (no indication of residual disease), and consequently, it is vital to investigate organ preservation approaches to identify those patients who may qualify for bladder preservation. For precision oncology, we need to develop quantitative and non-invasive diagnostic methodologies to help the oncologist tailor the treatments to individual patients and monitor them for further clinical decision-making. Methods: Cell-free DNA (cfDNA) mutation detection has shown significant promise in its ability to monitor minimal residual disease and disease relapse by detection of cancer mutations in the peripheral blood. However, the combination of low tumor fraction and limited input material obtained from a typical plasma sample restricts the probability of detecting low metastatic burden in cfDNA through current deep targeted sequencing methods. Results: Here we present results from applying whole-genome sequencing (WGS) of cfDNA. We integrate a genome-wide mutation and copy number monitoring approach coupled with advanced signal processing and Artificial Intelligence (AI) for measuring the tumor load from low-input blood samples (̃1mL of plasma) with ultra-sensitive detection. The increased sensitivity allowed clinical detection of tumor fraction down to 8*10 -5 and recurrence detection sensitivity achieving 〉 65% at the first two months post-surgery. The WGS cfDNA approach is being evaluated on a patient cohort of more than 50 bladder cancer patients with longitudinal plasma sampling during neoadjuvant chemotherapy (response measure), pre-cystectomy (complete response measure), and post-surgery (relapse monitoring). Conclusions: The results indicate the clinical potential of genome-wide mutation integration as an ultra-sensitive, non-invasive diagnostic method for bladder cancer clinical management and bladder organ preservation.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.e16527
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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    BIOM-23. A PILOT STUDY OF WHOLE GENOME SEQUENCING (WGS) OF PLASMA CELL-FREE DNA (cfDNA) FOR ULTRASENSITIVE DETECTION OF TUMOR DNA IN PATIENTS WITH GLIOBLASTOMA (GBM)
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi15-vi15
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_6 ( 2021-11-12), p. vi15-vi15
    Abstract: Plasma circulating tumor DNA (ctDNA) is rarely detectable by traditional methods in patients with GBM. As a result, unlike in lung and other cancers, serial next generation sequencing of ctDNA for monitoring GBM tumor burden has been challenging. In light of the low tumor fraction (TF) of DNA fragments in GBM patient plasma and the urgent need to improve upon MRI for tracking GBM tumor burden, we conducted a pilot study in patients with newly diagnosed GBM using the C2 intelligence platform (C2i Genomics), which leverages genome-wide mutational integration for highly sensitive ctDNA detection. METHODS Plasma was collected pre- and post-operatively in patients with newly diagnosed GBM undergoing surgical resection/biopsy. cfDNA was extracted, quantified, and analyzed for fragment size. Genomic DNA (gDNA) was extracted from matched tumor tissue. Whole genome sequencing (WGS) was performed on both gDNA and cfDNA. A specific copy number alteration (CNA) compendium was created for each patient to generate a readout of TF (Zviran, Nat Medicine 2020). We assessed the association between TF at post-operative day 1 (a surrogate for residual disease) and OS, adjusting for other prognostic factors using Cox regression. RESULTS 37 patients were enrolled. For samples with high tumor fraction (n=5), a statistically significant (p & lt; 1e-4) correlation between CNA profiles of tumor tissue and plasma samples was observed. Post-operative TF above the median value was associated with inferior OS (median 7.7 vs. 19.3 months, p=0.019). This association persisted after adjusting for age, O6-methylguanine-DNA methyltransferase methylation status, extent of resection, and performance status (adjusted HR 2.5, 95% CI 1.1-5.6, p=0.03). CONCLUSION Genome-wide mutational integration enables ultra-sensitive detection of ctDNA in GBM patient plasma. Post-operative TF measured by the C2i test is independently associated with OS in newly diagnosed GBM, providing the foundation to evaluate this technology for personalized prognostication and disease monitoring.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab196.054
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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    Abstract 2305: Ultra-sensitive detection of circulating tumor DNA by whole-genome sequencing of blood samples from locally advanced rectal cancer patients receiving neoadjuvant therapy and enrolled in watch-and-wait strategies for organ preservation
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2305-2305
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2305-2305
    Abstract: Background. We hypothesized that circulating tumor DNA (ctDNA) can be used as a prognostic biomarker, improve the assessment of response and enhance detection of minimal residual disease in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant therapy (NAT). Methods. We analyzed data from 31 LARC patients treated at Memorial Sloan Kettering as part of the Organ Preservation in Rectal Adenocarcinoma (OPRA) phase II clinical trial. Patients had stage II or III rectal adenocarcinoma and received NAT including chemoradiation and chemotherapy. Patients without a clinical complete response (cCR) underwent surgical resection, while patients with a cCR were enrolled in a watch-and-wait protocol for organ preservation. Complete response (CR) after NAT was defined as either pathological complete response or a cCR sustained for ≥2 years. Disease-free survival (DFS) was measured from the start of NAT. Median follow-up was 5.41 years [range 2.96-8.38]. ctDNA analyses were performed using the C2i Genomics platform. A patient-specific molecular profile was created by performing whole-genome sequencing (WGS) of their tumor and matched normal DNA (40x coverage). WGS (20x coverage) was performed on plasma samples collected at baseline (before NAT), interval evaluation (halfway through NAT), re-staging evaluation (8 weeks after NAT) and follow-up (3-6 months after NAT). Results. Tumor was detected in plasma samples from 24/25 patients at baseline (96% sensitivity). The tumor fraction (TF) levels detected at baseline separated responders from non-responders (median TF 6.2e-4 vs 1.4e-3; p=0.055). Tumor detection at interval was associated with a lower rate of CR (25% vs. 75%, p=0.0095) and shorter time to recurrence (58.3% vs. 94.1% 3-year DFS, p=0.02). Tumor detection at follow-up was associated with a higher rate of recurrence (p=0.037) and tumor was detected at follow-up for all 5/5 patients who developed recurrence. Overall TF dynamics showed clearance of ctDNA down to the non-detection level throughout treatment in patients with a CR, while non-responders exhibited non-decreasing and often increasing estimates of ctDNA burden. Analysis of tissue WGS data identified multiple patients with colibactin associated mutational signatures, which provides additional insights into their cancer etiology. Conclusions. The WGS-based approach for ctDNA analysis exhibited very high sensitivity for detection at baseline. TF across multiple time points separated responders from non-responders, suggesting potential value as a prognostic marker. Detection of ctDNA at follow-up for all patients who recurred is indicative of potential clinical utility for treatment de-escalation in the context of organ preservation strategies. Citation Format: Francisco Sanchez-Vega, Chin-Tung Chen, Danielle Afterman, Dana Omer, Madison Darmofal, Ino de Bruijn, Walid K. Chatila, Matthew Drescher, Grittney Tam, Tomer Lauterman, Maja Kuzman, Santiago Gonzalez, Dunja Glavas, James Samdbeck, Dillon Maloney, Jurica Levatic, Sunil Deochand, Michael Yahalom, Ryan Ptashkin, Iman Tavassoly, Zohar Donenhirsh, Eric White, Ravi Kandasamy, Ury Alon, Michael F. Berger, Brian Loomis, Paz Polak, Boris Oklander, Asaf Zviran, Julio Garcia-Aguilar. Ultra-sensitive detection of circulating tumor DNA by whole-genome sequencing of blood samples from locally advanced rectal cancer patients receiving neoadjuvant therapy and enrolled in watch-and-wait strategies for organ preservation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2305.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-2305
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract 1036: Detection of circulating tumor DNA by whole genome sequencing enables prediction of recurrence in stage III colorectal cancer patients with great inter-lab reproducibility
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1036-1036
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1036-1036
    Abstract: Background: Detection of circulating tumor DNA (ctDNA) in plasma indicates the presence of cancer. In patients with very few copies of tumor DNA circulating in the blood, the blood sampling process becomes a potentially limiting factor. For ctDNA methods based on a single or a few genomic targets, it becomes stochastic whether the collected sample contains any tumor DNA fragments from targeted regions. To overcome this sampling limitation, we developed C2inform; a whole genome sequencing (WGS) approach, which detects ctDNA using a cumulative patient-specific signal from thousands of mutations throughout the entire genome. Aim: Here, we aim to I) evaluate the performance of C2inform in patients with UICC stage III colorectal cancer (CRC) using samples collected after the end of curatively intended treatment and serially during surveillance, II) assess the inter-lab reproducibility of C2inform and, III) investigate the potential for using the serial WGS data to track tumor genomic evolution in recurrence patients. Methods: From a cohort of 146 stage III CRC patients, including 37 patients with recurrence, 2 mL plasma samples were collected serially for up to three years (n = 1309, median 10 samples per patient). By WGS of tumor and blood-derived normal DNA, a mutational signature was established for each patient. Enhanced by an AI-based error suppression model, this signature was used to screen 20x WGS plasma cfDNA profiles for the presence of ctDNA. To evaluate the reproducibility, paired samples (n = 2 x 187 samples) were processed and sequenced at two independent laboratories while the bioinformatics processing of samples was identical. Using coverage, split-read, and discordant read-pair information, genomic structural alterations were identified in serial plasma samples from 19 recurrence patients and compared to tissue WGS from subsequent recurrence metastasis. Results: Preliminary results showed that detection of ctDNA after the end of treatment was associated with poor prognosis (HR = 7.1, 95% CI: 3.2-15.9). The presence of ctDNA during surveillance was a predictor of recurrence (HR = 9.5, 95% CI: 3.6-25.5) and enabled the detection of recurrence up to 21 months (median: 9.5 months) before detection by radiological imaging. We found indication of tumor evolution by searching serially collected plasma samples for novel genomic changes, which were confirmed by WGS of the metastatic tissue. Analysis of paired samples showed great reproducibility of C2inform with a high agreement between both ctDNA detection (Cohens Kappa = 0.9) and the estimated ctDNA level (r² = 0.99). Conclusion: C2inform showed great inter-lab reproducibility and enabled prediction of recurrence after treatment and during surveillance. Thus, C2inform has the potential to guide clinical decision-making during the postoperative management of CRC patients. Citation Format: Amanda Frydendahl, Jesper Nors, Mads Heilskov, Ester Ellegaard Sørensen, Thomas Reinert, Jesper Bramsen, Danielle Afterman, Tomer Lauterman, Maja Kuzman, Santiago Gonzalez, Dunja Glavas, James Samdbeck, Dillon Maloney, Jurica Levatic, Sunil Deochand, Michael Yahalom, Ryan Ptashkin, Iman Tavassoly, Zohar Donenhirsh, Eric White, Ravi Kandasamy, Ury Alon, Paz Polak, Anders Husted Madsen, Uffe Schou Løve, Per Vadgaard Andersen, Ole Thorlacius-Ussing, Lene Hjerrild Iversen, Kåre Andersson Gotschalck, Boris Oklander, Asaf Zviran, Claus Lindbjerg Andersen. Detection of circulating tumor DNA by whole genome sequencing enables prediction of recurrence in stage III colorectal cancer patients with great inter-lab reproducibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1036.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-1036
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract 5114: Ultra-sensitive detection of minimal residual disease (MRD) through whole genome sequencing (WGS) using an AI-based error suppression model in resected early-stage non-small cell lung cancer (NSCLC)
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5114-5114
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5114-5114
    Abstract: Background: Early detection of recurrence and monitoring of MRD post-surgery is critical for clinical decision-making to tailor adjuvant therapy. In early-stage NSCLC, circulating tumor DNA (ctDNA) detection is especially challenging, requiring highly sensitive and specific assays. Therefore, we used a WGS approach (MRDetect) for ultra-sensitive ctDNA detection in NSCLC patients (pts) undergoing curative surgery. Methods: We conducted a pilot study to evaluate the MRDetect approach in serial plasma samples (including pre-surgery, post-surgery and follow-up [f/u] timepoints) from resected stage IB-IIIA NSCLC pts. Pts underwent routine surveillance by computed tomography scans. ctDNA was extracted from ~1mL plasma. MRDetect uses WGS by a tumor-informed approach (sequencing coverage 40x for tumor, 20x for plasma DNA) combined with AI-based error suppression models (trained and calibrated with a non-cancer cohort, n=17) to increase the signal to noise ratio for precise ctDNA detection, and improve the accuracy of readouts especially for low tumor burden scenarios. The assay reports the detection and quantification of ctDNA burden in blood with a prognostic value for risk of recurrence. The ability of the assay to predict recurrence from a single sample, taken at the clinical landmark point (median 1.6 mths post-surgery, range 0.1-6.5) was evaluated. Results: Overall, 52 NSCLC pts were enrolled (n=88 plasma samples) with median clinical f/u of 32.6 mths (range 3.1-98.6). There were 43 pts with post-surgery landmark samples, with median age 62 years, 70% were male, 79% were adenocarcinoma and 49% were EGFR mutated. 26% were stage IB and 37% each were stage II and III. There were 15/18 (sensitivity 83%) pts with confirmed radiological recurrence in which MRDetect was positive, including 6/7 (86%) EGFR mutated pts. The median RFS in MRDetect positive pts was 15.2 mths (range 3.7-33.4). Among 25 pts with no recurrence (median f/u 25.6 mths), MRDetect reported 4 pts to be MRD positive (specificity 84%). These results were consistent between EGFR mutated (sensitivity 86%, specificity 86%) and wildtype pts (sensitivity 82%, specificity 82%). For longitudinal samples (n=17 pts), negative ctDNA was associated with absence of recurrence in 14/15 pts (specificity 93%). At the AACR meeting, results from a planned larger validation study will be presented. Conclusion: Using a robust WGS implemented AI-based computational platform (MRDetect), we demonstrate high sensitivity and specificity detection of MRD in both EGFR mutated and wildtype NSCLC. With an increasing number of therapeutic options in the adjuvant setting for NSCLC, an ultra-sensitive MRD assay has the potential to facilitate personalized clinical decision-making for tailoring both the need and choice of adjuvant therapies. Citation Format: Aaron C. Tan, Stephanie P. Saw, Gillianne G. Lai, Kevin L. Chua, Angela Takano, Boon-Hean Ong, Tina P. Koh, Amit Jain, Wan Ling Tan, Quan Sing Ng, Ravindran Kanesvaran, Tanujaa Rajasekaran, Sunil Deochand, Dillon Maloney, Danielle Afterman, Tomer Lauterman, Noah Friedman, Imane Bourzgui, Nidhi Ramaraj, Zohar Donenhirsh, Ronel Veksler, Jonathan Rosenfeld, Ravi Kandasamy, Iman Tavassoly, Boris Oklander, Asaf Zviran, Wan-Teck Lim, Eng-Huat Tan, Anders J. Skanderup, Mei-Kim Ang, Daniel S. Tan. Ultra-sensitive detection of minimal residual disease (MRD) through whole genome sequencing (WGS) using an AI-based error suppression model in resected early-stage non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5114.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-5114
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    Lab validation of an ultrasensitive ctDNA pan-cancer MRD assay using whole-genome sequencing.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. e13582-e13582
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e13582-e13582
    Abstract: e13582 Background: Minimal residual disease (MRD) monitoring using liquid biopsy for solid tumors requires a highly sensitive and specific assay that can overcome the limitation of low abundance cfDNA in a standard blood draw. We developed a whole-genome sequencing (WGS)-based assay to detect the presence of circulating tumor DNA (ctDNA) in plasma. The C2i assay is a tumor-informed assay that uses personalized tumor signature, advanced noise models, and artificial intelligence (AI) modalities to interrogate plasma for the presence of ctDNA longitudinally. Methods: The C2i test was developed in accordance with CAP/CLIA and New York state validation principles. We used contrived samples to establish analytical validation of the assay performance, which was then validated with a large clinical cohort of early-stage patients across various cancer types. Briefly, aggregated tumor signatures derived from cancer cell lines were fragmented and spiked into a contrived healthy plasma pool; the mixed samples were used to assess the presence of tumor DNA signature down to tumor fractions of 10e-4. Positive samples are identified by tumor-derived variants detected above the noise levels. Noise modeling was established using a panel of normal (PON) approach. We assessed the analytical sensitivity, specificity, and accuracy using 348 contrived samples derived from five different cancer cell lines. Reproducibility and precision were assessed with multiple replicates, and statistical concordance was reported. This validation was complemented by a cohort of 200 patients and ̃1000 plasma samples across a variety of cancer types including, NSCLC, MIBC, CRC, GBM, Breast Cancer, and a mixture of other cancer types. Results: Cancer cell lines, representing the five most prevalent disease indications, used for determining analytical sensitivity are as follows: CRC HT-29, Breast SK-BR3, Bladder HT-1376, Lung HCI-H526, and Prostate LNCaP. The cell line DNA was enzymatically fragmented and size-selected to mimic ctDNA. This ctDNA was spiked into cfDNA extracted from healthy volunteers at various dilution levels, varying from 10e0 to 10e-4. The 95% probability of detecting ctDNA was established at 10e-4. The reproducibility of tumor signature between replicates was assessed to be greater than 90%. The assay was performed using both normal and maximum input amounts. These performance estimates were then validated on a cohort of plasma collected from early-stage (stage I-III) patients across various cancer types. Conclusions: C2i MRD test is an ultrasensitive pan-cancer MRD monitoring assay used in several clinical trials across the world. We present an extensive analytical and clinical validation of the assay supporting its high performance.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.e13582
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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    Abstract 1959: Sensitive detection of circulating tumor DNA by whole genome sequencing: Validation of MRDetect using serial blood samples from stage III colorectal cancer patients
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1959-1959
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1959-1959
    Abstract: Background: While detection of circulating tumor DNA (ctDNA) is associated with poor cancer prognosis, the clinical utility for guiding treatment decisions is unresolved. Patients with minimal residual disease (MRD) often have less than one genome equivalent of ctDNA per 10 mL blood. Consequently, it is stochastic whether a 10 mL sample contains ctDNA from a particular genomic locus. Consequently, the sensitivity of ctDNA detection methods targeting a limited number of tumor loci is heavily affected by sampling bias. To overcome this challenge, we developed MRDetect; a whole genome sequencing (WGS) approach, which detects ctDNA using the patient-specific cumulative signal from tens of thousands of mutations throughout the genome. Recently, we showed how MRDetect found ctDNA fractions down to 10-4. Here, we performed a validation study to confirm the prognostic impact of MRDetect. Aim: Validation of MRDetect for sensitive ctDNA detection to monitor residual disease in stage III colorectal cancer (CRC) patients treated with curative intent. Methods: From a large, uniform cohort of stage III CRC patients n = 146), we had plasma samples collected every third month (n = 938, median = 9 per patient) and a median follow-up of 34 months. For each patient, a genome-wide mutational signature was established by WGS of tumor and matched normal DNA. Enhanced by an AI-based error suppression model, this signature was used to detect ctDNA in 1-2 mL plasma samples using WGS (20x coverage). We used de-novo point mutation and copy number variation analysis to investigate cancer evolution after treatment. To evaluate the reproducibility of MRDetect, aliquot samples (n = 2x190 samples) from 5 recurrence and 10 non-recurrence patients were processed and sequenced at two independent laboratories. Outcome measures: ctDNA status, tumor fraction, false positive rate, Time To ctDNA Recurrence (TTcR), and Time To radiological Recurrence (TTrR). Results: Analysis of paired samples showed great reproducibility with high agreement between both ctDNA status calls (Cohens Kappa = 0.81) and the estimated tumor fractions (r2 = 0.99). MRDetect revealed post-operative ctDNA in all recurrence patients (5/5) with detected tumor fractions down to 2 x 10-4. Median TTcR was 0.9 month (range 0.5 - 7.3 months) while median TTrR was 12.8 months (range 11.3 - 31.1 months). The false positive rate was 1% (1/100), assessed in longitudinal samples from the 10 non-relapsing patients. Tumor evolution dynamics in plasma samples revealed novel amplification and deletions, which were absent in the primary tissue but confirmed in metachronous metastases. We will present results from the full cohort at AACR 2022. Conclusion: MRDetect detects ctDNA with high sensitivity and specificity and enables effective postoperative assessment of MRD, cancer evolution dynamics and early relapse detection. Citation Format: Amanda Frydendahl, Thomas Reinert, Jesper Nors, Sunil Deochand, Dillon Maloney, Noah Friedman, Tomer Lauterman, Danielle Afterman, Imane Bourzgui, Nidhi Ramaraj, Zohar Donenhirsh, Ronel Veksler, Ravi Kandasamy, Iman Tavassoly, Jonathan Rosenfeld, Anders Husted Andersen, Uffe S. Løve, Per V. Andersen, Ole Thorlacius-Ussing, Lene Hjerrild Iversen, Kåre Andersson Gotschalck, Boris Oklander, Asaf Zviran, Claus Lindbjerg Andersen. Sensitive detection of circulating tumor DNA by whole genome sequencing: Validation of MRDetect using serial blood samples from stage III colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1959.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1959
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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