Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy

Hong, Xin; Sullivan, Ryan J.; Kalinich, Mark; Kwan, Tanya T.; Giobbie‐Hurder, Anita; Pan, Shiwei; LiCausi, Joseph A.; Milner, John; Nieman, Linda T.; Wittner, Ben S.; Ho, Uyen; Chen, Tianqi; Kapur, Ravi; Lawrence, Donald P.; Flaherty, Keith T.; Sequist, Lecia V.; Ramaswamy, Sridhar; Miyamoto, David T.; Lawrence, Michael S.; Toner, Mehmet; Isselbacher, Kurt J.; Maheswaran, Shyamala; Haber, Daniel A.

doi:10.1073/pnas.1719264115

Cited by 112 publications

(114 citation statements)

References 37 publications

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“…The study provides preliminary data to support that PD‐L1 is evaluable on HNC and NSCLC CTCs, consistent with a number of recent studies . CTCs have been shown to have a higher PD‐L1 positivity compared to tumor tissue .…”

Section: Discussionsupporting

confidence: 88%

The prognostic significance of circulating tumor cells in head and neck and non‐small‐cell lung cancer

et al. 2018

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Tumor biopsy is the gold standard for the assessment of clinical biomarkers for treatment. However, tumors change dynamically in response to therapy, and there remains a need for a more representative biomarker that can be assayed over the course of treatment. Circulating tumor cells (CTCs) may provide clinically important and comprehensive tumoral information that is predictive of treatment response and outcome. Blood samples were processed for CTCs from 56 patients using the ClearCell FX system. Captured cells were phenotyped for CTC clusters and markers for immunotherapy (PD‐L1) CTC chromosomal architecture (ALK, EGFR). CTCs were isolated in 11/23 (47.8%) of head and neck cancer (HNC) patients and 17/33 (51.5%) of non‐small‐cell lung cancer (NSCLC) patients. CTCs were determined to be PD‐L1‐positive in 6/11 (54.4%) HNC and 11/17 (64.7%) NSCLC cases, respectively. 3D chromosomal DNA FISH for ALK and EGFR molecular targets showed better resolution than in 2D when imaging CTCs. HNC CTC‐positive patients had shorter progression‐free survival (PFS) (hazard ratio[HR]: 4.946; 95% confidence internal[CI]:1.571‐15.57; P = 0.0063), and PD‐L1‐positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011‐26.33; P = 0.0485). In the advanced stage NSCLC patient cohort, PFS was not found to be associated with CTCs prior to therapy ([HR]:2.246; 95% [CI]:0.9565‐5.273; P = 0.0632), nor the presence of PD‐L1 expression ([HR]:1.646; 95% [CI]:0.5128‐5.283; P = 0.4023). This study demonstrated that CTCs are predictive of poorer outcomes in HNC and provides distinct and separate utility for CTCs in HNC and NSCLC, which may be more representative of the disease burden and overall survival than the parameters used to measure them.

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Section: Discussionsupporting

confidence: 88%

The prognostic significance of circulating tumor cells in head and neck and non‐small‐cell lung cancer

et al. 2018

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“…This may be affected by the effectiveness of pembrolizumab to divert the natural disease progression regardless of tumor burden. Similarly, in a recent study by Hong et al , using a combination of a microfluidic device and 19 transcripts for detection of melanoma CTCs, no correlation was found between baseline CTC scores and survival or response to treatment. In addition, the authors noted that using serial monitoring of patients with melanoma treated with immune checkpoint inhibitors, rapid decline in CTC score preceded response by standard clinical assessment and was highly predictive of long‐term clinical outcome.…”

Section: Discussionmentioning

confidence: 85%

PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study

et al. 2019

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Background PD‐1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD‐L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD‐1 inhibitor pembrolizumab. Methods Blood samples were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6–12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD‐L1. Results CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD‐L1+ CTCs (14/25, 64%) had significantly longer progression‐free survival (PFS) compared with patients with PD‐L1− CTCs (26.6 months vs. 5.5 months; p = .018). The 12‐month PFS rates were 76% versus 22% in the PD‐L1+ versus PD‐L1− CTCs groups (p = .012), respectively. A multivariate linear regression analysis confirmed that PD‐L1+ CTC is an independent predictive biomarker of PFS (hazard ratio, 0.229; 95% confidence interval, 0.052–1.012; p = .026). Conclusion Our results reveal the potential of CTCs as a noninvasive real‐time biopsy to evaluate PD‐L1 expression in patients with melanoma. PD‐L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS. Implications for Practice The present data suggest that PD‐L1 expression on circulating tumor cells may predict response to pembrolizumab in advanced melanoma. This needs further validation in a larger trial and, if proven, might be a useful liquid biopsy tool that could be used to stratify patients into groups more likely to respond to immunotherapy, hence leading to health cost savings.

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“…Another study developed an assay based on eight CTC-derived transcripts in prostate cancer that was predictive of abiraterone response in the metastatic setting and of early dissemination in localized disease [122]. Along the same lines, RNA expression profiling of melanoma CTCs allowed the definition of a 19-gene RNA signature that, when tested in a prospective cohort of 49 melanoma patients, correlated with progression-free survival and overall survival during therapy with immune checkpoint inhibitors [123]. In myeloma, single-cell RNA-seq of plasma cells can be used to detect rare residual neoplastic cells after treatment [68].…”

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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Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy

Cited by 112 publications

References 37 publications

The prognostic significance of circulating tumor cells in head and neck and non‐small‐cell lung cancer

The prognostic significance of circulating tumor cells in head and neck and non‐small‐cell lung cancer

PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study

Tracking cancer progression: from circulating tumor cells to metastasis

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