Circulating Tumor Cells Status Research Articles

The role of mir96 in predicting CTC status and prognostic evaluation in gastric cancer patients.

In this study, 20 patients clinically diagnosed with advanced gastric cancer were selected as subjects. Circulating tumor cells (CTCs) in the peripheral blood of gastric cancer patients were detected and counted by collecting peripheral blood samples at Ningbo No. 2 Hospital and using the Cell Rich TM system combined with a negative enrichment strategy. In addition, routine pathological examination and immunohistochemical staining were performed on surgical specimens, including HER2, EBER, E-cadherin, and vimentin indicators. These indicators were correlated and analyzed with CTC counts and routine clinical tests. At the same time, miRNA groups were performed to explore the miRNAs with or without correlation with CTC and to try to construct a predictive model for CTC status. Tumor tissue from patients whose CTC counts did not match the results of the miRNA prediction model was subjected to second-generation gene sequencing to analyze indicators such as tumor heterogeneity and immune microenvironment. The results of the study showed that CTCs were detected in the peripheral blood of 50% (10/20) of gastric cancer patients using the Cell Rich TM system, serum fibrinogen was negatively correlated with CTC counts, whereas TNM staging elements, HER2 receptor and p53 were not correlated with CTC counts. miRNA assays showed that the expression levels of miR218, miR1207, miR96, miR409, miR149, miR148a, miR155, miR370 and miR223 were significantly different between the two groups of CTC≥2 and CTC<2. Among them, miR-96 showed good efficacy as an indicator for predicting CTC status and assisting in determining the prognosis of gastric cancer. In conclusion, the present study demonstrated that the Cell Rich TM system combined with the negative enrichment strategy can effectively detect CTCs in the peripheral blood of gastric cancer patients and that the expression of miR-96 can be used as an effective indicator to predict CTC status and assist in determining the prognosis of gastric cancer. These findings have important implications for the diagnosis and treatment of gastric cancer and provide new clues for the further study of the tumor immune microenvironment and tumor heterogeneity.

Preliminary result of anatomical hepatectomy on recurrence based on preoperative circulating tumor cell status in hepatocellular carcinoma-update to august 2023

Preliminary result of anatomical hepatectomy on recurrence based on preoperative circulating tumor cell status in hepatocellular carcinoma-update to august 2023

Prognostic Role of Circulating Tumor Cells in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel: A Prospective Biomarker Study.

Circulating tumor cells (CTCs) appear to be a promising tool for predicting the clinical outcome and monitoring the response to treatment in patients with solid tumors. The current study assessed the clinical relevance of monitoring CTCs in patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel. Patients with histologically confirmed mCRPC who were previously treated with a docetaxel-containing regimen and experienced disease progression were enrolled in this multicenter prospective study. CTC counts were enumerated using the CellSearch system at baseline (before cabazitaxel initiation), after one cabazitaxel cycle (post 1st cycle) and at disease progression (PD). Patients were stratified into predetermined CTC-positive and CTC-negative groups. The phenotypic characterization was performed using double immunofluorescence staining with anti-CKs and anti-Ki67, anti-M30 or anti-vimentin antibodies. The median PFS and OS were 4.0 (range, 1.0-17.9) and 14.5 (range, 1.2-33.9) months, respectively. At baseline, 48 out of 57 (84.2%) patients had ≥1 CTCs/7.5 mL of peripheral blood (PB) and 37 (64.9%) had ≥5 CTCs/7.5 mL of PB. After one treatment cycle, 30 (75%) out of the 40 patients with available measurements had ≥1 detectable CTC/7.5 mL of PB and 24 (60%) ≥ 5CTCs/7.5 mL of PB; 12.5% of the patients with detectable CTCs at the baseline sample had no detectable CTCs after one treatment cycle. The detection of ≥5CTCs/7.5 mL of PB at baseline and post-cycle 1 was associated with shorter PFS and OS (p = 0.002), whereas a positive CTC status post-cycle 1 strongly correlated with poorer OS irrespective of the CTC cut-off used. Multivariate analysis revealed that the detection of non-apoptotic (CK+/M30-) CTCs at baseline is an independent predictor of shorter OS (p = 0.005). In patients with mCRPC treated with cabazitaxel, CTC counts both at baseline and after the first cycle retain their prognostic significance, implying that liquid biopsy monitoring might serve as a valuable tool for predicting treatment efficacy and survival outcomes.

Nomograms for postsurgical extrahepatic recurrence prediction of hepatocellular carcinoma based on presurgical circulating tumor cell status and clinicopathological factors.

Extrahepatic recurrence (EHR) is one of the major reasons for the poor prognosis of hepatocellular carcinoma (HCC). The present study aimed to develop and assess the performance of predictive models by using a combination of presurgical circulating tumor cell (CTCs) data and clinicopathological features to screen patients at high risk of EHR to achieve precise decision-making. A total of 227 patients with recurrent HCC and preoperative CTC data from January 2014 to August 2019 were enrolled. All patients were randomly assigned to one of two cohorts: development or validation. Two preoperative and postoperative nomogram models for EHR prediction were developed and multi-dimensionally validated. Patients with EHR had generally lower recurrence-free survival (p < 0.001), and overall survival (p < 0.001), and significantly higher CTC counts (epithelial CTCs, epithelial/mesenchymal hybrid CTCs, and mesenchymal CTCs count, all p < 0.05) than those without EHR. Univariate and multivariate analyses revealed that EHR was associated with four risk factors in the development cohort: total CTC count (p = 0.014), tumor size (p = 0.028), node number (p = 0.045), and microvascular invasion (p = 0.035). These factors were incorporated into two nomogram models (preoperative and postoperative), which reliably predicted EHR through multidimensional verification (e.g., calibration plot, receiver operating characteristic analysis, decision curve analysis, and clinical impact curve analysis) in the development and validation cohorts, respectively. With threshold of scores of 100.3 and 176.8 before and after surgery respectively, both nomograms were able to stratify patients into two distinct prognostic subgroups (all p < 0.05). The present study proposed two nomogram models integrating presurgical CTC counts and clinicopathological risks and showed relatively good predictive performance of EHR, which may be beneficial to the clinical practice of HCC recurrence. Further multicenter studies are needed to assess its general applicability.

Bone scan index (BSI) scoring by using bone scintigraphy and circulating tumor cells (CTCs): predictive factors for enzalutamide effectiveness in patients with castration-resistant prostate cancer and bone metastases

Reports of Bone Scan Index (BSI) calculations as imaging biomarkers to predict survival in patients with metastatic castration-resistant prostate cancer (mCRPC) have been mainly from retrospective studies. To evaluate the effectiveness of enzalutamide (ENZ) in Japanese patients with mCRPC and bone metastases using BSI (bone scintigraphy) and circulating tumor cell (CTC) analysis. Prospective, single-arm study at Juntendo University affiliated hospitals, Japan. Patients were administered 160 mg ENZ daily, with 3 monthly assessments: BSI, prostate specific antigen (PSA), CTC and androgen receptor splicing variant-7 (AR-V7) status. Primary endpoint: BSI-decreasing rate after ENZ treatment. Secondary endpoints: PSA-decreasing rate and progression free survival (PFS). Statistical analyses included the Wilcoxon t-test, Cox proportional hazard regression analysis, and log-rank test. Median observation period: 17.9 months, and median PFS: 13.8 (2.0–43.9) months (n = 90 patients). A decrease in BSI compared to baseline as best BSI change on ENZ treatment was evident in 69% patients at the end of the observation period (29% patients showed a complete response, BSI 0.00). At 3 months 67% patients showed a ≥ 50% PSA reduction, and 70% after ENZ treatment. PSA decline (3 months) significantly associated with a prolonged median PFS: 18.0 (estimated) versus 6.4 months (HR 2.977 [95% CI 1.53–5.78], p = 0.001). Best BSI decline response significantly associated with a prolonged PFS: 18.1(estimated) versus 7.8 months (HR 2.045 [95% CI: 1.07–3.90], p = 0.029). CTC negative status (n = 20) significantly associated with a prolonged PFS: 13.4 [estimated] vs 8.6 months (HR 2.366, 95% CI 0.97–5.71, p = 0.041). CTC positive/AR-V7 positive status significantly associated with a shorter PFS: 5.9 months (HR 8.56, 95% CI 2.40–30.43, p = 0.0087). -reduction (3 months) and BSI-reduction (on ENZ treatment) were significant response biomarkers, and a negative CTC status was a predictive factor for ENZ efficacy in patients with mCRPC.

Association Between Obesity and Circulating Tumor Cells in Early Breast Cancer Patients

BackgroundObesity and the presence of circulating tumor cells (CTCs) before and/or after chemotherapy are associated with poor outcome in breast cancer (BC) patients. The activation of oncogenic pathways in fatty tissue leads to cell proliferation, suggesting a possible link between obesity and CTCs. Materials and MethodsIn the phase III SUCCESS A trial, 3754 patients with early BC were randomized to 3 cycles of fluorouracil, epirubicin and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine. Data of 1088 patients with CTC assessments (CellSearch-System; Menarini Silicon Biosystems, Italy) and body mass index (BMI) measurements both before and after chemotherapy were available. Patients were classified according to the WHO's international definitions as underweight, normal weight, overweight, or obese, and according to their weight-change during chemotherapy into a weight-loss group (> 5% decrease), stable-weight group (≤ 5% weight-change) or weight-gain group (>5% increase). Associations between CTC positivity and, BMI or weight-change group were analyzed using frequency-table methods. ResultsAt study entry, 47.4% patients were underweight or normal weight, 33.6% were overweight and 18.9% were obese. Before and after chemotherapy, CTCs were detected in 20.1% and 22.6% of patients, respectively. There was no association between CTC positivity and BMI before (P = 0.104) or after (P = 0.051) chemotherapy. Furthermore, there was no association between weight-change group and CTC status before/after chemotherapy (P = 0.332). ConclusionsAccording to our analysis, the risk factors obesity and prevalence of CTCs are not associated and may represent independent prognostic factors.

PD36-02 A COMPOSITE BIOMARKER APPROACH TO SPARE NEOADJUVANT CHEMOTHERAPY IN SELECT MUSCLE-INVASIVE BLADDER CANCER PATIENTS

You have accessJournal of UrologyCME1 Apr 2023PD36-02 A COMPOSITE BIOMARKER APPROACH TO SPARE NEOADJUVANT CHEMOTHERAPY IN SELECT MUSCLE-INVASIVE BLADDER CANCER PATIENTS Joep De Jong, A. Gordon Robertson, Nick Beije, John Martens, Ellen Zwarthoff, Arno Van Leenders, Ewan Gibb, and Joost Boormans Joep De JongJoep De Jong More articles by this author , A. Gordon RobertsonA. Gordon Robertson More articles by this author , Nick BeijeNick Beije More articles by this author , John MartensJohn Martens More articles by this author , Ellen ZwarthoffEllen Zwarthoff More articles by this author , Arno Van LeendersArno Van Leenders More articles by this author , Ewan GibbEwan Gibb More articles by this author , and Joost BoormansJoost Boormans More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003334.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Clinical guidelines recommend neoadjuvant chemotherapy (NAC) for the treatment of muscle-invasive bladder cancer (MIBC). However, NAC prior to radical cystectomy (RC) is associated with treatment-related toxicity and confers a modest survival benefit. Here, we aimed to identify MIBC patients who may avoid NAC by combining circulating tumor cell status and molecular subtypes in a composite biomarker approach. METHODS: TURBT tissue specimen were collected from clinical stage T2-T4aN0-N1M0 MIBC cases that were included within the CirGuidance study (NL3954), a prospective trial that analyzed circulating tumor cell (CTC) status in a patient’s blood sample using the CELLSEARCH system. For the present study, transcriptome-wide expression profiling was performed on 234 TURBT samples using an array-based approach. Molecular subtypes, long non-coding RNA (lncRNA) based FGFR3+ status and gene signatures were determined as described previously (de Jong et al., Genome Med. 2019). The primary endpoint of this study was cancer-specific mortality (CSM), calculated as the date of study inclusion till date of bladder cancer related death. Median follow-up was 28.8 (IQR: 16.6-40.2) months. RESULTS: Of 234 patients, 21 (9%) were treated with NAC and RC, while 213 (91%) received RC alone. A CTC-negative status was observed in 172 (81%) of RC-only cases. Molecular subtyping identified 28 luminal FGFR3+ cases with high FGFR3, SHH and p53 pathway activity, and lower EMT hallmark scores. Adjusting for clinical risk factors, both CTC and FGFR3+ status were significant predictors for cancer specific mortality on MVA (p<0.05). Of interest, the subgroup of FGFR3+ cases that were CTC-negative (N=26) showed most favorable outcomes with only one CSM event after a median of 33.4 (IQR: 24.8-44.5) months of follow-up. CONCLUSIONS: Using a composite biomarker approach of blood-based CTC status and molecular subtyping, we identified a biologically distinct subgroup of MIBC with favorable prognosis after RC-only, validating the performance of a previously developed lncRNA based FGFR3+ classifier. Clinical trials which withhold NAC from CTC-negative, FGFR3+ MIBC patients are warranted. Source of Funding: Gene expression profiles were generated using the Decipher Bladder assay © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e980 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joep De Jong More articles by this author A. Gordon Robertson More articles by this author Nick Beije More articles by this author John Martens More articles by this author Ellen Zwarthoff More articles by this author Arno Van Leenders More articles by this author Ewan Gibb More articles by this author Joost Boormans More articles by this author Expand All Advertisement PDF downloadLoading ...

MicroRNA expression profile in isolated circulating tumor cells in colorectal cancer

Introduction. Colorectal cancer is a frequently diagnosed disease being in the third place among oncological diseases both in incidence and mortality. Currently, researchers focus on development of more accessible and reliable biomarkers of colorectal cancer to overcome the problems in diagnosis and progression prognosis of this pathology.Aim. To investigate characteristics of microRNA expression in circulating tumor cells (CTC) of patients with colorectal cancer. Materials and methods. The study included blood samples from 299 patients with colon cancer, stages II (T3–4N0M0), III (T1–4N1–2M0) and IV (T1–4N0–2M1). Circulating tumor cells were identified using EpCAM marker detection system. Relative expression of hsa-let-7i-5p, hsa-miR-126-5p, hsa-miR-143-3p, hsa-miR-21-5p, hsa-miR-25-3p, hsa-miR-26a-5p, hsa-miR-92a-3p micro RNA in CTC was measured using polymerase chain reaction.Results. Positive CTC status was observed in 188 (62.9 %) of 299 patients, negative in 111 (37.1 %). In the patient group with pT1–2 tumors, the majority of patients did not have CTC (53.3 %). In other patients with pT1–2 disease, the number of CTC was 1.2 and 4.4 times lower than in patients with pT3 and pT4 disease, respectively. In pT4, 1–3 CTC were found 2.7 and 1.7 times more frequently, 3 CTC 1.4 times more frequently than in pT1–2 and pT3, respectively (p ≤0.05). Presence of metastatic lesions increases the probability of CTC detection by the factor of 2.1: in metastases, &gt;3 CTC were observed 60.1 times more frequently than in M0 (p ≤0.05). Expression of hsa-miR-143-3p and hsa-miR-26a-5p microRNA in CTC of patients with stage III colorectal cancer was respectively 2.5 and 5 times lower than in patients with stage II disease (p &lt;0.05) and expression of hsa-miR-21-5p and hsa-miR-92a-3p microRNA was respectively 3.2 and 3 times higher (p &lt;0.05). In CTC of patients with stage IV colorectal cancer, the relative level of expression of hsa-miR-143-3p and hsa-miR-26a-5p was respectively 4.6 and 5.3 times lower (p &lt;0.05) compared to the level of expression in stage II disease, and hsa-miR-126-5p, hsa-miR-21-5p, hsa-miR-25-3p and hsa-miR-92a-3p expression levels were respectively 2.6, 4.6, 2.6 and 5.0 times higher (p&lt;0.05) (statistically significant results).Conclusion. The level of microRNA expression in CTC can be used for differential diagnosis of regional and distant metastases.

Abstract P6-01-43: Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: OncotypeDX versus MammaPrint versus Liquid Biopsy

Abstract Background: OncotypeDX (ODX) is a 21-gene recurrence score (RS) assay that is predictive of the benefit of adjuvant chemotherapy in early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. MammaPrint (MP) is a 70-gene signature validated to prognosticate distant metastasis and survival. We have previously presented data suggesting that the presence of circulating tumor cells (CTCs) evaluated via liquid biopsy may also have prognostic and predictive utility in HR+/HER2- breast cancer. In this study, we compare the value of ODX, MP and liquid biopsy evaluating CTCs and disseminated tumor cells (DTCs) in predicting pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC). Methods: This retrospective analysis used the National Cancer Database (NCDB) 2004-2017 breast cancer dataset to identify a cohort of patients with HR+/HER2-, AJCC clinical stage I-III breast cancer who received NAC. A series of multiple logistic regression models were used to assess the value of a. ODX (RS &amp;lt; 26 versus ≥26), b. MP, c. the presence of CTCs, and d. the presence of DTCs in predicting pCR to NAC. Each model controlled for age, race, Charlson/Deyo comorbidity scoring, disease histology, grade, and nodal status. Results: A total of n=52,463 patients with stages I-III HR+/HER2- breast cancer received NAC. The patient characteristics of this cohort were as follows: the majority were White (n=42,826, 81.6%), between 50-70 years of age (n=27,683, 52.8%), and with invasive ductal carcinomas of the breast (n=40,197, 76.6%). N=6,111 (11.6%) had Grade I or well-differentiated disease, n=23,546 (44.9%) Grade II or moderately-differentiated disease, and n=2,605 (43.5%) had Grade III or poorly-differentiated disease. N=3,823 have documented recurrence scores based on ODX: with n=2,653 having RS &amp;lt; 26 (69.4%) and n=1,170 (30.6%) having RS ≥26. After controlling for age, race, comorbidity scoring, disease histology, grade and nodal status, RS ≥26 was found to be significantly associated with pCR to NAC (OR 1.85, 95% CI 1.46-2.35, p&amp;lt; 0.001). High-risk scoring per MP was also correlated with pCR but this relationship was not statistically-significant (OR 1.68, 95% CI 0.93-3.03, p=0.084), possibly due to the smaller size of this sample (n=828 patients underwent MP testing). Liquid biopsy data was also limited, with n=250 patients having documented CTC status and n=211 having documented DTC status. Neither the presence of CTCs (OR 0.96, 95% CI 0.44-2.09, p=0.908) nor DTCs (OR 0.61, 95% CI 0.25-1.50, p=0.279) was significantly associated with pCR to NAC. Conclusions: ODX is found to be predictive of pCR to NAC in early-stage, HR+/HER2- breast cancer. Utility of MP and liquid biopsy data in this context appears less robust, however, data is limited. More research is needed to validate existing data in a prospective trial setting, and explore for novel biomarkers across breast cancer subtypes. Citation Format: Nadeem Bilani, Mira Itani, Mohamed Mohanna, Neha Debnath, Barbara Dominguez, Hong Liang, Zeina Nahleh. Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: OncotypeDX versus MammaPrint versus Liquid Biopsy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-43.

Abstract P3-05-45: Circulating tumor cells, immunohistochemical subtypes, and genes mutation as prognostic markers in HER2 negative metastatic breast cancer patients candidates to chemotherapy

Abstract Background: In the era of targeted therapies, chemotherapy (CT) is still a valuable treatment option for patients (pts) with HER2 negative metastatic breast cancer (MBC). The identification of predictive and prognostic markers might improve treatment response and survival. Here we investigated the role of tumor subtypes, circulating tumor cells (CTCs), and mutations in genes or pathways of interest, in predicting response to CT and prognosis of HER2 negative MBC pts within AARES trial. Methods: AARES is an open label multicentric randomised phase 2 trial comparing a DNA-damaging (arm A: cisplatin 25 mg/m2/day, day 1-3 + cyclophosphamide 600 mg/m2 day 1) versus (vs) a non-DNA-damaging (arm B: capecitabine 1000 mg/m2 bid/day, day 1-14 + vinorelbine 60 mg/m2/day, day 1,8) CT regimen in pts with HER2 negative MBC. Archival tumor tissue samples and blood samples were collected at baseline. The Cell SearchTM system was used for CTCs isolation and enumeration and a cut-off of 5 CTC/7,5 ml was used. Tumor subtypes were based on locally assessed hormone receptors and HER2 status. The luminal-like subtype (Lum) was defined by ER or PR positivity, while the triple negative subtype (TN) by ER, PR, and HER2 negativity. Tissue samples were used for DNA extraction and next generation sequencing analysis using a target enrichment panel of 170 genes (TruSight 170, Illumina). Primary endpoint was objective response rate (ORR) assessed for the two treatment arms. Progression free survival (PFS) and overall survival (OS) were evaluated as secondary endpoints, and estimated with the Kaplan-Meier method. ORR, PFS and OS were correlated with CTC counts, tumor subtypes, and mutational status of genes/pathway of interest (PIK3CA, TP53, BRCA1, BRCA2, PI3K/AKT pathway (PI3K/AKT)). Results: AARES enrolled 102 pts from 2011 to 2016 across 9 Italian centers. Of these, 77 pts were evaluable for ORR. Median follow up was 32 months. Overall, median age was 57. The majority of pts had Lum tumors (73%), while 27% had TN. 86% of pts had visceral metastases, and 52% had 3 or more metastatic sites. 48% of pts received the study treatment as 1st line, 32% as 2nd line, and 19% as 3rd line. Out of the 77 pts with ORR data, 41 (53%) were CTC- and 36 (47%) CTC+. A larger proportion of pts with Lum tumors were CTC+ (54% n=30), while TN tumors were mainly CTC- (71% n=15). 49 pts had adequate tumor tissue for sequencing analysis. TP53 mutations (mut) were found in 33% of pts, BRCA1/2 mut in 14%, PIK3CA mut in 35%, and PI3K/AKT mut in 47%. ORR was 24% and 37% in arm A vs arm B, respectively (p= 0.2), and no difference in ORR was observed by tumor subtypes (Lum vs TN), and CTCs count (+ vs -). PFS and OS were assessable on the whole population (n=102) and did not significantly differ by treatment arms. Median OS (mOS) was higher in Lum pts compared to TN (24 months (mo) vs 15.4 mo, p=0.048) while median PFS (mPFS) did not differ according to tumor subtypes (p=0.28). Overall, CTCs count was not significantly associated with mPFS or OS however in pts with TN tumors and CTC-, mPFS and mOS were significantly longer (mPFS: 4.44 mo vs 2.56 mo in CTC- and CTC+ subgroups, respectively, p=0.00087 and mOS: 22.07 mo vs 3.57 mo in CTC- and CTC+ subgroups, respectively, p&amp;lt; 0.0001). On the other hand, no differences were observed in Lum pts categorized according to CTC status (p=0.83 for mPFS, p=0.54 for mOS). Finally, pts with PI3K/AKT mut had a significantly worse PFS compared to wild type in the overall population (p=0.0091) as well as in Lum (p=0.034) and TN pts (p=0.0052). Conclusions: CTCs and tumor subtypes were not predictive of response to CT regimens in HER2 negative MBC pts. A number of CTC &amp;gt;5 in TN MBC, and mutations in the PI3K/AKT pathway, identified a subgroup of pts with worse prognosis, potentially candidates for alternative treatments. Further studies are needed to confirm these results in a larger population. Citation Format: Emanuela Risi, Marta Pestrin, Chiara Biagioni, Dario Romagnoli, Ilenia Migliaccio, Francesca Galardi, Francesca De Luca, Matteo Benelli, Erica Moretti, Giuseppina Sanna, Luca Livraghi, Silvia Cappadona, Roberta Di Marsico, Domenico Amoroso, Angelo Martignetti, Angela S. Ribecco, Elena Rota Caremoli, Luigi Coltelli, Fabio Puglisi, Luca Malorni, Laura Biganzoli. Circulating tumor cells, immunohistochemical subtypes, and genes mutation as prognostic markers in HER2 negative metastatic breast cancer patients candidates to chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-45.

Preliminary Result of Anatomical Hepatectomy on Recurrence Based on Preoperative Circulating Tumor Cell Status in Hepatocellular Carcinoma

Preliminary Result of Anatomical Hepatectomy on Recurrence Based on Preoperative Circulating Tumor Cell Status in Hepatocellular Carcinoma

Dynamic monitoring of PD-L1 and Ki67 in circulating tumor cells of metastatic non-small cell lung cancer patients treated with pembrolizumab.

Programmed cell death protein ligand-1 (PD-L1) expression in non-small cell lung cancer (NSCLC) tumors guides treatment selection. PD-L1 expression in circulating tumor cells (CTCs) may provide further information. We have explored PD-L1 and marker of proliferation Ki-67 (Ki67; also known as MKI67) in CTCs in longitudinal samples of 47 advanced NSCLC patients receiving pembrolizumab. A triple immunofluorescence, against cytokeratin, PD-L1, and Ki67, was performed on peripheral blood mononuclear cells, at baseline, post-first cycle, post-third, and primary resistance (PMR). Patients displaying PMR (progression at first evaluation) were classified as progressive disease (PD) and those with clinical benefit as disease control (DC). CTCs were categorized as PD-L1high/low/medium/negative and Ki67+ or Ki67- . CTC evaluation revealed a significant increase in the PD-L1low CTC rate at PMR compared to baseline (2.5% at baseline vs. 36.5% at PMR), whereas a reduction in the PD-L1high CTC rate was observed (31.5% vs. 0%, respectively). Investigation of CTC status between PD and DC patients showed that PD patients more frequently increased total and PD-L1low CTCs after first cycle compared to DC (83% of PD vs. 37% of DC and 67% of PD vs. 8% of DC, respectively). Progression-free survival (PFS) was longer in patients with decreased total and PD-L1low CTCs after first cycle compared to those with increased CTCs (median PFS: not reached vs. 2 months). PD-L1+ patients presenting a high Ki67 index (% Ki67+ CTCs > 30%) before treatment had a shorter PFS compared to those with a low Ki67 (≤ 30%), and overall survival (OS) was shorter in PD-L1+ patients harboring Ki67+ CTCs compared to those not presenting (median OS: 11.8 months vs. 33.1 months, respectively). In sequential samples of patients with a durable benefit, a low Ki67 index was observed. Our results suggest that monitoring PD-L1 and Ki67 expression in CTCs of NSCLC patients treated with pembrolizumab may be predictive for pembrolizumab efficacy.

107P Preliminary result of anatomical hepatectomy on recurrence based on preoperative circulating tumor cell status in hepatocellular carcinoma

Hepatocellular carcinoma (HCC), which comprises the majority of liver cancer was a leading cause of death worldwide. The high rate of recurrence severely hampers the long-term survival of HCC patients after hepatectomy. Early recurrence, which is mainly caused by intrahepatic dissemination, accounts for nearly 70% of all recurrent cases. Circulating tumor cells (CTC) has shown potential clinical implications. CTC was associated with the severity of microvascular invasion (mVI) in the peritumoral tissue.

Circulating miR-200 Family and CTCs in Metastatic Breast Cancer before, during, and after a New Line of Systemic Treatment.

The extracellular circulating microRNA (miR)-200 regulates epithelial-mesenchymal transition and, thus, plays an essential role in the metastatic cascade and has shown itself to be a promising prognostic and predictive biomarker in metastatic breast cancer (MBC). Expression levels of the plasma miR-200 family were analyzed in relationship to systemic treatment, circulating tumor cells (CTC) count, progression-free survival (PFS), and overall survival (OS). Expression of miR-200a, miR-200b, miR-200c, miR-141, and miR-429, and CTC status (CTC-positive ≥ 5 CTC/7.5 mL) was assessed in 47 patients at baseline (BL), after the first completed cycle of a new line of systemic therapy (1C), and upon the progression of disease (PD). MiR-200a, miR-200b, and miR-141 expression was reduced at 1C compared to BL. Upon PD, all miR-200s were upregulated compared to 1C. At all timepoints, the levels of miR-200s were elevated in CTC-positive versus CTC-negative patients. Further, heightened miR-200s expression and positive CTC status were associated with poorer OS at BL and 1C. In MBC patients, circulating miR-200 family members decreased after one cycle of a new line of systemic therapy, were elevated during PD, and were indicative of CTC status. Notably, increased levels of miR-200s and elevated CTC count correlated with poorer OS and PFS. As such, both are promising biomarkers for optimizing the clinical management of MBC.

Does the Presence of Circulating Tumor Cells in High-Risk Early Breast Cancer Patients Predict the Site of First Metastasis-Results from the Adjuvant SUCCESS A Trial.

Simple SummaryDue to recent advances in breast cancer detection and treatment strategies, the number of breast cancer survivors has increased over the past decades. However, breast cancer follow-up guidelines have not changed for years. The presence of CTCs detected during follow-up has been shown to indicate poor prognosis in high-risk breast cancer patients. Here, we evaluated if the presence of CTCs also indicates the site of metastatic disease by analyzing CTC status and metastatic location in 206 patients with distant recurrence from the large adjuvant breast cancer trial SUCCESS A. Patients who were CTC-positive both before and after chemotherapy were more likely to show bone-only first distant disease (37.5% vs. 21.0%) and first distant disease at multiple sites (31.3% vs. 12.6%) than patients without CTCs. These data indicate that CTCs might serve as a liquid biopsy surveillance-marker enabling risk-stratification for deciding on further adjuvant add-on-treatment.The prognostic relevance of circulating tumor cells (CTCs) in breast cancer is well established. However, little is known about the association of CTCs and site of first metastasis. In the SUCCESS A trial, 373 out of 3754 randomized high-risk breast cancer patients developed metastatic disease. CTC status was assessed by the FDA-approved CellSearch®-System (Menarini Silicon Biosystems, Bologna, Italy) in 206 of these patients before chemotherapy and additionally in 159 patients after chemotherapy. CTCs were detected in 70 (34.0%) of 206 patients before (median 2 CTCs, 1–827) and in 44 (27.7%) of 159 patients after chemotherapy (median 1 CTC, 1–124); 16 (10.1%) of 159 patients were CTC-positive at both timepoints. The site of first distant disease was bone-only, visceral-only, and other-site-only in 44 (21.4%), 60 (29.1%), and 74 (35.9%) patients, respectively, while 28 (13.6%) patients had multiple sites of first metastatic disease. Patients with CTCs at both timepoints more often showed bone-only first distant disease (37.5% vs. 21.0%) and first distant disease at multiple sites (31.3% vs. 12.6%) than patients without CTCs before and/or after chemotherapy (p = 0.027). In conclusion, the presence of CTCs before and after chemotherapy is associated with multiple-site or bone-only first-distant disease and may trigger intensified follow-up and perhaps further treatment.

Comparison of circulating tumor cells and AR-V7 as clinical biomarker in metastatic castration-resistant prostate cancer patients

Biomarker in metastatic castration resistant prostate cancer (mCRPC) treatment are rare. We aimed to compare the clinical value of circulating tumor cells (CTCs) and androgen receptor splice variant 7 (AR-V7) as biomarker in mCRPC patients undergoing androgen receptor-targeted agent (ARTA) treatment. Overall cohort (65 patients) was stratified regarding either CTC or AR-V7 status followed by further sub-stratification of the respective other marker. Subsequently, prostate specific antigen (PSA) response, progression free survival (PFS) and overall survival (OS)) of subgroups was compared. CTCs and AR-V7 were detected in 54 (83%) and 33 (61%) patients, respectively. All AR-V7 + were CTC +. We detected PSA response in all subgroups. For PFS and OS, biomarker stratification revealed differences between all subgroups. Interestingly, no significant differences of AR-V7 transcript copy numbers were detected between responding and non-responding patients. Additionally, multivariable analysis revealed no independent prognostic value of AR-V7 positivity. Both biomarkers show clinical value in prognosticating clinical outcome. Nonetheless, AR-V7 stratification underestimates the heterogenous subgroup of CTC − and CTC + patient, the latter requiring more intense clinical surveillance. Additionally, AR-V7 level does not correlate with clinical response. Thus, the value of AR-V7 as a clinical biomarker must be considered skeptically.

Circulating Tumor Cells as an Indicator of Treatment Options for Hepatocellular Carcinoma Less Than or Equal to 3 cm in Size: A Multi-Center, Retrospective Study.

BackgroundThe status of circulating tumor cells (CTCs) is related to the recurrence of hepatocellular carcinoma (HCC), which is also one of the reasons for the poor prognosis of HCC. The purpose of this study was to explore whether CTCs can help guide the choice of treatment methods for HCC.MethodsThis study is a multicenter retrospective study, including 602 patients with HCC. CTCs were detected in the overall cohort before operation. There were 361 patients in the training cohort and 241 patients in the validation cohort. Patients were divided into CTC-negative group (CTCs = 0/5 mL) and the CTC-positive group (CTCs ≥ 1/5 mL) according to CTCs status. Subgroup analysis was performed according to CTCs status. We compared overall survival, and recurrence outcomes for HCC patients with different CTC statuses after undergoing radiofrequency ablation (RFA) or surgical resection (SR)ResultsThere was no significant difference in overall survival (OS) and recurrence-free survival (RFS) between the RFA group and SR group for CTC-negative patients in both the training cohort and the validation cohort (P > 0.05). However, among CTC-positive patients, the clinical outcome of patients in the SR group was significantly better than those in the RFA group. CTC-positive patients who underwent RFA had increased early recurrence compared to those who underwent SR. RFA is an independent risk factor for survival and recurrence in CTC-positive HCC patientsConclusionsThe CTC status could serve as an indicator to guide the choice between surgical resection or radiofrequency ablation for early hepatocellular carcinoma. Surgical resection is recommended for CTC-positive patients.

Guiding Value of Circulating Tumor Cells for Preoperative Transcatheter Arterial Embolization in Solitary Large Hepatocellular Carcinoma: A Single-Center Retrospective Clinical Study.

BackgroundLarge hepatocellular carcinoma (LHCC) is highly malignant and prone to recurrence, leading to a poor long-term prognosis for patients. There is an urgent need for measures to intervene in postoperative recurrence. Preoperative Transcatheter Arterial Embolization (TACE) is an effective treatment. However, there is a lack of reliable preoperative indicators to guide the application of preoperative TACE. We, therefore, investigated whether the preoperative status of circulating tumor cells (CTCs) could be used to guide preoperative TACE for HCC treatment.MethodsThis study recruited 361 HCC patients and compared recurrence-free survival (RFS) and overall survival (OS) in patients treated with TACE prior to surgery and those not treated with TACE. Patients were divided into CTC-positive group and CTC-negative group according to CTC status, and the effect of preoperative TACE on RFS and OS was compared in each subgroup.ResultsIn CTC-positive patients, preoperative TACE reduces early recurrence and improves long-term survival. However, HCC patients did not benefit from preoperative TACE for the overall population and CTC-negative patients.ConclusionsPreoperative CTC testing is a reliable indicator of whether HCC patients received TACE preoperatively. CTC positivity was associated with early tumor recurrence, and preoperative TACE could reduce early recurrence and long-term prognosis in CTC-positive patients.

The Role of Circulating Tumor Cells in the Prognosis of Metastatic Triple-Negative Breast Cancers: A Systematic Review of the Literature.

Breast cancer is one of the leading causes of death in women worldwide. One subtype of breast cancer is the triple-negative, which accounts for 15% of total breast cancer cases and is known for its poor prognosis. The main cause of death is due to metastasis. Circulating tumor cells (CTCs) play a key role in the metastatic process. CTCs arise either by detaching from the primary tumor or from cancer stem cells undergoing an epithelial-to-mesenchymal transition (EMT). This review aims to present up-to-date data concerning the role of CTC numbers in relation to the prognostic and treatment response in metastatic triple-negative breast cancer (mTNBC) patients, and also to discuss the methods used for CTCs’ identification. A search in the MEDLINE database was performed. A total of 234 articles were identified. The results of the 24 eligible studies showed that positive CTC status is associated with shorter overall survival (OS) and progression-free survival (PFS) in mTNBC patients. Furthermore, a decrease in number of CTCs during therapy seems to be a favorable prognostic factor, making CTCs’ detection an important prognostic tool before and during therapy in mTNBC patients. The methods used for CTC detection are still developing and need further improvement.

Circulating tumor cells may serve as a supplement to RECIST in neoadjuvant chemotherapy of patients with locally advanced breast cancer.

Circulating tumor cells (CTCs) have been shown to be associated with the response to neoadjuvant chemotherapy (NCT) and the prognosis of locally advanced breast cancer (LABC) patients. Our study aimed to investigate whether the change of CTC status during NCT could serve as a supplement to the Response Evaluation Criteria in Solid Tumors (RECIST) in the treatment and evaluation of LABC patients. 6ml of blood samples were collected before NCT, after the first cycle of NCT and after the completion of NCT, respectively. According to the change of CTC number during NCT, the patients were divided into "CTC low-response (low-R)" group and "CTC high-response (high-R)" group. Survival data of each group of patients were obtained through long-term follow-up. A total of 35 patients diagnosed with LABC were enrolled. The median follow-up for distant metastasis was 27months (range 7-36months). There was no significant difference in distant metastasis-free survival (DMFS) between PR/CR group and PD/SD group (P = 0.0914), while CTC low-R group had a worse DMFS than CTC high-R group (P = 0.0199). In PR/CR subgroup, patients with CTC low-R showed a lower DMFS compared with those with CTC high-R (P = 0.0159). However, in PD/SD subgroup, there was no significant difference in DMFS between CTC low-R and CTC high-R group (P = 0.7521). In terms of assessing response to NCT, CTC change or RECIST classification alone had an AUC of 0.533 (95% CI 0.277-0.790) and 0.700 (95% CI 0.611-0.789), respectively. When combining the two, the AUC slightly increased to 0.713 (95% CI 0.532-0.895). The change of CTC number during NCT has a potential to serve as a supplement to RECIST in the assessment of NCT efficacy and the prognosis of LABC patients.