Correlating tumor metabolic progression index measured by serial FDG PET-CT, apparent diffusion coefficient measured by magnetic resonance imaging (MRI) and blood genomics to patient's outcome in advanced colorectal cancer: the CORIOLAN study.
ABSTRACT: Metastatic colorectal cancer (mCRC) may present various behaviours that define different courses of tumor evolution. There is presently no available tool designed to assess tumor aggressiveness, despite the fact that this is considered to have a major impact on patient outcome.CORIOLAN is a single-arm prospective interventional non-therapeutic study aiming mainly to assess the natural tumor metabolic progression index (TMPI) measured by serial FDG PET-CT without any intercurrent antitumor therapy as a prognostic factor for overall survival (OS) in patients with mCRC.Secondary objectives of the study aim to test the TMPI as a prognostic marker for progression-free survival (PFS), to assess the prognostic value of baseline tumor FDG uptake on PFS and OS, to compare TMPI to classical clinico-biological assessment of prognosis, and to test the prognostic value on OS and PFS of MRI-based apparent diffusion coefficient (ADC) and variation of vADC using voxel-based diffusion maps.Additionally, this study intends to identify genomic and epigenetic factors that correlate with progression of tumors and the OS of patients with mCRC. Consequently, this analysis will provide information about the signaling pathways that determine the natural and therapy-free course of the disease. Finally, it would be of great interest to investigate whether in a population of patients with mCRC, for which at present no known effective therapy is available, tumor aggressiveness is related to elevated levels of circulating tumor cells (CTCs) and to patient outcome.Tumor aggressiveness is one of the major determinants of patient outcome in advanced disease. Despite its importance, supported by findings reported in the literature of extreme outcomes for patients with mCRC treated with chemotherapy, no objective tool allows clinicians to base treatment decisions on this factor. The CORIOLAN study will characterize TMPI using FDG-PET-based metabolic imaging of patients with chemorefractory mCRC during a period of time without treatment. Results will be correlated to other assessment tools like DW-MRI, CTCs and circulating DNA, with the aim to provide usable tools in daily practice and in clinical studies in the future. ClinicalTrials.gov Number: NCT01591590.
Project description:Colorectal cancer (CRC) is one of the major causes of cancer-related deaths. Early detection of tumor relapse is crucial for determining the most appropriate therapeutic management. In clinical practice, computed tomography (CT) is routinely used, but small tumor changes are difficult to visualize, and reliable blood-based prognostic and monitoring biomarkers are urgently needed. The aim of this study was to prospectively validate a gene expression panel (composed of GAPDH, VIL1, CLU, TIMP1, TLN1, LOXL3 and ZEB2) for detecting circulating tumor cells (CTCs) as prognostic and predictive tool in blood samples from 94 metastatic CRC (mCRC) patients. Patients with higher gene panel expression before treatment had a reduced progression-free survival (PFS) and overall-survival (OS) rates compared with patients with low expression (p = 0.003 and p ? 0.001, respectively). Patients with increased expression of CTCs markers during treatment presented PFS and OS times of 8.95 and 11.74 months, respectively, compared with 14.41 and 24.7 for patients presenting decreased expression (PFS; p = 0.020; OS; p ? 0.001). Patients classified as non-responders by CTCs with treatment, but classified as responders by CT scan, showed significantly shorter survival times (PFS: 8.53 vs. 11.70; OS: 10.37 vs. 24.13; months). In conclusion, our CTCs detection panel demonstrated efficacy for early treatment response assessment in mCRC patients, and with increased reliability compared to CT scan.
Project description:Using approved methods, circulating tumor cells (CTCs) are only isolated from blood in 30%-50% of metastatic colorectal cancer (mCRC) patients. We previously validated a technique to isolate circulating tumor cells (CTCs) in a cohort of mCRC patients by combining immunomagnetic enrichment of EpCAM+/CD45- cells with qRT-PCR amplification of CK20 and survivin expression. Here, we examined the prognostic utility of CTC epithelial-mesenchymal transition (EMT) and stem cell gene expression. An 8?ml blood sample was collected from 78 consecutive mCRC patients before treatment with investigational and standard chemotherapeutics. The mRNA expression of EMT (PI3K?, Akt-2, Twist1) and stem cell (ALDH1) markers was measured. Associations between CTC gene expression and progression-free survival (PFS) and overall survival (OS) were determined using Cox regression models. Among patients without CK20 or survivin-expressing CTCs (n=17), 55% had expression of ALDH1, PI3K? and/or Akt-2. Patients with positive CTC Akt-2 expression had a significantly shorter median PFS (3.0 versus 4.0 months) compared with those without CTC Akt-2 expression in univariable (hazard ratio (HR)=1.61; log-rank P=0.034) and multivariable analyses (HR=1.70; adjusted P=0.041). In univariable analysis, CTC ALDH1 expression was associated with shorter OS (10.0 versus 38.6 months; HR=2.04, P=0.021). Patients with CTCs expressing ALDH1, PI3K? and/or Akt-2 had a significantly inferior PFS (3.0 versus 7.7 months; HR=1.88, P=0.015) and OS (10.0 versus 26.8+ months; HR=2.25, P=0.050) in univariable, but not multivariable, analysis. CONCLUSIONS:CTC Akt-2 expression may serve as a clinically useful prognostic marker in mCRC patients and warrants further evaluation in prospective trials.
Project description:Background Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ? 210 for CXCR4+ tumor, ?7% CTCs with CXCR4 expression (CXCR4+ CTCs), and ?6 CTCs/7.5 mL blood. Baseline H-score for CXCR4+ tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4+ CTCs ?7% was prognostic of shorter PFS. CTCs ?6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4+ CTCs ?7% was prognostic of shorter PFS. CTC count ?6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS.
Project description:The presence of KRAS mutations in patients with metastatic colorectal cancer (mCRC) predicts poor response to agents targeting the EGFR. Even in patients with RAS wild type (WT) tumors, resistance eventually develops due to multiple mechanisms, including the expansion of previously undetected KRAS mutated clones. In this feasibility study, we aimed to detect KRAS exon 2 mutations in serial samples of circulating tumor cells (CTCs) of RAS WT patients with mCRC captured by the Isolation by Size of Epithelial Tumor cells (ISET) system.CTC isolation using the ISET system was performed from prospectively collected blood samples obtained from patients with RAS and BRAF WT mCRC prior to first-line therapy initiation, at first imaging assessment and on disease progression. CTCs were enumerated using hematoxylin & eosin and CD45 double stain on a single membrane spot. DNA was extracted from 5 spots and KRAS exon 2 mutations were detected using a custom quantitative Polymerase Chain Reaction (qPCR) assay.Fifteen patients were enrolled and 28 blood samples were analyzed. In 9 (60%) patients, at least one sample was positive for the presence of a KRAS exon 2 mutation. In 11 out of 28 samples (39.2%) with detectable CTCs a KRAS mutation was detected; the corresponding percentages for baseline and on progression samples were 27% and 37.5%, respectively. The most commonly detected mutations were G13D and G12C (n=3). The presence of KRAS mutated CTCs at baseline was not prognostic for either PFS (P=.950) or OS (P=.383). CTC kinetics did not follow tumor response patterns.The results demonstrate that using a qPCR-based assay, KRAS exon 2 mutations could be detected in CTCs captured by the ISET system from patients with RAS WT primary tumors. However, the clinical relevance of these CTCs remains to be determined in future studies.
Project description:It is not well determined whether primary tumor resection is associated with better outcomes in metastatic colorectal cancer (mCRC) patients treated with bevacizumab. In this meta-analysis, we aimed to assess the prognostic role of primary tumor resection in mCRC treated with bevacizumab. Electronic databases including the Cochrane library, Embase, and Pubmed were searched until April 2018. Clinical studies assessing the influence of primary tumor resection on the efficacy of bevacizumab in patients with mCRC were identified. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Seven studies including 2760 mCRC patients were finally included. The results of the meta-analysis were in favor of bevacizumab to patients with resected primary tumor in terms of OS (HR?=?0.50, 95%CI: 0.39-0.64; p?<?0.01), and PFS (HR?=?0.65, 95%CI: 0.51-0.81; p?<?0.01). Administration of bevacizumab in mCRC patients with resected primary tumor had a better OS (HR?=?0.65, 95%CI: 0.56-0.74; p?<?0.01), when compared to chemotherapy(CT). Adding bevacizumab to mCRC patients without resection of primary tumor also had a better OS (HR?=?0.78, 95%CI: 0.65-0.94; p?<?0.01) and PFS (HR?=?0.71, 95%CI: 0.57-0.88; p?<?0.01) compared to chemotherapy alone. In conclusion, mCRC patients with resected primary tumor have better survival than those without surgery of primary tumor when treated with bevacizumab. Primary tumor resection status should be taken into consideration when using bevacizumab in mCRC.
Project description:Fluorine-18 flurodeoxyglucose positron emission tomography (FDG-PET) imaging has rapidly become the standard of care for staging patients with lung cancer. We evaluated the prognostic value of metabolic tumor volume (MTV), a measure of tumor burden on FDG-PET imaging, in patients with non-small-cell lung cancer (NSCLC) treated definitively.A retrospective review identified 61 patients with NSCLC who underwent FDG-PET imaging for pretreatment staging. Metabolically active tumor regions were segmented on the PET scans semiautomatically to calculate the total body MTV. We determined the relationship of overall survival (OS) and progression-free survival (PFS) with MTV in the entire cohort, and in the subgroup treated definitively.The estimated median PFS and OS for the entire cohort were 11.1 months and 18.9 months. Higher MTV was significantly associated with worse OS (P = 0.00075) and PFS (P = 0.00077). For definitively treated patients, when MTV was analyzed as a binary value above or below the median value, 2-year PFS was 60% versus 39.7% (median PFS 34.9 vs. 11.9 months) and 2-year OS was 79.7% versus 33.3% (median OS 41.9 vs. 18.9 months), respectively (log-rank P = 0.12 for PFS and P = 0.066 for OS). When MTV was analyzed as a continuous variable, multivariate Cox proportional hazards analysis demonstrated a trend to worse PFS (hazard ratio [HR] = 1.31; P = 0.12) and significantly worse OS (HR = 1.53; P = 0.018) with increasing MTV after controlling for known prognostic variables.Tumor burden as assessed by MTV yields prognostic information on survival beyond that of established prognostic factors in patients with NSCLC treated definitively.
Project description:Background and objectives: The importance of induction chemotherapy (ICT) followed by concurrent chemoradiotherapy (CCRT) has been re-established in recent years aiming at fewer metastatic sites and better control of the disease. We prospectively studied the possibility of early prediction of overall survival (OS) and progression-free survival (PFS) after 3 cycles of chemotherapy with doxetacel, cisplatin and 5-fluorouracil using 18-fluoro-2-deoxy-glucose positron emission tomography computed tomography (18F-FDG PET/CT) in patients with head and neck squamous cell cancer. To our knowledge, this is the first such study. Materials and Methods: Thirty-five patients were studied. They underwent an 18F-FDG PET/CT examination twice: a day before ICT and 10⁻14 days after the last cycle of ICT. Tumor-standardized uptake value (SUVmax) and hypermetabolic tumor volume were measured on both scans. The mean age of patients was 56.5 years. Complete responses to CCRT PFS and OS were calculated. Results: Our results showed that a decrease of ≥30% in the SUVmax value after ICT was a prognostic factor of tumor response to PFS and OS (p = 0.026 and p = 0.021). The groups of patients with a SUVmax between 10 and 14.5 in the primary tumor on a pre-ICT 18F-FDG PET/CT scan had statistically shorter PFS and OS (p = 0.001, p = 0.006) when compared with other groups of patients with SUVmax less than 10 or SUVmax more than 14.5. A decrease of less than 55% of hypermetabolic tumor volume of the primary tumor was significantly related to poor prognosis in PFS and OS (p = 0.033, p = 0.017). Conclusions: SUVmax and hypermetabolic tumor volume measured on 18F-FDG PET/CT after ICT might be valuable prognostic tools for predicting OS and PFS and, thus, for the selection of patients with head and neck cancer who will benefit from CCRT.
Project description:Purpose:This study aimed to evaluate the role of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in expression of tumor programmed death ligand-1 (PD-L1) expression and prognostic significance of 18F-FDG PET/CT at different PD-L1 status in patients with lung adenocarcinoma. Patients and Methods:Seventy-three patients with primary lung adenocarcinoma who received 18F-FDG PET/CT before treatment were retrospectively included in this study. Expression of tumor PD-L1, programmed death-1 (PD-1) and glucose metabolic parameters were evaluated. Results:Tumor PD-L1 expression was positively correlated with maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), hexokinase II (HK-II) and glucose transporter 1 (GLUT-1) (P<0.0001 for all). SUVmax was a unique independent predictor of tumor PD-L1 expression, with an optimal cut-off value of 9.5. For all the patients, tumor stage (P<0.001) and SUVmax (P=0.009) were independent prognostic indicators of disease-free survival (DFS)/progression-free survival (PFS) while carcino-embryonic antigen (CEA) (P=0.003), Ki67 (P=0.042), PD-L1 (P=0.048) and TLG (P=0.004) were independent prognostic indicators of overall survival (OS). Tumor stage (P=0.004) and SUVmax (P=0.022) were independent prognostic indicators of DFS/PFS while TLG (P=0.012) and CEA (P=0.045) were independent prognostic indicators of OS in the PD-L1-positive group. In the PD-L1-negative group, tumor stage (P=0.002) and CEA (P=0.006) were unique independent prognostic indicators of DFS/PFS and OS, respectively. Conclusion:18F-FDG PET/CT may potentially predict tumor PD-L1 expression and play a role in predicting prognosis of PD-L1/PD-1 immunotherapy in lung adenocarcinoma.
Project description:BACKGROUND:Circulating tumour cells (CTCs) in blood associate with overall survival (OS) of cancer patients, but they are detected in extremely low numbers. Large tumour-derived extracellular vesicles (tdEVs) in castration-resistant prostate cancer (CRPC) patients are present at around 20 times higher frequencies than CTCs and have equivalent prognostic power. In this study, we explored the presence of tdEVs in other cancers and their association with OS. METHODS:The open-source ACCEPT software was used to automatically enumerate tdEVs in digitally stored CellSearch® images obtained from previously reported CTC studies evaluating OS in 190 CRPC, 450 metastatic colorectal cancer (mCRC), 179 metastatic breast cancer (MBC) and 137 non-small cell lung cancer (NSCLC) patients before the initiation of a new treatment. RESULTS:Presence of unfavourable CTCs and tdEVs is predictive of OS, with respective hazard ratios (HRs) of 2.4 and 2.2 in CRPC, 2.7 and 2.2 in MBC, 2.3 and 1.9 in mCRC and 2.0 and 2.4 in NSCLC, respectively. CONCLUSIONS:tdEVs have equivalent prognostic value as CTCs in the investigated metastatic cancers. CRPC, mCRC, and MBC (but not NSCLC) patients with favourable CTC counts can be further prognostically stratified using tdEVs. Our data suggest that tdEVs could be used in clinical decision-making.
Project description:Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC).Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions.Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8-10.5) and 4.2 months (95% CI: 3.4-4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21-0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36-0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS.The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC.ClinicalTrials.gov NCT01290926.