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Cell-free tumor DNA (ctDNA) has the potential to enable non-invasive diagnostic tests for personalized medicine in providing similar molecular information as that derived from invasive tumor biopsies. The histology-independent phase II SHIVA trial matches patients with targeted therapeutics based on previous screening of multiple somatic mutations using metastatic biopsies. To evaluate the utility of ctDNA in this trial, as an ancillary study we performed de novo detection of somatic mutations using plasma DNA compared to metastasis biopsies in 34 patients covering 18 different tumor types, scanning 46 genes and more than 6800 COSMIC mutations with a multiplexed next-generation sequencing panel. In 27 patients, 28 of 29 mutations identified in metastasis biopsies (97%) were detected in matched ctDNA. Among these 27 patients, one additional mutation was found in ctDNA only. In the seven other patients, mutation detection from metastasis biopsy failed due to inadequate biopsy material, but was successful in all plasma DNA samples providing three more potential actionable mutations. These results suggest that ctDNA analysis is a potential alternative and/or replacement to analyses using costly, harmful and lengthy tissue biopsies of metastasis, irrespective of cancer type and metastatic site, for multiplexed mutation detection in selecting personalized therapies based on the patient's tumor genetic content. •We report de novo multiplexed detection of targetable ctDNA mutations.•We report ctDNA mutations detection from multiple tumor types (SHIVA trial).•There is no correlation between ctDNA and total plasma DNA quantity.•ctDNA corresponds to ∼25% of total cfDNA fraction for detectable plasma mutations.•ctDNA is as remarkable surrogate of tumor biopsy for de novo mutation calling.

Background Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation. Methods Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood samples were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. Samples with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR. Results All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 ( n  = 26) had a worse PFS than those with 0 CTCs ( n  = 16) ( p  = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, ( p  = 0.004). Finally, patients with ≥ 5 CTCs at T2 ( n  = 6/23) who received chemotherapy as post-study treatment had a shorter TTF ( p  = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels. Conclusions CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied sample size.

Immune checkpoint inhibitors (ICIs) have been introduced in breast cancer (BC) treatment and better biomarkers are needed to predict benefit. Circulating tumor cells (CTCs) are prognostic in BC, but knowledge is limited on CTCs in the context of ICI therapy. In this study, serial sampling of CTCs (CellSearch system) was evaluated in 82 patients with metastatic BC enrolled in two randomized trials investigating ICI plus chemotherapy. Programmed death‐ligand 1 (PD‐L1) expression on CTCs was also measured. Patients with ≥ 2 CTCs per 7.5 mL at baseline had gene expression profiles in tumor suggestive of increased T‐cell activity, including increased tumor inflammation signature (TIS) in both triple‐negative (P = 0.010) and hormone receptor‐positive (P = 0.024) disease. Patients with luminal A BC had higher CTC levels. The association between CTC status and outcome was most apparent 4 weeks into therapy. PD‐L1 expression in CTCs was observed in 6/17 CTC‐positive patients and was associated with inferior survival. In conclusion, our study indicates that CTC numbers may inform on tumor immune composition, as well as prognosis. These findings suggest a potential of using CTCs as an accessible biomarker source in BC patients treated with immunotherapy. In this explorative biomarker analysis, we assessed serial sampling of circulating tumor cells (CTCs) with CellSearch in two randomized trials testing immune checkpoint inhibitors (ICIs) in metastatic breast cancer. Our data demonstrate a prognostic potential of CTCs, most apparent 4 weeks into ICI therapy. Furthermore, higher CTC counts were associated with increased markers of tumor immune activity.

Circulating tumour cells (CTCs) represent a morphologically distinct subset of cancer cells, which aid the metastatic spread. The ExPeCT trial aimed to examine the effectiveness of a structured exercise programme in modulating levels of CTCs and platelet cloaking in patients with metastatic prostate cancer. Participants (n = 61) were randomised into either standard care (control) or exercise arms. Whole blood was collected for all participants at baseline (T0), three months (T3) and six months (T6), and analysed for the presence of CTCs, CTC clusters and platelet cloaking. CTC data was correlated with clinico-pathological information. Changes in CTC number were observed within group over time, however no significant difference in CTC number was observed between groups over time. Platelet cloaking was identified in 29.5% of participants. A positive correlation between CTC number and white cell count (WCC) was observed (p = 0.0001), in addition to a positive relationship between CTC clusters and PSA levels (p = 0.0393). The presence of platelet cloaking has been observed in this patient population for the first time, in addition to a significant correlation between CTC number and WCC. ClincalTrials.gov identifier NCT02453139.

To evaluate the efficacy of lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, in therapy-resistant HER2-positive CTCs in metastatic breast cancer (MBC). Patients with MBC and HER2-positive CTCs despite disease stabilization or response to prior therapy, received lapatinib 1500 mg daily in monthly cycles, till disease progression or CTC increase. CTC monitoring was performed by immunofluorescent microscopy using cytospins of peripheral blood mononuclear cells (PBMCs) double stained for HER2 or EGFR and cytokeratin. A total of 120 cycles were administered in 22 patients; median age was 62.5 years, 15 (68.2%) patients were post-menopausal and 20 (90.1%) had HER2-negative primary tumors. At the end of the second course, HER2-positive CTC counts decreased in 76.2% of patients; the median number of HER2-positive CTCs/patient also declined significantly (p = 0.013), however the decrease was significant only among patients presenting disease stabilization (p = 0.018) but not among those with disease progression during lapatinib treatment. No objective responses were observed. All CTC-positive patients harbored EGFR-positive CTCs on progression compared to 62.5% at baseline (p = 0.054). The ratio of EGFR-positive CTCs/total CTCs detected in all patients increased from 17.1% at baseline to 37.6% on progression, whereas the mean percentage of HER2-negative CTCs/patient increased from 2.4% to 30.6% (p = 0.03). The above results indicate that lapatinib is effective in decreasing HER2-positive CTCs in patients with MBC irrespectively of the HER2 status of the primary tumor and imply the feasibility of monitoring the molecular changes on CTCs during treatment with targeted agents. Clinical trial.gov NCT00694252.

Purpose To evaluate the prognostic value of IGF-1R expression on circulating tumor cells (CTCs) in a prospective randomized clinical trial comparing chemotherapy plus metformin with chemotherapy alone in metastatic breast cancer (MBC) patients. Methods CTCs were collected at baseline and at the end of chemotherapy. An automated sample preparation and analysis system (CellSearch) were customized for detecting IGF-1R expression. The prognostic role of CTC count and IGF-1R was assessed for PFS and OS by univariate and multivariate analyses. Results Seventy-two out of 126 randomized patients were evaluated: 57% had ≥ 1 IGF-1R positive CTC and 37.5% ≥ 4 IGF-1R negative cells; 42% had CTC count ≥ 5/7.5 ml. At univariate analysis, the number of IGF-1R negative CTCs was strongly associated with risk of progression and death: HR 1.93 ( P  = 0.013) and 3.65 ( P  = 0.001), respectively; no association was detected between number of IGF-1R positive CTCs and PFS or OS ( P  = 0.322 and P  = 0.840). The prognostic role of CTC count was confirmed: HR 1.69, P  = 0.042 for PFS and HR 2.80 for OS, P  = 0.002. By multivariate analysis, the prognostic role of the number of IGF-1R negative CTCs was maintained, while no residual prognostic role of CTC count or number of IGF-1R positive cells was found. Conclusion Loss of IGF-1R in CTCs is associated with a significantly worse outcome in MBC patients. This finding supports further evaluation for the role of IGF-1R on CTCs to improve patient stratification and to implement new targeted strategies. Clinical trial registration: Clinicaltrials.gov (NCT01885013); European Clinical Trials Database (EudraCT No.2009-014,662-26).

Background: Obesity is associated with aggressive prostate cancer. To explore whether weight loss favourably affects tumour biology and other outcomes, we undertook a presurgical trial among overweight and obese men with prostate cancer. Methods: This single-blinded, two-arm randomised controlled trial explored outcomes of a presurgical weight loss intervention (WLI) that promoted ∼1 kg per week loss via caloric restriction and increased physical activity (PA). Forty overweight/obese men with clinically confirmed prostate cancer were randomised to the WLI presurgery or to a control arm; changes in weight, body composition, quality-of-life, circulating biomarkers, gene expression, and immunohistochemical markers in tumour and benign prostatic tissue were evaluated. Results: The study period averaged 50 days. Mean (s.d.) change scores for the WLI vs control arms were as follows: weight: −4.7 (3.1) kg vs −2.2 (4.4) kg ( P =0.0508); caloric intake: −500 (636) vs −159 (600) kcal per day ( P =0.0034); PA: +0.9 (3.1) vs +1.7 (4.6) MET-hours per day (NS); vitality: +5.3 (7.l4) vs −1.8 (8.1) ( P =0.0491); testosterone: +55.1 (86.0) vs −48.3 (203.7) ng dl −1 ( P =0.0418); sex hormone-binding globulin: +14.0 (14.6) vs +1.8 (7.6) nmol l −1 ( P =0.0023); and leptin: −2.16 (2.6) vs −0.03 (3.75) ( P =0.0355). Follow-up Ki67 was significantly higher in WLI vs control arms; median (interquartile range): 5.0 (2.5,10.0) vs 0.0 (0.0,2.5) ( P =0.0061) and several genes were upregulated, for example, CTSL, GSK3B, MED12, and LAMC2. Conclusions: Intentional weight loss shows mixed effects on circulating biomarkers, tumour gene expression, and proliferative markers. More study is needed before recommending weight loss, in particular rapid weight loss, among men with prostate cancer.

Modern technologies enable detection and characterization of circulating tumor cells (CTC) in peripheral blood samples. Thus, CTC have attracted interest as markers for therapeutic response in breast cancer. First studies have incorporated CTC analyses to guide therapeutic interventions and stratification of breast cancer patients. Aim of this study was to analyze characteristic features of CTC as biomarker for predicting resistance to HER2-targeted therapies. Therefore, CTC from metastatic breast cancer patients with HER2-negative primary tumors screened for the prospective randomized phase III trial DETECT III were explored for their HER2 status and the presence of PIK3CA mutations. Detection and characterization of HER2 expression of CTC were conducted with the CellSearch® system. Fifteen of 179 CTC-positive patients (8.4%) contained ≥1 CTC with strong HER2 expression. Genomic DNA from individual CTC isolated by micromanipulation was propagated by whole genome amplification and analyzed for PIK3CA mutations in exons 9 and 20 by Sanger sequencing. One or more CTC/7.5 mL were detected in 179/290 patients (61.7%). In 109 patients (34.8%), ≥5 CTC/7.5 mL were found. We detected at least one CTC with the mutation p.E542K, p.E545K, p.H1047R, p.H1047L or p.M1043V in 12/33 patients (36.4%). Thirty six of 114 CTC (31.6%) harbored one of these mutations. CTC in individual patients exhibited heterogeneity concerning PIK3CA mutations and HER2 expression. In conclusion, clinically relevant genomic aberrations such as mutations in the hotspot regions of exon 9 and 20 of the PIK3CA gene can be detected in single CTC and might provide insights into mechanisms of resistance to HER2-targeted therapies. •HER2 positive CTC are rarely detected in HER2-negative metastatic breast cancer.•PIK3CA mutations can be detected frequently in single CTC.•CTC HER2 and PIK3CA status might assist decision making for HER2-targeted therapy.

Abstract Background/Aims: We evaluated the clinical effectiveness of irreversible electroporation (IRE) in combination with immunotherapy using allogenic natural killer cells (NK) for stage IV hepatocellular carcinoma (HCC). Methods: The study involved 40 patients with stage IV HCC who were divided equally into two groups: 1) simple IRE; and 2) IRE plus allogenic NK cells (IRE-NK); we mainly assessed the overall survival (OS). Results: The effect of the IRE-NK treatment was synergistic, i.e., not only did it enhance immune function, it also decreased alpha-fetoprotein expression and showed significantly good clinical effectiveness. At the median 7.6-month follow-up (range, 3.8–12.1 months), median OS was higher in the IRE-NK group (10.1 months) than in the IRE group (8.9 months, P = 0.0078). Conclusion: IRE combined with allogeneic NK cell immunotherapy significantly increases the median OS of patients with stage IV HCC.

Background It is supposed that the improvement of prognosis in hepatocellular carcinoma (HCC) patient by anterior approach for liver resection was related to the decreasing hematogenic dissemination of circulating cancer cells. Methods The EpCAM + circulating tumor cells (CTCs) were detected in HCC patients having liver resection with either anterior approach (AA) or conventional approach (CA). The relation of CTCs to the 2-year recurrence and survival after surgery was investigated. Results Overall, patients with ≥3.5 CTCs had much higher recurrence rate than those with <3.5 CTCs (62.0 vs. 18.0%, P  = 0.001). Less CTCs were detected in AA group than that in CA group (mean, 2.1 vs. 3.0; median, 1.2 vs. 3.5; all P  = 0.001). The 2-year recurrence rate in AA group was much lower than in CA group (27.1 vs. 44.9%, P  = 0.009). The 2-year survival rate in AA group was much higher than in CA group (83.3 vs. 66.7%, P  = 0.001). The CTCs in >5 cm AA group were much less than that in >5 cm CA group (3.7 vs. 2.4, P  = 0.002). Moreover, the 2-year recurrence rate in >5 cm AA group was much lower than that in >5 cm CA group (29.2 vs. 54.7%, P  = 0.001). Also, the 2-year survival rates in >5 cm AA group were much higher than that in >5 cm CA group (72.9 vs. 49.1%, P  = 0.01). By multivariate analysis, CA is one of the independent risk factors for poor prognosis in HCC patients after liver resection. Conclusions Like the liver-directed therapies, AA can reduce the dissemination of CTCs, especially in patients with large-size HCC (>5 cm) and successively improve the early prognosis.