Metastatic Colorectal Carcinoma Patients Research Articles

34P Circulating tumor DNA (ctDNA) testing in tissue RAS/BRAF wild-type metastatic colorectal carcinoma (mCRC) patients (pts) enrolled in the LIquid BIopsy monoclonal Antibodies (LIBImAb) study

34P Circulating tumor DNA (ctDNA) testing in tissue RAS/BRAF wild-type metastatic colorectal carcinoma (mCRC) patients (pts) enrolled in the LIquid BIopsy monoclonal Antibodies (LIBImAb) study

Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?

Colorectal carcinoma (CRC) with deficiency of the deficient mismatch repair (dMMR) pathway/microsatellite instability (MSI) is characterized by a high mutation load and infiltration of immune cells in the tumor microenvironment. In agreement with these findings, clinical trials have demonstrated a significant activity of immune checkpoint inhibitors (ICIs) in dMMR/MSI metastatic CRC (mCRC) patients and, more recently, in CRC patients with early disease undergoing neoadjuvant therapy. However, despite high response rates and durable clinical benefits, a fraction of mCRC patients, up to 30%, showed progressive disease when treated with single agent anti-programmed cell death 1 (PD-1) antibody. This article discusses the three main causes that have been associated with early progression of dMMR/MSI mCRC patients while on treatment with ICIs, i.e., misdiagnosis, pseudoprogression and tumor heterogeneity. While pseudoprogression probably does not play a relevant role, data from clinical studies demonstrate that some dMMR/MSI CRC cases with rapid progression on ICIs may be misdiagnosed, underlining the importance of correct diagnostics. More importantly, evidence suggests that dMMR/MSI mCRC is a heterogeneous group of tumors with different sensitivity to ICIs. Therefore, we propose novel diagnostic and therapeutic strategies to improve the outcome of dMMR/MSI CRC patients.

The Oncology Biomarker Discovery framework reveals cetuximab and bevacizumab response patterns in metastatic colorectal cancer

Precision medicine has revolutionised cancer treatments; however, actionable biomarkers remain scarce. To address this, we develop the Oncology Biomarker Discovery (OncoBird) framework for analysing the molecular and biomarker landscape of randomised controlled clinical trials. OncoBird identifies biomarkers based on single genes or mutually exclusive genetic alterations in isolation or in the context of tumour subtypes, and finally, assesses predictive components by their treatment interactions. Here, we utilise the open-label, randomised phase III trial (FIRE-3, AIO KRK-0306) in metastatic colorectal carcinoma patients, who received either cetuximab or bevacizumab in combination with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI). We systematically identify five biomarkers with predictive components, e.g., patients with tumours that carry chr20q amplifications or lack mutually exclusive ERK signalling mutations benefited from cetuximab compared to bevacizumab. In summary, OncoBird characterises the molecular landscape and outlines actionable biomarkers, which generalises to any molecularly characterised randomised controlled trial.

RAS testing of circulating cell-free DNA (cfDNA) from tissue RAS/BRAF wild-type metastatic colorectal carcinoma (mCRC) patients: Preliminary data from the Liquid Biopsy Monoclonal Antibodies in mCRC (LIBImAb) study.

3046 Background: In mCRC patients RAS/BRAF testing is usually performed on tissue biopsy in order to select patients for treatment with anti-EGFR monoclonal antibodies. Several studies described discordant RAS status between tissue and cfDNA testing from the same patients. In addition, up to 30% of patients with secondary resistance to anti-EGFR therapies become RAS mutant at progression. The LIBImAb study is a phase III, randomized, open-label, comparative, multi-centre trial to assess the superiority in terms of efficacy of bevacizumab versus cetuximab in combination with FOLFIRI chemotherapy in patients with mCRC, RAS/BRAF wild-type on tumor tissue and RAS mutant (RASmut) at liquid biopsy. This study is supported by the Italian Drug Agency (AIFA). We report preliminary data of liquid biopsy testing. Methods: Plasma samples from enrolled patients are analyzed for variants in exons 2, 3 and 4 of KRAS and NRAS genes and for codon 600 BRAF mutations using the fully automated Idylla system (Biocartis). Patients RASmut on liquid biopsy at baseline are randomized to receive FOLFIRI plus Cetuximab or FOLFIRI plus Bevacizumab. Patients RAS wild-type on cfDNA at baseline, are treated with FOLFIRI plus Cetuximab up to 8 cycles and, if not progressed, they are retested for RAS mutations on cfDNA. RASmut patients at re-screening are randomized to continue Cetuximab or to switch to Bevacizumab. Results: Plasma samples from 169 tissue RAS/BRAF wild-type mCRC patients at baseline and 75 patients at 8 cycles of treatment have been tested as of January 31, 2023. Analysis of baseline plasma samples detected 16 RAS mutations in 16/169 patients (9.5%). In particular, 12 KRAS variants (7.1%, 8 in exon 2 and 4 in exon 3) and 4 NRAS variants (2.3%, all in exon 2) were found. The Idylla test also detected 3 BRAFV600 mutations (1.8%) in 3 additional patients. The overall concordance between tissue and cfDNA testing for RAS/BRAF variants was 88.8%. RAS mutations were also detected in 6/75 (8%) plasma samples obtained at 8 cycles of FOLFIRI/cetuximab treatment. The cfDNA test revealed the presence of 5 KRAS (6.7%, 3 in exon 2 and 1 in exon 3) and 1 NRAS mutation (1.3%, exon 2). A BRAFV600 variant was detected in 1 additional patient (1.3%). The rate of RAS/BRAF mutant cases at 8 cycles of treatment was 9.3%. Conclusions: These preliminary data suggest that liquid biopsy might better recapitulate the heterogeneity of mCRC and might be useful in clinical practice to complement tissue testing. The clinical relevance of RAS variants detected in cfDNA will be determined in the LIBImAb trial.

Analysis of Circulating Tumor DNA in Synchronous Metastatic Colorectal Cancer at Diagnosis Predicts Overall Patient Survival.

Sporadic colorectal cancer (sCRC) initially presents as metastatic tumors in 25-30% of patients. The 5-year overall survival (OS) in patients with metastatic sCRC is 50%, falling to 10% in patients presenting with synchronous metastatic disease (stage IV). In this study, we systematically analyzed the mutations of RAS, PIK3CA and BRAF genes in circulating tumor DNA (ctDNA) and tumoral tissue DNA (ttDNA) from 51 synchronous metastatic colorectal carcinoma (SMCC) patients by real-time PCR, and their relationship with the clinical, biological and histological features of disease at diagnosis. The highest frequency of mutations detected was in the KRAS gene, in tumor biopsies and plasma samples, followed by mutations of the PIK3CA, NRAS and BRAF genes. Overall, plasma systematically contained those genetic abnormalities observed in the tumor biopsy sample from the same subject, the largest discrepancies detected between the tumor biopsy and plasma from the same patient being for mutations in the KRAS and PIK3CA genes, with concordances of genotyping results between ttDNA and ctDNA at diagnosis of 75% and 84%, respectively. Of the 51 SMCC patients in the study, 25 (49%) showed mutations in at least 1 of the 4 genes analyzed in patient plasma. From the prognostic point of view, the presence and number of the most common mutations in the RAS, PIK3CA and BRAF genes in plasma from SMCC patients are independent prognostic factors for OS. Determination of the mutational status of ctDNA in SMCC could be a key tool for the clinical management of patients.

A Cost-effectiveness Analysis of Adding Cetuximab to the First-line Treatment of Metastatic Colorectal Carcinoma in Iran; Considering Genetic Screening for Precision Medicine.

This study aimed to evaluate the cost-effectiveness of cetuximab in different genetic populations of metastatic colorectal carcinoma patients, including KRAS and RAS wild types and mutants, when added to FOLFIRI treatment regimens for evidence-based disease management in Iran. A Markov decision model was designed in TreeAge software with the three states of stable, progress, and death. Clinical outcomes were extracted from published clinical studies, and costs were extracted from the Iranian local data. The primary outcome was an incremental cost-effectiveness ratio (ICER) in the simulated population. The cost-utility model from the perspective of the health system indicated that the average direct medical costs of a patient that has not been genetically screened are $56,985.27 and $20,767.74 in FOLFIRI + cetuximab and FOLFIRI regimens, respectively. However, costs per patient in the KRAS wild-type population were $21,845.52 in FOLFIRI and $78,321.22 in FOLFIRI + cetuximab. In RAS wild-type patients, FOLFIRI and FOLFIRI + cetuximab costs per patient were $23,111.62 and $84,976.39, respectively. Incremental QALYs for the above scenarios were 0.069, 0.193, and 0.285, respectively. Therefore, the ICER of add-on cetuximab in Iran compared to the treatment alternatives in the scenarios with and without KRAS screening was $520,771.55/QALY, $292,768.16/QALY, and $217,460.51/QALY. Although genetic screening in precision medicine reduces costs per outcome, according to the willingness-to-pay threshold of $4349.50 in the Iranian health system, add-on cetuximab to the FOLFIRI regimen is not a cost-effective strategy even with genetic screening and a 20% price reduction.

P-106 Evaluating sex as a predictive marker for response to bevacizuamb in metastatic colorectal carcinoma: Pooled analysis of 3,369 patients in the ARCAD database

Previous studies suggest a possible sex-specific response to bevacizumab in metastatic colorectal carcinoma, showing a benefit in males, while the effect in females is less significant. Therefore, we evaluated response to bevacizumab according to sex. Data from 3369 metastatic colorectal carcinoma patients enrolled on four first-line randomized trials testing chemotherapy with or without bevacizumab (2000-2007) were pooled. Association between sex and progression-free survival and overall survival was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction effect between sex and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut-point of 60 years to evaluate the possible role of menopausal-related effects. Median overall survival was not statistically different between males and females in the entire study population (18.8 vs. 17.6 months, respectively; adjusted hazard ratio=0.92, 95% CI=0.84-1.02, p=0.11). Bevacizumab was associated with an improved median overall survival in males and females, with a 2.3- and 0.6-months benefit, respectively, as well as an improved progression-free survival (2.0 and 1.9-months benefit, respectively). Stratified by age, bevacizumab resulted in improved progression-free survival and overall survival in males at both age categories. In females at or above the age of 60 (n=731), bevacizumab resulted in improved progression-free survival and overall survival. However, in females below the age of 60 (n=634), overall survival benefit did not reach statistical significance (adjusted hazard ratio=0.94, 95% CI 0.74-1.20). Our results confirmed the median overall survival benefit from addition of bevacizumab to first-line chemotherapy in metastatic colorectal carcinoma in both sexes. Among females, the benefit was less than 1 month. For females under the age of 60, there was no overall survival benefit.

Dynamics of RAS/BRAF Mutations in cfDNA from Metastatic Colorectal Carcinoma Patients Treated with Polychemotherapy and Anti-EGFR Monoclonal Antibodies.

Simple SummaryIncreasing evidence suggests that circulating cell-free DNA (cfDNA) testing might allow for monitoring the response to anti-EGFR monoclonal antibodies in patients with metastatic colorectal carcinoma (mCRC). However, few data are available in treatment-naïve patients. We tested cfDNA samples obtained from mCRC patients enrolled in a phase III trial of the anti-EGFR monoclonal antibody cetuximab plus chemotherapy as first-line treatment. Analysis of serial plasma samples revealed a complex dynamic of RAS/BRAF mutations in response to treatment, with transitory peaks of these mutations that were not associated with resistance to therapy. Overall, our findings suggest that early appearance of RAS/BRAF mutations in the plasma of patients receiving first-line anti-EGFR agents in combination with chemotherapy should not be considered as marker of resistance.Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline (n = 37), at 8 weeks of treatment (n = 32), progressive disease (PD; n = 36) and 3 months after PD (n = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients (p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.

Dynamics of neutrophil-to-lymphocyte ratio predict outcomes of metastatic colorectal carcinoma patients treated by FOLFOX.

Peripheral blood cell count is the most common clinical laboratory test. Neutrophil-to-lymphocyte ratio (NLR) as an economic marker has been reported in various cancer types. It is believed that NLR is associated with the prognosis and treatment outcomes of some cancers. Low baseline NLR has been reported as associated with better overall survival (OS) in advanced cancer patients. In this study, we aimed to determine whether the changes of NLR may predict the outcome of metastatic colorectal carcinoma (mCRC) patients treated with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) combined with bevacizumab/cetuximab. The clinical data obtained from 128 mCRC patients between January 2014 and December 2018 were retrospectively analyzed. The NLR values of patients were calculated after 4 cycles of treatments. Kaplan-Meier analysis and Cox regression modeling were performed to assess the impact of NLR dynamics on OS and progression-free survival (PFS). Among the 128 participants, the optimum pre-treatment NLR cutoff value was 3. A total of 70 (54.7%) participants had a pre-treatment of NLR lower than 3. The median of PFS was 9.1 months for NLR <3 compared with 6.1 months for pre-treatment NLR >3. A lower pre-treatment NLR was significantly associated with better PFS (P<0.001), but not associated with OS (P=0.064). A total of 94 (73.4%) participants had a post-treatment NLR <3, which was associated with better PFS and OS (P=0.007). However, changes in NLR significantly affected PFS and OS. Decrease in post-treatment NLR was associated with longer PFS and OS. Patients with changes from low pre-treatment NLR to high post-treatment NLR had worse OS and PFS than that of NLR changes from high to low. It is not the NLR but the changes of NLR that may predict the efficacy of FOLFOX treatment in mCRC patients.

448P Efficacy of combinations of BRAF inhibitors and anti-EGFR antibodies in metastatic colorectal carcinoma (mCRC) patients with mBRAF in the real clinical practice

Combination of BRAF inhibitors and anti-EGFR antibodies is a standard of 2nd and subsequent line of treatment in pts with mBRAF mCRC. We performed analysis of prospective multicentric database of pts with mBRAF metastatic CRC to evaluate the efficacy of such approach in the real clinical practice.

ChIP-seq of plasma cell-free nucleosomes identifies gene expression programs of the cells of origin.

Cell-free DNA in human plasma provides access to molecular information about the pathological processes in the organs or tumors from which it originates. These DNA fragments are derived from fragmented chromatin in dying cells, and retain some of the cell of origin histone modifications. Here, we apply chromatin immunoprecipitation of cell-free nucleosomes carrying active chromatin modifications followed by sequencing (cfChIP-seq) to 268 human samples. In healthy donors, we identified bone marrow megakaryocytes, but not erythroblasts, as major contributors to the cfDNA pool. In patients with a range of liver diseases, we show that we can identify pathology- related changes in hepatocyte transcriptional programs. In metastatic colorectal carcinoma patients, we detected clinically relevant, and patient-specific information, including transcriptionally active HER2 amplifications. Altogether, cfChIP-seq using low sequencing depth, provides systemic and genome-wide information, can inform diagnosis, and facilitate interrogation of physiological and pathological processes using blood samples.

Mutational profiles and clinical outcomes in metastatic colorectal carcinoma patients with different metastases sites.

e16020 Background: To compare the difference of genomic and survival of first metastases site between first metastases site of metastatic colorectal cancer (mCRC) in liver and other sites (bone, brain, lung, and so on). Methods: Genomic mutations and clinic data of 113,4 CRCs (consisting of 533 metastases) were collected from TCGA database. According to first site(s) of metastases, patients were categorized into group 1 (liver as first metastases site, n = 405) and group 2 (other organs as first metastases site, n = 128). OS curves were estimated with Kaplan-Meier method, p values were calculated by fisher exact test. Results: Mutation frequency in GNAS (2.34%), KRAS (37.78%), BRAF (16.41%) and proportion of MSI-high (8.5%) was significantly higher in group2. Compared with group2, group1 showed significantly higher mutation rate of APC (78.52%) and TP53 (77.28%). We assessed overall survival in the two groups. OS was significantly better for patients in group1 than in group2 (HR 0.57, 95% CI 0.41-0.79, p = 0.00075). Conclusions: According to the results of this study, mCRC patients showed different mutational signatures with respect to the site of first metastases, and presented higher OS rate in liver metastases group. Our findings provided new knowledge to understand the biological progress of different metastases and develop new prognostic markers for metastatic colorectal cancer.

Peripheral Innate Lymphoid Cells Are Increased in First Line Metastatic Colorectal Carcinoma Patients: A Negative Correlation With Th1 Immune Responses

Several distinct innate lymphoid cell (ILC) populations have been recently identified and shown to play a critical role in the immediate immune defense. In the context of tumors, there is evidence to support a dual role for ILCs with pro- or antitumor effects, depending on the ILC subset and the type of cancer. This ambivalent role has been particularly well-described in colorectal cancer models (CRC), but the presence and the evolution of ILCs in the peripheral blood of metastatic CRC (mCRC) patients have not yet been explored. Here, we investigated the distribution of ILC subsets in 96 mCRC patients who were prospectively included in the “Epitopes-CRC02” trial. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry at metastatic diagnosis and after 3-months of treatment. The treatments consisted of Oxaliplatin-based chemotherapies for 76% of the patients or Folfiri (5FU, Irinotecan) chemotherapies for 14% of patients. Compared to healthy donors, the frequency of total ILCs was dramatically increased at metastatic diagnosis. CD56+ ILC1-like cells were expanded, whereas ILC2, NCR− ILCP and NCR+ ILCP subsets were decreased. Combined analysis with the systemic anti-telomerase hTERT Th1 CD4 response revealed that patients with low anti-TERT Th1 CD4 responses had the highest frequencies of total ILCs at diagnosis. Of those, 91% had synchronous metastases, and their median progression-free survival was 7.43 months (vs. 9.17 months for the other patients). In these patients, ILC1 and ILC2 were significantly decreased, whereas CD56+ ILC1-like cells were significantly increased compared to patients with low frequency of total ILCs and high anti-TERT responses. After treatment, the NCR+ ILCP were further decreased irrespective of the chemotherapy regimen, whereas the balance between ILC1 and CD56+ ILC1-like cells was modulated mainly by the Folfiri regimen in favor of ILC1. Altogether our results describe the effects of different chemotherapies on ILCs in mCRC patients. We also establish for the first time a link between frequency of ILCs and anti-tumor CD4 T cell responses in cancer patients. Thus, our study supports an interest in monitoring ILCs during cancer therapy to possibly identify predictive biomarkers in mCRC.

Efficacy and Safety of Aflibercept in Combination With Chemotherapy Beyond Second-Line Therapy in Metastatic Colorectal Carcinoma Patients: An AGEO Multicenter Study

BackgroundAlthough no data have been reported beyond second-line therapy, aflibercept is approved in this setting in many countries. We conducted a multicenter study to analyze the efficacy and safety of a aflibercept–chemotherapy regimen beyond second-line therapy in patients with metastatic colorectal cancer. Patients and MethodsMetastatic colorectal cancer patients treated with aflibercept beyond second-line therapy were included. Objective response rate, overall survival (OS), and progression-free survival (PFS) were assessed. ResultsA total of 130 patients were included. Median OS and PFS were 7.6 months (95% confidence interval, 6.2-9.3) and 3.3 months (95% confidence interval, 2.7-3.8), respectively. The best response rates were partial response 6.9%, stable disease 38.5%, progressive disease 42.5%, and not evaluable 12%. According to whether patients received previous FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin)-bevacizumab or not, OS was 7.7 and 8.1 months (P = .31), and PFS was 2.9 and 3.9 months (P = .02), respectively. Interestingly, PFS and OS were both significantly improved by 4% and 5% per month, respectively, without antiangiogenic treatment before the initiation of the aflibercept regimen. The negative effect of prior FOLFIRI–bevacizumab or shorter time since last bevacizumab was maintained in multivariate analysis for both OS and PFS. ConclusionThe aflibercept–chemotherapy regimen is a therapeutic option in patients with chemorefractory disease beyond second-line therapy, in particular in patients with an antiangiogenic-free interval.

P-099 - Triplet chemotherapy plus cetuximab as first-line treatment in RAS wild-type metastatic colorectal carcinoma patients

P-099 - Triplet chemotherapy plus cetuximab as first-line treatment in RAS wild-type metastatic colorectal carcinoma patients

Genomic Profiling of KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer Patients Reveals Novel Mutations in Genes Potentially Associated with Resistance to Anti-EGFR Agents.

Previous findings suggest that metastatic colorectal carcinoma (mCRC) patients with KRAS/NRAS/BRAF/PIK3CA wild-type (quadruple-wt) tumors are highly sensitive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs). However, additional molecular alterations might be involved in the de novo resistance to these drugs. We performed a comprehensive molecular profiling of 21 quadruple-wt tumors from mCRC patients enrolled in the “Cetuximab After Progression in KRAS wild-type colorectal cancer patients” (CAPRI-GOIM) trial of first line FOLFIRI plus cetuximab. Tumor samples were analyzed with a targeted sequencing panel covering single nucleotide variants (SNVs), insertions/deletions (Indels), copy number variations (CNVs), and gene fusions in 143 cancer-related genes. The analysis revealed in all 21 patients the presence of at least one SNV/Indel and in 10/21 cases (48%) the presence of at least one CNV. Furthermore, 17/21 (81%) patients had co-existing SNVs/Indels in different genes. Quadruple-wt mCRC from patients with the shorter progression free survival (PFS) were enriched with peculiar genetic alterations in KRAS, FBXW7, MAP2K1, and NF1 genes as compared with patients with longer PFS. These data suggest that a wide genetic profiling of quadruple-wt mCRC patients might help to identify novel markers of de novo resistance to anti-EGFR MoAbs.

Analysis of liquid biopsies from metastatic colorectal carcinoma (mCRC) patients (pts) enrolled in the ERMES clinical trial.

e15507Background: Liquid biopsy is an alternative to tissue biopsy for biomarker testing. In addition, it can be used to monitor the response to therapy and the molecular evolution of the disease. ...

RAS testing of liquid biopsy correlates with the outcome of metastatic colorectal cancer patients treated with first-line FOLFIRI plus cetuximab in the CAPRI-GOIM trial

Liquid biopsy is an alternative to tissue for RAS testing in metastatic colorectal carcinoma (mCRC) patients. Little information is available on the predictive role of liquid biopsy RAS testing in patients treated with first-line anti-EGFR monoclonal antibody-based therapy. In the CAPRI-GOIM trial, 340 KRAS exon-2 wild-type mCRC patients received first-line cetuximab plus FOLFIRI. Tumor samples were retrospectively assessed by next generation sequencing (NGS). Baseline plasma samples were analyzed for KRAS and NRAS mutations using beads, emulsion, amplification, and magnetics digital PCR (BEAMing). Discordant cases were solved by droplet digital PCR (ddPCR) or deep-sequencing. A subgroup of 92 patients with available both NGS data on tumor samples and baseline plasma samples were included in this study. Both NGS analysis of tumor tissue and plasma testing with BEAMing identified RAS mutations in 33/92 patients (35.9%). However, 10 cases were RAS tissue mutant and plasma wild-type, and additional 10 cases were tissue wild-type and plasma mutant, resulting in a concordance rate of 78.3%. Analysis of plasma samples with ddPCR detected RAS mutations in 2/10 tissue mutant, plasma wild-type patients. In contrast, in all tissue wild-type and plasma mutant cases, ddPCR or deep-sequencing analysis of tumor tissue confirmed the presence of RAS mutations at allelic frequencies ranging between 0.15% and 1.15%. The median progression-free survival of RAS mutant and wild-type patients according to tissue (7.9 versus 12.6 months; P = 0.004) and liquid biopsy testing (7.8 versus 13.8 moths; P < 0.001) were comparable. Similar findings were observed for the median overall survival of RAS mutant and wild-type patients based on tissue (22.1 versus 35.8 months; P = 0.016) and plasma (19.9 versus 35.8 months; P = 0.013) analysis. This study indicates that RAS testing of liquid biopsy results in a similar outcome when compared with tissue testing in mCRC patients receiving first-line anti-EGFR monoclonal antibodies.

Association of peripheral blood cell count-derived ratios, biomarkers of inflammatory response and tumor growth with outcome in previously treated metastatic colorectal carcinoma patients receiving cetuximab

Abstract The aim of the present study was to investigate the association of peripheral-blood cell count (PBC)-derived ratios, other biomarkers of inflammation and biomarkers of tumor growth with outcome in a cohort of patients presenting for the next line of therapy after the failure of prior systemic treatment. The data of 51 patients with advanced/metastatic colorectal carcinoma treated with cetuximab in the second or higher line of therapy were retrospectively analyzed. The median duration of cetuximab therapy and the median survival were 5.1 and 12.1 months, respectively. C-reactive protein (CRP), but not urinary neopterin correlated significantly with PBC-derived ratios. Both CRP and urinary neopterin correlated positively with carcinoembryonic antigen (CEA) concentrations and biomarkers of liver dysfunction. Although a number of parameters predicted overall survival in univariate analysis, only hemoglobin, CEA change and serum bilirubin were independent predictors of survival. In conclusion, in patients with metastatic colorectal carcinoma and predominantly liver metastases, the outcome of therapy in the advanced line setting was associated with initial hemoglobin level, a decrease of CEA concentration and initial presence of liver dysfunction. Urinary neopterin did not correlate with PBC-derived ratios, in contrast to CRP, but both urinary neopterin and serum CRP concentrations correlated with laboratory parameters of liver dysfunction.

158P - Comparative pharmacokinetics of a proposed biosimilar bevacizumab Bmab-100 and reference product bevacizumab in a multicentre double blind randomized clinical trial in metastatic colorectal carcinoma (mCRC) patients

158P - Comparative pharmacokinetics of a proposed biosimilar bevacizumab Bmab-100 and reference product bevacizumab in a multicentre double blind randomized clinical trial in metastatic colorectal carcinoma (mCRC) patients