Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy

Adams, Daniel L.; Adams, Diane K.; He, Jianzhong; Kalhor, Neda; Zhang, Ming; Xu, Ting; Gao, Hui; Reuben, James M.; Qiao, Yawei; Komaki, Ritsuko; Liao, Zhongxing; Edelman, Martin J.; Tang, Cha Mei; Lin, Steven H.

doi:10.1158/1078-0432.ccr-17-0802

Cited by 90 publications

(94 citation statements)

References 51 publications

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“…The authors interpreted their data such that the DSBs labeled by γH2AX in these primary tumors represent sites of failed repair attempts, causing persistence of the radiation-induced DSBs and promoting rearrangements. Adams et al further noticed that another early DSB repair component, RAD50, can be detected on CTCs from primary lung cancer patients, but only once they undergo radiotherapy [32]. Importantly, our patients were MBC and not primary cancer patients treated by chemo-and not radiotherapy.…”

Section: Discussionmentioning

confidence: 55%

53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients

Schochter

Werner

Köstler

et al. 2020

Cancers

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Evidence suggests that the DNA end-binding protein p53-binding protein 1 (53BP1) is down-regulated in subsets of breast cancer. Circulating tumor cells (CTCs) provide accessible "biopsy material" to track cell traits and functions and their alterations during treatment. Here, we prospectively monitored the 53BP1 status in CTCs from 67 metastatic breast cancer (MBC) patients with HER2-CTCs and known hormone receptor (HR) status of the primary tumor and/or metastases before, during, and at the end of chemotherapeutic treatment with Eribulin. Nuclear 53BP1 staining and genomic integrity were evaluated by immunocytochemical and whole-genome-amplification-based polymerase chain reaction (PCR) analysis, respectively. Comparative analysis of CTCs from patients with triple-negative and HR+ tumors revealed elevated 53BP1 levels in CTCs from patients with HR+ metastases, particularly following chemotherapeutic treatment. Differences in nuclear 53BP1 signals did not correlate with genomic integrity in CTCs at baseline or with nuclear γH2AX signals in MBC cell lines, indicating that 53BP1 detected features beyond DNA damage. Kaplan-Meier analysis revealed an increasing association between nuclear 53BP1-positivity and progression-free survival (PFS) during chemotherapy until the final visit. Our data suggest that 53BP1 detection in CTCs could be a useful marker to capture dynamic changes of chemotherapeutic responsiveness in triple-negative and HR+ MBC.Cancers 2020, 12, 930 2 of 18 13.3 months after diagnosis of metastatic sites, TNBC has a particularly poor prognosis. Often patients develop a resistance to first-line chemotherapy very rapidly, resulting in a median duration of first-line palliative chemotherapy of 11.9 weeks [1].Triple-negative tumors are characterized by the lack of HR and HER2 expression, but aside from this common feature this subgroup includes very heterogeneous tumors. A mutation in BRCA1 or 2 is found in up to 20% of triple-negative metastatic patients [2]. The proteins encoded by BRCA genes are critically involved in DNA double-strand break (DSB) repair, more specifically, in the error-free pathway of homologous recombination repair (HRR) [3]. In TNBC, a high prevalence of gene mutations as well as epigenetic changes result in BRCAness, compromising safe DNA repair through HRR [2,4,5]. The DNA damage response factor 53BP1 is crucial in protecting DNA ends in BRCA1-defective cells from resection and entry into error-prone repair pathways [6][7][8]. It has been demonstrated that 53BP1 expression in breast cancer is associated with poor prognosis, particularly in TNBC frequently showing BRCA1 dysfunction [7,9].Due to the lack of predictive targets, chemotherapy was the only treatment option available for a long time. This results in an urgent clinical need for new therapies. During the last years, new drugs such as the Poly(ADP-ribose) polymerase (PARP)-inhibitors targeting HRR-defective tumors were studied in several clinical trials. Two different phase III trials (OlympiaAD and EMBRACA) showed an impro...

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Section: Discussionmentioning

confidence: 55%

53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients

Schochter

Werner

Köstler

et al. 2020

Cancers

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“…Clinically, one important CStC subtype is the cancer‐associated macrophage‐like cell (CAML) . CAMLs are more prevalent than CTCs in many solid tumor subtypes, and unlike CTCs, CAMLs are found in all stages of solid tumors . Combined, our data suggest that CAMLs and CTCs isolated from the same patient blood sample provide more robust clinical utility than CTCs alone.…”

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confidence: 77%

“…A number of methods to isolate rare cells from the billions of hematopoietic cells in whole blood sample have been investigated. Of these methods, microfiltration is one of the effective methods to isolate CTCs and circulating tumor‐associated cells from multiple types of cancers . Filtration by size is a suitable method to consistently capture multiple types of tumor‐associated cells in the blood (i.e., CTCs, EMTs, and CStCs).…”

Section: Methodsmentioning

confidence: 99%

Blood‐based biopsies—clinical utility beyond circulating tumor cells

Tang

Zhu

et al. 2018

Cytometry Pt A

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Circulating tumor cells (CTCs), epithelial–mesenchymal transition (EMT) cells, as well as a number of circulating cancer stromal cells (CStCs) are known to shed into the blood of cancer patients. Individually, and together, these cells provide biological and clinical information about the cancers. Filtration is a method used to isolate all of these cells, while eliminating red and white blood cells from whole peripheral blood. We have previously shown that accurate identification of these cell types is paramount to proper clinical assessment by describing the overlapping phenotypes of CTCs to one such CStC, the cancer‐associated macrophage‐like cell (CAML). We report that CAMLs possess a number of parallel applications to CTCs but have a broader range of clinical utility, including cancer screening, companion diagnostics, diagnosis, prognosis, monitoring of treatment response, and detection of recurrence. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.

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“…We believe that CTCs can be used as an alternative material, instead of tumor tissues, for detecting PD‐L1 expression. Preliminary data have been shown by several groups …”

Section: Discussionmentioning

confidence: 83%

“…Preliminary data have been shown by several groups. [46][47][48] There are some challenges to be addressed with the On-chip Sort System. To capture the most CTCs, the sorting gate was expanded to the maximum.…”

Section: Discussionmentioning

confidence: 99%

Isolation and molecular analysis of circulating tumor cells from lung cancer patients using a microfluidic chip type cell sorter

Watanabe

Kenmotsu

et al. 2018

Cancer Science

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Circulating tumor cells (CTCs) are a tumor‐derived material utilized for liquid‐based biopsy; however, capturing rare CTCs for further molecular analysis remains technically challenging, especially in non‐small‐cell lung cancer. Here, we report the results of a clinical evaluation of On‐chip Sort, a disposable microfluidic chip‐based cell sorter, for capture and molecular analysis of CTCs from patients with lung adenocarcinoma. Peripheral blood was collected from 30 metastatic lung adenocarcinoma patients to enumerate CTCs using both On‐chip Sort and CellSearch in a blind manner. Captured cells by On‐chip Sort were subjected to further molecular analysis. Peripheral blood samples were also used for detection of EGFR mutations in plasma using droplet digital PCR. Significantly more CTCs were detected by On‐chip Sort (22/30; median 5; range, 0–18 cells/5 mL blood) than by CellSearch (9/30; median, 0; range, 0–12 cells/7.5 mL) (P < 0.01). Thirteen of 30 patients who had a negative CTC count by CellSearch had a positive CTC count by On‐chip Sort. EGFR mutations in CTCs captured by On‐chip Sort were observed in 40.0% (8/20) of patients with EGFR‐mutated primary tumor. EGFR mutations were often observed in 53.3% (8/15) of patients detected in plasma DNA. Expressions of EGFR and vimentin protein on CTCs were also successfully assessed using On‐chip Sort. These results suggest that On‐chip Sort is an efficient method to detect and capture rare CTCs from patients with lung adenocarcinoma that are undetectable with CellSearch. Mutation detection using isolated CTCs remains to be further tackled (UMIN000012488).

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Sequential Tracking of PD-L1 Expression and RAD50 Induction in Circulating Tumor and Stromal Cells of Lung Cancer Patients Undergoing Radiotherapy

Cited by 90 publications

References 51 publications

53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients

53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients

Blood‐based biopsies—clinical utility beyond circulating tumor cells

Isolation and molecular analysis of circulating tumor cells from lung cancer patients using a microfluidic chip type cell sorter

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