Tumor Cell–Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy

Weiss, Glen J.; Beck, Julia; Braun, Donald P.; Bornemann-Kolatzki, Kristen; Barilla, Heather; Cubello, Rhiannon; Quan, Walter; Sangal, Ashish; Khemka, Vivek; Waypa, Jordan; Mitchell, William M.; Urnovitz, Howard B.; Schütz, Ekkehard

doi:10.1158/1078-0432.ccr-17-0231

Cited by 126 publications

(105 citation statements)

References 31 publications

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“…Whilst some lung cancer studies have recently investigated LBs, currently none have truly examined their use for histological subtyping [25,[30][31][32][33][34]. To evaluate the adopted modeling approach, we therefore compared ours to other published tissue-based alternatives.…”

Section: Discussionmentioning

confidence: 99%

Shallow whole-genome sequencing of plasma cell-free DNA accurately differentiates small from non-small cell lung carcinoma

et al. 2020

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Background: Accurate lung cancer classification is crucial to guide therapeutic decisions. However, histological subtyping by pathologists requires tumor tissue-a necessity that is often intrinsically associated with procedural difficulties. The analysis of circulating tumor DNA present in minimal-invasive blood samples, referred to as liquid biopsies, could therefore emerge as an attractive alternative. Methods: Concerning adenocarcinoma, squamous cell carcinoma, and small cell carcinoma, our proof of concept study investigates the potential of liquid biopsy-derived copy number alterations, derived from single-end shallow whole-genome sequencing (coverage 0.1-0.5×), across 51 advanced stage lung cancer patients. Results: Genomic abnormality testing reveals anomalies in 86.3% of the liquid biopsies (16/20 for adenocarcinoma, 13/16 for squamous cell, and 15/15 for small cell carcinoma). We demonstrate that copy number profiles from formalin-fixed paraffin-embedded tumor biopsies are well represented by their liquid equivalent. This is especially valid within the small cell carcinoma group, where paired profiles have an average Pearson correlation of 0.86 (95% CI 0.79-0.93). A predictive model trained with public data, derived from 843 tissue biopsies, shows that liquid biopsies exhibit multiple deviations that reflect histological classification. Most notably, distinguishing small from non-small cell lung cancer is characterized by an area under the curve of 0.98 during receiver operating characteristic analysis. Additionally, we investigated how deeper paired-end sequencing, which will eventually become feasible for routine diagnosis, empowers tumor read enrichment by insert size filtering: for all of the 29 resequenced liquid biopsies, the tumor fraction could be increased in silico, thereby "rescuing" three out of five cases with previously undetectable alterations.(Continued on next page)

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Section: Discussionmentioning

confidence: 99%

Shallow whole-genome sequencing of plasma cell-free DNA accurately differentiates small from non-small cell lung carcinoma

et al. 2020

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“…Interestingly, Weiss et al recently reported that chromosomal instability as reflected by copy number variation in cell-free DNA correlated with response to immunotherapy, consistent with our observations with number of alterations. (25). Future studies should also compare cfDNA and tissue NGS mutational burden, preferably with biopsies and blood tests obtained on the same day.…”

Section: Discussionmentioning

confidence: 99%

Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor–Based Immunotherapy

Khagi

Goodman

Daniels

et al. 2017

Clinical Cancer Research

183

135

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Purpose Tumor mutational burden detected by tissue next generation sequencing (NGS) correlates with checkpoint inhibitor response. However, tissue biopsy may be costly and invasive. We sought to investigate the association between hyper-mutated blood-derived circulating tumor DNA (ctDNA) and checkpoint inhibitor response. Experimental Design We assessed 69 patients with diverse malignancies who received checkpoint inhibitor-based immunotherapy and blood-derived circulating tumor DNA (ctDNA) NGS testing (54–70 genes). Rates of stable disease (SD) ≥6 months, partial and complete response (PR, CR), as well as progression-free survival (PFS) and overall survival (OS) were assessed based on total and VUS alterations. Results Statistically significant improvement in PFS was associated with high versus low alteration number in variants of unknown significance (VUS, >3 alterations versus VUS ≤3 alterations), SD≥6 months/PR/CR 45% versus 15%, respectively; p = 0.014. Similar results were seen with high versus low total alteration number (characterized plus VUS, ≥6 versus <6). Statistically significant OS improvement was also associated with high VUS alteration status. Two-month landmark analysis showed that responders versus non-responders with VUS>3 had a median PFS of 23 versus 2.3 months (p = 0.0004). Conclusion Given the association of alteration number on liquid biopsy and checkpoint inhibitor-based immunotherapy outcomes, further investigation of hyper-mutated ctDNA as a predictive biomarker is warranted.

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“…CNAs are a major contributing factor that modulate tumorigenesis and drug responses . Two PDX models of non‐small cell lung carcinoma (NSCLC) showed higher copy number signals compared to parental tumors .…”

Section: Differences In Molecular Characteristics Among Pdx Modelsmentioning

confidence: 99%

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

Shi

Jia

et al. 2019

Intl Journal of Cancer

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Patient‐derived xenograft (PDX) models are widely used as preclinical cancer models and are considered better than cell culture models in recapitulating the histological features, molecular characteristics and intratumoral heterogeneity (ITH) of human tumors. While the PDX model is commonly accepted for use in drug discovery and other translational studies, a growing body of evidence has suggested its limitations. Recently, the fidelity of cancer cells within a PDX has been questioned, which may impede the future application of these models. In this review, we will focus the variable phenotypes of xenograft tumors and the genomic instability and molecular inconsistency of PDX tumors after serial transplantation. Next, we will discuss the underlying mechanism of ITH and its clinical relevance. Stochastic selection bias in the sampling process and/or deterministic clonal dynamics due to murine selective pressure may have detrimental effects on the results of personalized medicine and drug screening studies. In addition, we aim to identify a possible solution for the issue of fidelity in current PDX models and to discuss emerging next‐generation preclinical models.

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Tumor Cell–Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy

Cited by 126 publications

References 31 publications

Shallow whole-genome sequencing of plasma cell-free DNA accurately differentiates small from non-small cell lung carcinoma

Shallow whole-genome sequencing of plasma cell-free DNA accurately differentiates small from non-small cell lung carcinoma

Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor–Based Immunotherapy

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

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