An Integrated Liquid Biopsy Analysis for Comprehensive Investigation of Uveal Melanoma

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Presence of Circulating Tumor Cells Predates Imaging Detection of Relapse in Patients with Stage III Melanoma

Stage III melanoma includes nodal metastasis or in-transit disease. Five-year survival rates vary between 32% and 93%. The identification of high-risk patients is important for clinical decision making. We demonstrated previously that ≥1 circulating tumor cells (CTCs) at baseline was associated with recurrence. In this study, we investigated how frequently CTCs were identified prior to radiologically detected recurrence. Stage III patients (n = 325) had imaging at baseline and q 3 months. Baseline and q 6-12 months blood draws (7.5 mL) were performed to identify CTCs up to 3.5 years from diagnosis. CTC assessment was performed using the immunomagnetic capture of CD146-positive cells and anti-MEL-PE. The presence of one or more CTCs was considered positive. We analyzed the cohort of patients with relapse confirmed by radiologic imaging. CTC collection dates were assessed to determine the lead time for CTC detection. CTC-negative patients were significantly less likely to relapse compared to patients positive for CTCs (p-value \u3c 0.001). Within the 325-patient cohort, 143 patients (44%) had recurrence, with a median follow-up of 52 months from diagnosis. The cohort (n = 143) with positive imaging and CTC results revealed 76% of patients (108/143) had CTC+ results before the radiological identification of relapse. The median time between positive CTC and positive imaging was 9 months. CTCs were positive in \u3e75% of patients prior to relapse at a median of 9 months before radiologic detection

Monitoring Response to Neoadjuvant Chemotherapy in Triple Negative Breast Cancer Using Circulating Tumor DNA

BACKGROUND: Triple negative breast cancer (TNBC) is an aggressive subtype with poor prognosis. We aimed to determine whether circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) could predict response and long-term outcomes to neoadjuvant chemotherapy (NAC). METHODS: Patients with TNBC were enrolled between 2017-2021 at The University of Texas MD Anderson Cancer Center (Houston, TX). Serial plasma samples were collected at four timepoints: pre-NAC (baseline), 12-weeks after NAC (mid-NAC), after NAC/prior to surgery (post-NAC), and one-year after surgery. ctDNA was quantified using a tumor-informed ctDNA assay (Signatera RESULTS: In total, 37 patients were enrolled. The mean age was 50 and majority of patients had invasive ductal carcinoma (34, 91.9%) with clinical T2, (25, 67.6%) node-negative disease (21, 56.8%). Baseline ctDNA was detected in 90% (27/30) of patients, of whom 70.4% (19/27) achieved ctDNA clearance by mid-NAC. ctDNA clearance at mid-NAC was significantly associated with pathologic complete response (p = 0.02), whereas CTC clearance was not (p = 0.52). There were no differences in overall survival (OS) and recurrence-free survival (RFS) with positive baseline ctDNA and CTC. However, positive ctDNA at mid-NAC was significantly associated with worse OS and RFS (p = 0.0002 and p = 0.0034, respectively). CONCLUSIONS: Early clearance of ctDNA served as a predictive and prognostic marker in TNBC. Personalized ctDNA monitoring during NAC may help predict response and guide treatment

17β-estradiol promotes extracellular vesicle release and selective miRNA loading in ERα-positive breast cancer

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor–positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7’s miRNAs into EVs. In multiple patient cohorts, we observed increased levels of let-7a-5p and let-7d-5p in EVs derived from the blood of premenopausal ER+ BC patients, and elevated EV levels in patients with high BMI, both conditions associated with higher levels of 17β-estradiol. In brief, we identified a unique estrogen-driven mechanism by which ER+ BC cells eliminate tumor suppressor miRNAs in EVs, with effects on modulating tumor-associated macrophages in the microenvironment

Pilot Study of Circulating Tumor Cells in Early-Stage and Metastatic Uveal Melanoma

Nearly 50% of uveal melanoma (UM) patients develop metastatic disease, and there remains no current standard assay for detection of minimal residual disease. We conducted a pilot study to check the feasibility of circulating tumor cell (CTC) detection in UM. We enrolled 40 patients with early or metastatic UM of which 20 patients had early-stage disease, 19 had metastatic disease, and one was not evaluable. At initial blood draw, 36% of patients had detectable CTCs (30% in early-stage vs. 42% in metastatic), which increased to 54% at data cutoff (40% in early-stage vs. 68% in metastatic). Five early-stage patients developed distant metastases, 60% (3/5) had detectable CTCs before radiographic detection of the metastasis. Landmark overall survival (from study enrollment) at 24 months was statistically lower in CTC-positive vs. negative early-stage UM (p < 0.05). Within this small dataset, the presence of CTCs in early-stage UM predicted an increased risk of metastatic disease and was associated with worse outcomes

1534 Clinical activity of SD-101 with immune checkpoint inhibition (ICI) in metastatic uveal melanoma liver metastasis (MUM-LM) from the PERIO-01 Phase 1 trial

BackgroundMUM-LM are resistant to ICIs for several reasons including the prevalence of myeloid-derived suppressor cells (MDSCs). PFS has been limited, even with approved therapies such as tebentafusp (median 3.3 months) with grade 3/4 AE rates typically >30%. TLR9 agonists are capable of MDSC polarization but drug delivery has historically been limited using an intra-tumoral approach. Pressure-enabled drug delivery (PEDDTM) of SD-101, a TLR9 agonist, has the potential to overcome these barriers to improve outcomes.MethodsPERIO-01 is a phase 1 trial of hepatic arterial SD-101 via PEDD in MUM-LM (NCT04935229), with dose-escalation cohorts as monotherapy (Cohort A), with nivolumab (Cohort B), or nivolumab + ipilimumab (Cohort C). SD-101 is delivered over 2 outpatient cycles, with 3 weekly doses/cycle.Results53 patients received at least one dose of SD-101: 13 in Cohort A, 25 in Cohort B, and 15 in Cohort C. Median age was 65 and 45% were female. 70% received prior MUM-LM treatment, and 8 (15%) received tebentafusp. Fifteen participants (28%) had LM >5cm and 18 (44%) had >10 LMs. One patient experienced partial response (Cohort B 4 mg) that is ongoing at 258 days. Six additional patients had decreases in target lesion size (SD), 3 ongoing at a median follow-up of 168 days. Across dose levels, median PFS was highest in Cohort B (2 mg) at 11.7 months, and disease control rate of 86% (6/7 SD). Serious grade 3/4 treatment-related AEs (TRAEs) to SD-101 or ICI were documented in 8% of subjects: 0% in Cohort A, 4% in Cohort B, and 20% in Cohort C, with an overall Grade 3/4 TRAE rate of 21%. PEDD of SD-101 resulted in reductions in LM monocytic MDSC (mMDSC) by immunofluorescence, along with decreased expression of ARG1, CD163, and FASN. We also observed evidence of immune activation in LM with increased CD4+ and CD8+ T cells, decreased Treg, and increased IFNg and IFNa2 gene expression. These were associated with evidence of systemic immune activation peripherally characterized by increased proliferating CD8+ T and NK cells, and increased IP-10, TNFa, IFNg, IL-2R, and IL-18. Among 25 patients with evaluable ctDNA data, 68% had a decrease relative to peak, with complete clearance in 28%.ConclusionsDelivery of SD-101 by PEDD plus systemic ICI in MUM-LM patients results in clinical activity with median PFS of 11.7 months, MDSC re-programming, and evidence of peripheral and intra-tumoral immune activation. Phase 2 of PERIO-01 is planned for expansion of the optimal dose.Trial RegistrationNCT04935229Ethics ApprovalThe study was IRB approved at all sites and participants signed written informed consen

Predicting treatment Response based on Dual assessment of magnetic resonance Imaging kinetics and Circulating Tumor cells in patients with Head and Neck cancer (PREDICT-HN): matching ‘liquid biopsy’ and quantitative tumor modeling

Abstract Background Magnetic resonance imaging (MRI) has improved capacity to visualize tumor and soft tissue involvement in head and neck cancers. Using advanced MRI, we can interrogate cell density using diffusion weighted imaging, a quantitative imaging that can be used during radiotherapy, when diffuse inflammatory reaction precludes PET imaging, and can assist with target delineation as well. Correlation of circulating tumor cells (CTCs) measurements with 3D quantitative tumor characterization could potentially allow selective, patient-specific response-adapted escalation or de-escalation of local therapy, and improve the therapeutic ratio, curing the greatest number of patients with the least toxicity. Methods The proposed study is designed as a prospective observational study and will collect pretreatment CT, MRI and PET/CT images, weekly serial MR imaging during RT and post treatment CT, MRI and PET/CT images. In addition, blood sample will be collected for biomarker analysis at those time intervals. CTC assessments will be performed on the CellSave tube using the FDA-approved CellSearch® Circulating Tumor Cell Kit (Janssen Diagnostics), and plasma from the EDTA blood samples will be collected, labeled with a de-identifying number, and stored at − 80 °C for future analyses. Discussion The primary objective of the study is to evaluate the prognostic value and correlation of weekly tumor response kinetics (gross tumor volume and MR signal changes) and circulating tumor cells of mucosal head and neck cancers during radiation therapy using MRI in predicting treatment response and clinical outcomes. This study will provide landmark information as to the utility of CTCs (‘liquid biopsy) and tumor-specific functional quantitative imaging changes during treatment to guide personalization of treatment for future patients. Combining the biological information from CTCs and the structural information from MRI may provide more information than either modality alone. In addition, this study could potentially allow us to determine the optimal time to obtain MR imaging and/ or CTCs during radiotherapy to assess tumor response and provide guidance for patient selection and stratification for future dose escalation or de-escalation strategies. Trial registration Clinicaltrials.gov (NCT03491176). Date of registration: 9th April 2018. (retrospectively registered). Date of enrolment of the first participant: 30th May 2017