Prognosis In Metastatic Colorectal Cancer Research Articles

Prognostic value of computed tomography associated body composition measurement changes in metastatic colorectal cancer patients.

Sarcopenia is associated with poor prognosis in metastatic colorectal cancer (mCRC) patients. To investigate the prognostic value of body composition measurement changes measured by computed tomography (CT) in mCRC patients. The abdominal skeletal muscle density (SMD) and skeletal muscle (SMI) indices, as well as the visceral (VATI) and subcutaneous fat tissue (SATI) indices, were calculated by automatic segmentation method on the abdominal CT images obtained before (n = 71) and after chemotherapy (n = 52). Skeletal muscle gauge (SMG = SMD × SMI) was calculated. We calculated the percentage change of body composition measurements with respect to the first measurements. The cutoff value for the change in SMG was calculated by receiver operating characteristic analysis. Kaplan-Meier and Cox regression analyses were performed to calculate the prognostic value of age, gender, tumor location, metastasis site and carcinoembriogenic antigen (CEA) elevation, hypoalbuminemia, body mass index classification, presence of sarcopenia and SMG changes in terms of overall survival. There was a significant association between SMG change and mortality (P = 0.037). According to survival analyses, highly decreased SMG, hypoalbuminemia and CEA variables of the patients were the significant factors (P < 0.001, P = 0.015 and P = 0.019, respectively). According to multivariate regression analysis, hypoalbuminemia (P = 0.004, hazard ratio = 3.60) and highly decreased SMG (P < 0.001, hazard ratio = 14.98) were found to be significant prognostic factors together. In mCRC patients, hypoalbuminemia and highly decreased SMG are significant prognostic factors for overall survival. Therefore, we suggest that the change in SMG calculated in follow-up images should also be evaluated in the prognosis estimation of this patient group.

Carcinoembryonic antigen kinetics predict response to first-line treatment in metastatic colorectal cancer: Analysis from PRODIGE 9 trial.

To examine the relationship between carcinoembryonic antigen (CEA) kinetics and prognosis in metastatic colorectal cancer (mCRC) patients receiving first-line chemotherapy in the PRODIGE9 trial. Associations between monthly CEA measurements within 6 months since baseline and progression-free survival (PFS) were evaluated using a joint-latent class-mixed model. A validation set was used to test our prognosis model. Correlations between CEA trajectories (classes) and baseline characteristics were also investigated. Three classes were identified. Class 1 had low baseline CEA with small variations. Class 2 had high baseline CEA with a rapid decrease reaching the same CEA level at 6 months as in class 1. Class 3 had high baseline CEA with a transient decrease followed by an increase to reach, at 6 months, the same CEA level as at baseline. Six-month PFS was significantly lower in class 3 than in classes 1 and 2 (57% vs. 91% and 93% respectively; p<0.01). Class 3 was significantly associated with ECOG 2 status, a high LDH level and non-resected primary tumor. Variations in CEA kinetics correlate with prognosis in patients receiving first-line chemotherapy for mCRC. We propose here a user-friendly application to classify CEA trajectory.

Prognostic impact of tumor size on patients with metastatic colorectal cancer: a large SEER-based retrospective cohort study

Given the poor prognosis of metastatic colorectal cancer (mCRC), this research aimed to investigate the correlation between tumor size and prognosis, and develop a novel prediction model to guide individualized treatment. Patients pathologically diagnosed with mCRC were recruited from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015, and were randomly divided (7:3 ratio) into a training cohort (n = 5597) and a validation cohort (n = 2398). Kaplan–Meier curves were used to analyze the relationship between tumor size and overall survival (OS). Univariate Cox analysis was applied to assess the factors associated with the prognosis of mCRC patients in the training cohort, and then multivariate Cox analysis was used to construct a nomogram model. The area under the receiver-operating characteristics curve (AUC) and calibration curve were used to evaluate the predictive ability of the model. Patients with larger tumors had a worse prognosis. While brain metastases were associated with larger tumors compared to liver or lung metastases, bone metastases tended to be associated with smaller tumors. Multivariate Cox analysis revealed that tumor size was an independent prognostic risk factor (HR 1.28, 95% CI 1.19–1.38), in addition to the other ten variables (age, race, primary site, grade, histology, T stage, N stage, chemotherapy, CEA level and metastases site). The 1-, 3-, and 5-year OS nomogram model yielded AUC values of more than 0.70 in both the training and validation cohorts, and its predictive performance was superior to that of the traditional TNM stage. Calibration plots demonstrated a good agreement between the predicted and observed 1-, 3-, and 5-year OS outcomes in both cohorts. The size of primary tumor was found to be significantly associated with prognosis of mCRC, and was also correlated with specific metastatic organ. In this study, we presented the first effort to create and validate a novel nomogram for predicting 1-, 3- and 5-year OS probabilities of mCRC. The prognostic nomogram was demonstrated to have an excellent predictive ability in estimating individualized OS of patients with mCRC.

TP53 gain of function mutation as a prognostic factor in high-methylated metastatic colorectal cancer: Translational research of TRICOLORE study.

179 Background: TP53 tumor suppressor gene is frequently inactivated by loss-of-function mutations. Some of the mutations gain additional oncogenic functions and are known as gain-of-function (GOF) mutations. This study analyzed the association among primary tumor site (PS), genome-wide DNA methylation status (GWMS), and TP53 mutation subtypes about prognosis in metastatic colorectal cancer (mCRC). Methods: Tumor tissues of mCRC patients registered in the TRICOLORE Study (clinical trial number) were analyzed for GWMS and TP53 mutation as translational research and were classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC) for GWMS, and wild-type , GOF mutation and non-GOF mutation for TP53 mutation. Overall survival (OS) was compared between single or combined subgroups, and Cox regression analysis was performed to identify factors contributing to OS. Results: A total of 209 patients were analyzed, HMCC and LMCC were 60 (28.7%) and 149 (71.3%), respectively. TP53 wild-type , GOF mutation and non-GOF mutation were 35 (16.7%), 79 (37.8%) and 95 (45.5%), respectively. HMCC showed a significantly worse prognosis than LMCC (median OS 25.3 vs. 40.3 months, P &lt; 0.01, hazard ratio 1.87). Combining GWMS and TP53 mutation subtypes about prognosis, the HMCC/GOF (n = 26) group had a significantly poorer prognosis than the other three groups including HMCC/non-GOF (n = 22), LMCC/GOF (n = 53), and LMCC/non-GOF groups (n = 73) (median OS 17.7, 35.3, 40.3, 41.2 months, p = 0.007, p &lt; 0.001, p &lt; 0.001, respectively). The HMCC/GOF group had a poorer prognosis than the other 3 groups regardless of the PS. In the multivariate analysis in the GOF mutation subgroup, HMCC (p &lt; 0.01) was the only poor prognostic factor, while right-sided colon cancer (p = 0.03) and RAS mutations (p = 0.01) were significant poor prognostic factors in the multivariate analysis in the non-GOF mutation subgroup. Conclusions: TP53 gain of function mutations are independent poor prognostic factors in high-methylated metastatic colorectal cancer.

A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAFV600E colorectal tumors

BRAFV600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF–MEK–EGFR co-targeting, we used a high-throughput kinase activity mapping platform. Here we show that SRC kinases are systematically activated in BRAFV600E CRC following targeted inhibition of BRAF ± EGFR and that coordinated targeting of SRC with BRAF ± EGFR increases treatment efficacy in vitro and in vivo. SRC drives resistance to BRAF ± EGFR targeted therapy independently of ERK signaling by inducing transcriptional reprogramming through β-catenin (CTNNB1). The EGFR-independent compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E2 loop that can be blocked with cyclooxygenase-2 (COX2) inhibitors. Co-targeting of COX2 with BRAF + EGFR promotes durable suppression of tumor growth in patient-derived tumor xenograft models. COX2 inhibition represents a drug-repurposing strategy to overcome therapeutic resistance in BRAFV600E CRC.

New developments in targeted therapy for metastatic colorectal cancer.

Colorectal cancer (CRC) is the second most lethal cancer worldwide and the prognosis of metastatic CRC (mCRC) remains poor. Recent advancements in translational research have led to the identification of several new therapeutic targets and improved the treatment outcome of patients with tumours harbouring BRAF V600E mutation, (HER2) ErBB2 alterations, NTRK gene fusions and KRAS(G12C) mutation. Improved understanding towards the mechanism of resistance to targeted therapy such as anti-epidermal growth factor receptor antibodies and the evolving role of therapeutic monitoring with circulating tumour DNA (ctDNA) has enabled the longitudinal tracking of clonal evolution during treatment and the individualization of subsequent treatments. To broaden the community-based implementation of precision oncology in directing targeted therapies for patients with gastrointestinal cancers including mCRC, the feasibility of 'Master Protocols' that utilizes ctDNA-based genotyping platforms is currently being evaluated. Such protocols encompass both observational and interventional clinical trials of novel targeted therapies conducted within a large clinical trial network. In this review, we will discuss the latest developments in targeted therapies, and therapeutic strategies for overcoming acquired drug resistance in patients with mCRC.

Relevancy of Serum SuPAR, PAI-1, MMP-9 Level, And Prognosis Of Metastatic Colorectal Cancer During Diagnosis

Relevancy of Serum SuPAR, PAI-1, MMP-9 Level, And Prognosis Of Metastatic Colorectal Cancer During Diagnosis

Does Elevated Pre-Treatment Plasma PD-L1 Level Indicate an Increased Tumor Burden and Worse Prognosis in Metastatic Colorectal Cancer?

Background: Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) have been reported as possibly favorable prognostic factors in colorectal cancer (CRC). However, their longitudinal effect is unknown. Methods: A pilot study was performed to investigate whether baseline PD-1/PD-L1 levels are associated with further laboratory changes and/or shorter survival. Results: A total of 506 laboratory measurements from 37 metastatic CRC patients were analyzed. The baseline plasma PD-1 and PD-L1 levels were 27.73 ± 1.20 pg/mL and 16.01 ± 1.09 pg/mL, respectively. Disease progression (p = 0.0443) and baseline high-sensitivity C-reactive protein (p = 0.0011), aspartate transaminase (p = 0.0253), alanine transaminase (p = 0.0386), and gamma-glutamyl transferase (p = 0.0103) were associated with higher PD-L1 levels. Based on the baseline PD-1/PD-L1 levels, low and high PD-1/PD-L1 groups were created. Constant, pathological levels of complete blood count values, high-sensitivity C-reactive protein, serum albumin, high-density lipoprotein cholesterol, and lactate dehydrogenase were characteristic for patients with high baseline PD-L1. High PD-L1 levels were significantly associated with increased tumor burden. Disease-specific survival and progression-free survival were significantly shorter in patients with high PD-L1. Conclusions: Abnormal levels of laboratory parameters and intensified tumor burden can be expected if elevated baseline plasma PD-1/PD-L1 levels are found.

A phase 2 trial of sintilimab (IBI 308) in combination with CAPEOX and bevacizumab (BBCAPX) as first-line treatment in patients with RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer.

3563 Background: The prognosis of metastatic colorectal cancer (mCRC) patients with RAS gene mutation and microsatellite stable (MSS) is poor. MSS patients account for 95% of CRC and have a low response rate to immunotherapy. Previous studies have reported that chemotherapy and anti-angiogenesis therapy can promote immunotherapy response. This study aims to assess the safety and antitumor activity of sintilimab (IBI308) combined with CapeOx and bevacizumab in the first-line treatment of patients with RAS-mutant and MSS mCRC. Methods: This is an open-label, single-arm, phase II trial. Eligible patients were aged 18 to 75 years with histologically confirmed unresectable metastatic colorectal adenocarcinoma by multidisciplinary team, and had RAS gene mutation and confirmed MSS status. All patients received treatment with sintilimab (200 mg, day 1) plus bevacizumab (7.5mg/kg, day 1) and oxaliplatin (135 mg/m2, day 1) and capecitabine (1g/m2, bid, day 1-14) of each 21-day cycle. The primary endpoint included objective response rate (ORR) evaluated via RECIST 1.1 criteria and adverse events according to CTCAE 5.0. Secondary endpoint was progression-free survival (PFS). Results: 25 patients were enrolled and received at least two cycle treatment. At baseline, median age was 60 years (range 45-74), 72% of patients were male, ECOG PS 0/1 was 100%, 60% had liver metastases (mets), and the primary tumor site was right-sided colon in 36.0% and left-side colorectum in 64.0%. 25 patients completed at least one efficacy evaluation. 2 (8.0%) patients showed complete response (CR), 19 (76.0%) patients had a partial response (PR) and 4 (16.0%) had stable disease (SD). Patients with liver or lung mets had a higher ORR (93.3% and 100%, respectively) compared to the overall ORR (84.0%). Disease control rate (DCR) reached 100%. Median PFS has not yet reached. No grade 5 adverse events occurred. The most common treatment-related adverse events (TRAEs) in all grades were anemia (19/25, 76.0%), peripheral neurotoxicity (6/25, 24.0%) and neutropenia (17/25, 68.0%). The most frequent grade 3/4 TRAEs were neutropenia (3/25, 12.0%), elevated aspartate transaminase (1/25, 4.0%), elevated alanine transaminase (1/25, 4.0%) and elevated bilirubin (1/25, 4.0%). Conclusions: Combination treatment with sintilimab (IBI308) plus CapeOx and bevacizumab demonstrated a high ORR (84.0%; 93.3% in patients with liver mets, and 100% in patients with lung mets) and a manageable safety profile in RAS-mutant and MSS mCRC. Clinical trial information: NCT05171660. [Table: see text]

Clinical Outcomes of Patients with Peritoneal Metastasis-Only Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI Through Irinotecan Dose Escalation According to UGT1A1 Polymorphism: Compared to Liver Metastasis-Only, and Lung Metastasis-Only.

BackgroundThe prognosis of metastatic colorectal cancer (mCRC) depends on the metastatic site and systemic therapy regimen. Peritoneal metastases are associated with a relatively unfavorable prognosis among patients with mCRC. In this article, we present the treatment outcomes of patients with peritoneal carcinomatosis (PC)-only, liver metastasis (LiM)-only, and lung metastasis (LuM)-only CRC.MethodsOverall, 206 mCRC patients with single-site metastasis and who had received treatment from January 2014 to December 2018 were recruited. Among 206 patients with mCRC, 15 had PC-only mCRC, 145 had LiM-only mCRC, and 46 had LuM-only mCRC. They attended regular follow-ups until November 2020, and the median follow-up period was 24.7 months (5.1–41.3 months). Patients’ characteristics, including clinical data, gene mutation profiles, and clinical outcomes, were evaluated. All patients with PC-only CRC were treated with first-line bevacizumab and FOLFIRI, and the irinotecan dose escalation depended on UGT1A1 polymorphism.ResultsOf the 206 patients, no statistical difference was observed between the PC-only, LiM-only, and LuM-only groups in terms of age, primary tumor location, RAS mutation status, BRAF mutation status, and epidermal growth factor receptor overexpression (all P > 0.05). Patients with PC-only CRC had a median progression-free survival (mPFS) of 18.0 months and a median overall survival (mOS) of 24.6 months. Patients with LiM-only or LuM-only CRC had mPFS of 18.2 and 26.6 months and mOS of 25.0 and 44.5 months, respectively. No significant differences regarding PFS and OS (both P > 0.05) between the three groups of patients with mCRC were observed.ConclusionOur study revealed that in patients with PC-only mCRC treatment of first-line bevacizumab and FOLFIRI through irinotecan dose escalation according to UGT1A1 polymorphism could confer such patients with comparable outcomes to that of patients with LiM-only and LuM-only mCRC.

Association of RAS/BRAF Status and Prognosis of Metastatic Colorectal Cancer: Analysis of 1002 Consecutive Cases.

This study aimed to analyze the association of RAS/BRAF status and the prognosis of patients with metastatic colorectal cancer (mCRC) based on multi-disciplinary team (MDT) treatment mode. The study retrospectively analyzed 1002 consecutive mCRC patients with different tumor RAS/BRAF status at Zhongshan Hospital Fudan University from April 2012 to December 2018. The association of RAS/BRAF status with clinicopathologic features and prognosis was analyzed. The mutation rate was 42.3% (424/1002) for RAS and 5.0% (50/1002) for BRAF. The RAS and BRAF mutations were mutually exclusive of each other. An association of RAS/BRAF status with sex (P < 0.001), age (P = 0.021), primary tumor location (P < 0.001), pathologic type (P < 0.001), differentiation (P < 0.001), metastatic organ (P < 0.001), carcinoembryonic antigen (CEA) (P < 0.001), and cancer antigen (CA)19-9 (P < 0.001) was observed. Overall survival (OS) was better for the RAS/BRAF wild-type patients than for the RAS-mutant patients, whereas the BRAF-mutant patients had the worst OS (51.0 vs 34.9 vs 18.9 months; P < 0.001). Regardless of RAS/BRAF status, metastases resection significantly improved OS (64.0 vs. 21.3 months; P < 0.001). Among the initially unresectable patients, the RAS/BRAF wild-type patients had a better conversional resection rate (32.9% vs 19.1% vs 0; P < 0.001) and a better OS (33.8 vs 23.3 vs 13.2 months; P = 0.005) than the RAS- and BRAF-mutant patients. Similarly, among the initially resectable patients, the RAS/BRAF wild-type patients had a better OS than the RAS- or BRAF- mutant patients (not assessable vs 51.7 vs 35.4 months; P = 0.005). This large-sample study showed that regardless of metastases resection or no resection, RAS and BRAF mutations were associated with a poor prognosis. Resection of metastases could bring survival benefits for patients regardless of RAS/BRAF status.

Real-World Outcomes of Patients With BRAF-Mutated Metastatic Colorectal Cancer Treated in the United States

BRAF mutations portend a poor prognosis in metastatic colorectal cancer (mCRC). Whether these patients may benefit from more aggressive frontline chemotherapy with a triplet regimen such as FOLFOXIRI remains unclear. We used real-world data from a cohort of patients in the United States to assess the BRAF testing rate, determine the prevalence of FOLFOXIRI use, and compare survival outcomes in mCRC, stratified by BRAF mutation status and first-line therapy. A nationwide electronic health record-derived deidentified database was reviewed for patients diagnosed with mCRC between 2013 and 2018. Those with documented BRAF mutation testing who received standard first-line therapy were included. Kaplan-Meier estimates with corresponding log-rank tests and Cox proportional hazards modeling compared survival outcomes stratified by BRAF status and first-line therapy. Of 4,457 included patients, 3,991 (89.5%) had BRAF wild-type (BRAFwt) and 466 (10.5%) had BRAF-mutated (BRAFmt) mCRC. Median overall survival (OS) was 15.4 months in the BRAFmt group versus 28.1 months in the BRAFwt group (hazard ratio [HR], 0.48; 95% CI, 0.41-0.56; P<.001). Only 3% of patients with BRAF mutations received first-line FOLFOXIRI ± bevacizumab, with a median OS of 13.8 months compared with 15.5 months in those treated with doublet chemotherapy ± bevacizumab (P=.38). In patients with BRAF mutations, propensity-weighted analysis did not detect a significant improvement in OS with FOLFIRI + bevacizumab (HR, 0.90; 95% CI, 0.58-1.39; P=.63) or FOLFOX/CAPEOX + bevacizumab (HR, 0.81; 95% CI, 0.52-1.26; P=.35) versus doublet chemotherapy alone. In 2018, only 56% of patients diagnosed with mCRC had documented BRAF testing at any time. This real-world data analysis confirms the negative prognostic impact of BRAF mutations in mCRC and suggests that FOLFOXIRI has not been widely adopted in the United States. The proportion of patients with documented BRAF testing in this real-world population was low at 56%. We were unable to show any significant difference in OS of patients with BRAFmt mCRC based on the first-line therapy received.

Prognostic value of C-reactive protein to albumin ratio in metastatic colorectal cancer: A systematic review and meta-analysis.

Background:In recent years, several observational studies have investigated the association between C-reactive protein to albumin ratio (CAR) and prognosis of metastatic colorectal cancer (mCRC), and yielded controversial outcomes.Methods:Eligible studies assessing the relationship of CAR with survival and clinicopathological parameters in mCRC were searched from PubMed, Cochrane library, and Embase databases up to February 3, 2021. Overall survival (OS), progression-free survival, recurrence-free survival, and disease-free survival were synthetically calculated and compared.Results:A total of 6 studies including 771 patients were enrolled in this systematic review. Pooled results indicated that elevated CAR was significantly associated with poorer OS (hazard ratio: 2.393; 95% confidence interval: 1.949–2.938, P < .01) as well as decreased progression-free survival/disease-free survival/recurrence-free survival (hazard ratio: 1.731; 95% confidence interval: 1.261–2.375, P < .01). Additionally, high CAR was significantly consistent with increased modified Glasgow Prognostic Score and neutrophil–lymphocyte ratio.Conclusion:High CAR could be a negative prognostic marker for mCRC patients. More large-sample clinical trials are still needed to confirm the prognostic significance of CAR in mCRC.

The Ratio of Platelets to Lymphocytes Predicts the Prognosis of Metastatic Colorectal Cancer: A Review and Meta-Analysis.

Background In recent years, the incidence of colorectal cancer (CRC) has continued to increase. Although the overall prognosis of CRC has improved with the continuous improvement of the level of treatment, the prognosis of metastatic colorectal cancer (mCRC) is still poor. The purpose of our study is to explore the prognostic value of platelet to lymphocyte ratio (PLR) in mCRC. Methods The PubMed, Web of Science, and Embase (via OVID) were systematically searched to obtain all relevant research. We used hazard ratio (HR) with 95% confidence interval (CI) to assess the associations of PLR and overall survival (OS) and progression free survival (PFS). Results A total of twelve studies containing 1452 patients were included in this meta-analysis. Pooled analysis showed that high levels of PLR were associated with poor OS (HR: 1.72, 95% CI: 1.27–2.33, and P < 0.01) and PFS (HR: 1.64, 95% CI: 1.16–2.31, and P = 0.033). Conclusion Our analysis suggested that high levels of PLR pretreatment may be an effective predictive biomarker for the prognosis of mCRC patients.

Tumour-Derived Cell Lines and Their Potential for Therapy Prediction in Patients with Metastatic Colorectal Cancer.

Simple SummaryColorectal cancer is a global issue with millions of patients in need for new treatment options. Surgical resection is often the first clinical intervention and can be, especially for primary tumours, curative. However, advanced tumours, recurrences, and metastases require drug treatment. Our aim was to compare material of primary tumours and corresponding metastases to draw conclusions from the first one to the latter. The feasibility of therapy prediction using the primary tumour material for the metastatic situation creates a time window for functional testing, which can realistically be integrated into the strict timeframe of clinical procedures. A reliable treatment recommendation, based on the tumour drug response, would improve treatment success in patients with metachronous metastases and spare them from unnecessary side effects of unsuccessful therapies.The prognosis of metastatic colorectal cancer (CRC) remains poor. Patients and physicians are in need of individual therapies and precise response predictions. We investigated the predictive capacity of primary tumour material for treatment response of metastases. Mutational landscapes of primary tumours and corresponding metastases of 10 CRC patients were compared. Cell line characteristics and chemosensitivity were investigated pairwise for primary and metastatic tumours of four patients. PDX models of one patient were treated in vivo for proof of concept. Driver mutations did not differ between primaries and metastases, while the latter accumulated additional mutations. In vitro chemosensitivity testing revealed no differences for responses to 5-FU and oxaliplatin between primary and metastatic cell lines. However, irinotecan response differed significantly: the majority of metastases-derived cell lines was less sensitive to irinotecan than their matching primary counterpart. Therapy recommendations based on these findings were compared to clinical treatment response and mostly in line with the predicted outcome. Therefore, primary tumour cell models seem to be a good tool for drug response testing and conclusion drawing for later metastases. With further data from tumour-derived cell models, such predictions could improve clinical treatment decisions, both recommending likely effective therapeutic options while excluding ineffective treatments.

Long-Term Survivors of Metastatic Colorectal Cancer: A Tertiary Care Centre Experience.

Background Prognosis of metastatic colorectal cancer (mCRC) is poor and goal of treatment is mainly palliative unless there is limited metastatic disease which is surgically resectable. Here, we report a case series of long-term survivors treated predominantly with chemotherapy. Methods This is a single-center retrospective analysis of patients of mCRC. Records of metastatic colorectal cancer patients registered at Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, between the year 2005 and 2015 were retrieved and reviewed. Inclusion criteria were patients who survived 5 years or more, treated mainly by chemotherapy, with either initial presentation as metastatic disease or those who progressed after initial surgery with or without adjuvant therapy. The details about the patient characteristics, treatment, and outcome were collected. The data were censored on September 30, 2020. Results Records of 370 mCRC patients were reviewed. Thirty-one patients with all the available details fulfilled the criteria for inclusion in the study. Median age was 53 years (range, 22–74 years). Sixteen were women (51.6%). Twenty-four (77%) were newly diagnosed cases with initial presentation as metastatic disease. Commonest site of primary was on the left (21, 67.6%) followed by right side and transverse colon in 5 patients each. Liver was the most common site of metastasis ( n = 18, 58.06%). In metastatic setting, the most common chemotherapy regimen used in the first line was CAPOX ( n = 11, 35.48%). Only three patients could undergo metastatectomy. Monoclonal antibodies could be used only in 14 patients. Median overall survival (OS) of this cohort is 81.6 months (95% confidence interval [CI], 69.73–117.9). Conclusion A small but significant proportion of mCRC patients may achieve and maintain durable responses and long term survival with use of combination of chemotherapy with or without biologics.

KRAS Mutational Regression Is Associated With Oligo-Metastatic Status and Good Prognosis in Metastatic Colorectal Cancer.

KRAS Mutational Regression Is Associated With Oligo-Metastatic Status and Good Prognosis in Metastatic Colorectal Cancer.

KRAS Mutational Regression Is Associated With Oligo-Metastatic Status and Good Prognosis in Metastatic Colorectal Cancer.

BackgroundWe previously reported that loss of KRAS mutations (“regressive” mutational trajectories) from primary tumors to metastases associated with the oligo-metastatic status in colorectal cancer (CRC). The present study was undertaken in order to analyze the mutational trajectories of KRAS in a well-characterized cohort of CRC patients who developed poly- or oligo-metastatic disease.Material and MethodsPatients were treated and followed-up according to European Society of Medical Oncology guidelines. Primary CRC FFPE tissue and metastatic circulating-free DNA were extracted using the QIAamp DNA specific kits (Qiagen, Hilden, Germany). Samples were sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Plasma collection for liquid biopsy was done from 1 to 14 days before starting first-line chemotherapy. Analysis of the prognostic power of KRAS evolutionary trajectories was done with uni- and multivariate analyses.ResultsOne-hundred-fourteen patients were enrolled. Sixty-three patients presented with mutated KRAS (mutKRAS) and 51 with wild-type KRAS (wtKRAS). KRAS mutational concordance was high (70.1%).Two divergent subsets were identified: mutKRAS in primary tumors and wtKRAS in metastatic ones (regressive: mutKRAS → wtKRAS in 8.8% of patients), and vice versa (progressive: wtKRAS → mutKRAS in 21.1% of patients). An association between KRAS regressive trajectory and the oligo-metastatic status (P <0.0001) was found. At multivariate analysis, regressive and progressive mutational trajectories emerged as independent prognostic factors for survival, with Hazard Ratios of 0.22 (CI 95%: 0.08–0.61; median survival: not reached) and 2.70 (CI 95%: 1.11–6.56, median survival: 12.1 months), respectively.ConclusionsOur data provide evidence that the evolutionary trajectories of KRAS can have a strong clinical prognostic role and that they can be involved in discriminating between poly-metastatic aggressive vs oligo-metastatic indolent CRC.

Impact of systemic inflammation and sarcopenia on prognosis of metastatic colorectal cancer.

38 Background: Systemic inflammation, evaluated with neutrophil-to-lymphocyte ratio (NLR), and sarcopenia, assessed with skeletal muscle index (SMI), appear to predict mortality in many cancers, although the optimal cut-offs are still a matter of debate. The goal of this study is to evaluate the cut-offs of NLR and SMI and their prognostic value on metastatic colorectal cancer (mCRC) under first line treatment. Methods: Retrospective cohort analysis of patients with mCRC under first-line treatment in two hospital units, between January 2015 and December 2018. Muscle mass area (MMA) was detected on computed tomography, on L3 segment, with ImageJ software. SMI was determined as MMA/height2. Statistical analysis was performed with IBM SPSS v25 software. Results: 178 patients were analysed, with mean age of 62 (±11) years old. 65% were male and 62.9% had ECOG PS 0. Two thirds of patients presented metastasis in a single organ, mainly in liver. The cut-off values were established based on ROC analysis. Systemic inflammation was defined as NLR &gt; 2.80 and sarcopenia was defined by SMI &lt; 49.12 cm2/m2 for men and &lt;35.85 cm2/m2 for women. 52% of patients presented sarcopenia. In a multivariate analysis using a Cox regression model, an association was observed between overall survival and ECOG PS (p=0.014; HR 5.46, CI 95% [1.42-21.10]), systemic inflammation (p=0,038; HR 2.20, CI 95% [1,05-4.62]) and sarcopenia (p=0.01; HR 4.73, CI 95% [1.85-12.09]). Conclusions: In this study, sarcopenia and systemic inflammation showed independent prognostic value on patients with mCRC. Future prospective studies are necessary to establish a definitive cut-off value for application in clinical practice.

Chromosome 20q11.21 Amplifications in Colorectal Cancer.

Colorectal cancer is the most common gastrointestinal carcinoma in western countries. Prognosis of metastatic colorectal cancer has improved in the last decades, but the disease continues to carry an adverse outcome in most cases. An improved understanding of molecular pathogenesis has provided incremental benefits in survival outcomes with the introduction of targeted therapies for specific sub-types and gives hope for further improvements. Publicly available data from genomic series of colorectal cancer published by the TCGA were analyzed with the aim of characterizing the sub-set of colorectal cancers carrying amplifications of chromosome 20q11.21, compared with cancers with no amplifications in this locus. Associations of 20q11.21-amplified cancers with other molecular lesions commonly observed in colorectal cancer were explored. mRNA expression of genes from the locus in amplified cases was analyzed. An exploratory survival analysis was also performed. Amplifications of genes at chromosome arm 20q are observed in 7% to 9% of colorectal cancers, representing the most commonly amplified loci in this type of cancer. The 20q11.21 presents the highest amplification rate in the 20q arm. 20q11.21 amplified cancers display concomitant mutations in the KRAS pathway and SMAD4 less often than non-amplified cancers. Mutations in DNA repair genes are also less often encountered in 20q11.21 amplified colorectal cancers than non-amplified ones. Amplification of genes at locus 20q11.21, representing the most frequently amplified locus in colorectal cancers, is associated with specific molecular characteristics and may have therapeutic implications.