Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse

Chemi, Francesca; Rothwell, Dominic G.; McGranahan, Nicholas; Gulati, Sakshi; Abbosh, Chris; Pearce, Simon P.; Zhou, Cong; Wilson, Gareth A.; Jamal‐Hanjani, Mariam; Birkbak, Nicolai J.; Pierce, Jackie; Kim, Chang Sik; Ferdous, Saba; Burt, Deborah J.; Slane-Tan, Daniel; Gomes, Fábio; Moore, David A.; Shah, Rajesh; Bakir, Maise Al; Hiley, Crispin; Veeriah, Selvaraju; Summers, Yvonne; Crosbie, Philip; Ward, Sophia; Mesquita, B.; Dynowski, Marek; Biswas, Dhruva; Tugwood, Jonathan; Blackhall, Fiona; Miller, Crispin; Hackshaw, Allan; Brady, Ged; Swanton, Charles; Dive, Caroline

doi:10.1038/s41591-019-0593-1

Cited by 162 publications

(144 citation statements)

References 33 publications

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“…19,35 These alterations in osteoblastic gene regulators, including ALPL, RUNX2, SPP1, CDH11, and TNFSF11, were present in CTCs and not in paired cfDNA. 46,47 Our collective data suggest that CTCs harbor critical genomic information that may be missed by cfDNA analysis alone. Furthermore, Cohen's kappa analysis of CTCs and cfDNA showed that AR has a discordance in the opposite direction, with greater detection in cfDNA than CTC DNA.…”

Section: Discussionmentioning

confidence: 82%

“…Additional larger studies of paired samples prospectively collected in clinically annotated datasets of patients with cancer in different disease states and during different treatments are needed to define whether CTCs, cfDNA, or a combined approach has greater clinical utility. 46,47 Our collective data suggest that CTCs harbor critical genomic information that may be missed by cfDNA analysis alone. Yet, reliance on CTC genomic data alone has limitations because many patients with metastatic prostate cancer lack detectable CTCs, particularly in earlier disease settings, limiting the clinical utility of this approach.…”

Section: Discussionmentioning

confidence: 82%

See 1 more Smart Citation

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

Gupta

Hovelson

Kemeny

et al. 2019

Genes Chromosomes & Cancer

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Circulating tumor cell (CTC) and cell-free (cf) DNA-based genomic alterations are increasingly being used for clinical decision-making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and low-pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radium-223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic AR-V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTC-specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNA-discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in AR-V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 82%

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

Gupta

Hovelson

Kemeny

et al. 2019

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

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“…Recently, Chemi et al evaluated the prognostic role of CellSearch-detected pulmonary venous (PV) CTCs, at the time of surgery, in 100 early-stage NSCLC patients, enrolled into the Tracking Non-Small Cell Lung Cancer Evolution through Therapy (TRACERx) trial. Although further studies are needed to confirm the clinical utility of PV-CTCs, the authors demonstrated that patients with detectable CTCs are more likely to experience disease recurrence [15].…”

Section: Circulating Tumor Cellsmentioning

confidence: 98%

Liquid Biopsy in Non-Small Cell Lung Cancer: Highlights and Challenges

Rijavec

Coco

Genova

et al. 2019

Cancers

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Non-small cell lung cancer is one leading cause of death worldwide, and patients would greatly benefit from an early diagnosis. Since targeted and immunotherapies have emerged as novel approaches for more tailored treatments, repeated assessments of the tumor biology have become pivotal to drive clinical decisions. Currently, tumor tissue biopsy is the gold standard to investigate potentially actionable biomarkers, but this procedure is invasive and may prove inadequate to represent the whole malignancy. In this regard, liquid biopsy represents a minimally invasive and more comprehensive option for early detection and investigation of this tumor. Today, cell-free DNA is the only approved circulating marker to select patients for a targeted therapy. Conversely, the other tumor-derived markers (i.e., circulating tumor cells, miRNAs, exosomes, and tumor educated platelets) are still at a pre-clinical phase, although they show promising results for their application in screening programs or as prognostic/predictive biomarkers. The main challenges for their clinical translation are the lack of reliable cutoffs and, especially for miRNAs, the great variability among the studies. Moreover, no established tool has been approved for circulating tumor cells and exosome isolation. Finally, large prospective clinical trials are mandatory to provide evidence of their clinical utility.

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“…Another proof-of-concept example is the large number of studies reporting the potential clinical utility of androgen receptor splice variant 7 (AR-V7) detection in CTCs as a marker for treatment selection in patients with castration-resistant prostate cancer (CRPC) [110][111][112][113][114][115][116][117][118][119]. Along these lines, in a recent case report within the TRACERx study in non-small cell lung cancer (NSCLC), exome sequencing of pulmonary venous CTCs (PV-CTC) collected at surgery showed that CTCs at surgery are more similar to subsequent metastatic disease than to the primary tumor, highlighting the potential of PV-CTCs as early predictors of NSCLC recurrence after surgery [120].…”

Section: Clinical Value Of Ctcsmentioning

confidence: 99%

Tracking cancer progression: from circulating tumor cells to metastasis

2020

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The analysis of circulating tumor cells (CTCs) is an outstanding tool to provide insights into the biology of metastatic cancers, to monitor disease progression and with potential for use in liquid biopsy-based personalized cancer treatment. These goals are ambitious, yet recent studies are already allowing a sharper understanding of the strengths, challenges, and opportunities provided by liquid biopsy approaches. For instance, through single-cellresolution genomics and transcriptomics, it is becoming increasingly clear that CTCs are heterogeneous at multiple levels and that only a fraction of them is capable of initiating metastasis. It also appears that CTCs adopt multiple ways to enhance their metastatic potential, including homotypic clustering and heterotypic interactions with immune and stromal cells. On the clinical side, both CTC enumeration and molecular analysis may provide new means to monitor cancer progression and to take individualized treatment decisions, but their use for early cancer detection appears to be challenging compared to that of other tumor derivatives such as circulating tumor DNA. In this review, we summarize current data on CTC biology and CTC-based clinical applications that are likely to impact our understanding of the metastatic process and to influence the clinical management of patients with metastatic cancer, including new prospects that may favor the implementation of precision medicine. Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse

Cited by 162 publications

References 33 publications

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

Liquid Biopsy in Non-Small Cell Lung Cancer: Highlights and Challenges

Tracking cancer progression: from circulating tumor cells to metastasis

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