Survival In Metastatic Colorectal Cancer Research Articles

The effect of genetic alterations detected by the circulating tumor DNA-based next-generation sequencing technique on prognosis and survival in metastatic colorectal cancer

Purpose: Studies conducted to date showed that circulating tumor DNA (ctDNA)-based next generation sequencing (NGS) panels are beneficial in the treatment strategies of patients with metastatic colorectal cancer (mCRC). In this study; we planned to determine the frequencies of various genetic alterations in patients with mCRC by ctDNA-based NGS analyses, evaluate the concordance rates by comparing these results with the results in standard polymerase chain reaction (PCR) analyses, and investigate the effect of the detected alterations on overall survival and progression-free survival. Materials and methods: The study was conducted by retrospective screening and analysis of the data on 48 patients, who were followed up with a diagnosis of mCRC and who received chemotherapy and/or biological agents. The data were analyzed using SPSS 25.0 [IBM SPSS Statistics 25 software (Armonk, NY: IBM Corp.)] package program. Results: In this study, ctDNA-based NGS analyses, compared to the quantitative PCR-based gold standard method, were found to have a sensitivity rate of 64.7%, specificity rate of 55.6% and concordance rate of 59.1% for KRAS mutation; a sensitivity rate of 100%, specificity rate of 86.7% and concordance rate of 87.1% for NRAS mutation; a sensitivity rate of 50%, specificity rate of 96.4% and concordance rate of 90.6% for BRAF mutation. In addition, concordance rates were evaluated based on to the time elapsed between the time of taking the liquid biopsy and tissue biopsy samples. As a result, concordance rates for KRAS, NRAS, and BRAF mutations were found to be 60.9%, 100%, and 100% respectively, in cases where this elapsed time was less than 6 months; and were found to be 57.1%, 78.9%, and 85% respectively, in cases where this elapsed time was more than 6 months. Furthermore, the comprehensive analyzes revealed that the frequency of many molecular changes in mCRC as well as the relationship of these changes with clinicopathological features and survival times. Conclusion: Our study demonstrates the clinical benefit of ctDNA-based NGS analyzes in patients with mCRC.

Clinicopathological characteristics and survival in metastatic colorectal cancer with short-form APC mutations.

3555 Background: Wnt/β-catenin signaling is activated by loss-of-function mutations in the adenomatous polyposis coli ( APC) gene and plays a key role in tumorigenesis in colorectal cancer (CRC). Tankyrase inhibitors, which cause degradation of β-catenin, are expected to have a promising therapeutic effect for CRC, and the short-form APC mutations predict the sensitivity of CRC cells to tankyrase inhibitors (Tanaka et al. Mol Cancer Ther 2017; Chen et al. Br J Cancer, in press).However, clinicopathological characteristics and survival in metastatic CRC (mCRC) with short-form APCmutations remain unclear. Methods: Patients with mCRC who were treated with chemotherapy between 2010 and 2021 and have tissue or circulating tumor DNA-based next-generation sequencing results were enrolled. Short-form APC mutations were defined as those truncated at amino acid 1,256 or shorter, lacking all seven 20-amino acid repeat (20-AAR) regions. Non-short-form APC mutations were defined as those possess more than one 20-AAR. Short-form and non-short-form heterozygous mutations were classified as non-short-form APC mutations. We confirmed incidence of mCRC with short-form APC mutations and compared clinicopathological characteristics and overall survival (OS) between mCRC patients with short-form and non-short-form APCmutations. Results: Of 177 patients (median age, 56.0 years) included in this study, 44 (25%) and 79 (45%) had short-form and non-short-form APC mutations, respectively. Patients with short-form APC mutations were not likely to have lung metastasis (P = 0.15). Logistic regression multivariate analysis, lung metastasis was related to mCRC patients with short-form APC mutations (Odds ratio: 0.46, P = 0.047). Patients with short-form APC mutations had significantly shorter overall survival (OS) than did those without (n = 133), with a median OS of 34.7 vs 50.5 months ( P Log-rank= 0.035, hazard ratio (HR), 1.59; 95% confidence interval (CI), 1.03-2.45). In multivariate analysis, short-form APC mutation was independent factor related to OS (hazard ratio (HR): 1.68, P = 0.02), as well as the BRAF V600E mutation, liver metastasis and peritoneal metastasis. Conclusions: Short-form APC mutation is more common in mCRC patients without lung metastases and is independently associated with a short prognosis.

Abstract 2200: Plant-based diet and survival among patients with metastatic colorectal cancer: Findings from CALGB/SWOG 80405 (Alliance)

Abstract Background: Plant-based diet is recommended by multiple cancer survivorship guidelines and was reported to be associated with better survival among patients with non-metastatic colorectal cancer. However, the association between plant-based diet and survival in metastatic colorectal cancer is unknown. Methods: Using an NCI-sponsored systemic therapy trial conducted from 2005 to 2015 (CALGB/SWOG 80405), we included 1,279 patients who completed validated food frequency questionnaires at the initiation of treatment for metastatic colorectal cancer. To emphasize different impact of healthful plant foods, less healthful plant foods, and animal foods, we used 18 food groups to calculate three plant-based indexes (ranges: 18-90 points): overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). The primary outcome was overall survival, and the secondary outcome was progression-free survival. We estimated the associations of three indexes (quintiles) with survival using multivariable Cox proportional hazards regression. Results: Of 1,279 patients (median follow-up: 6.1 years), mean (SD) age at diagnosis was 58.8 (11.7) years, 57.4% were men, 85.6% were White, and 1,096 deaths and 1,201 events of progression occurred. The mean (SD) points of three indexes were 51.2 (6.3) for PDI, 51.1 (6.7) for hPDI, and 51.2 (8.1) for uPDI. Compared to the lowest quintile (Q1), the highest quintile (Q5) of PDI was significantly associated with better overall survival (HR: 0.80 [0.65-0.99]) and progression-free survival (HR: 0.80 [0.65-0.98]). Similar findings were observed for hPDI, but uPDI was not significantly associated with worse survival. Conclusions: Our findings suggest that plant-based diet is associated with better survival among patients with metastatic colorectal cancer, and plant-based dietary interventions should be considered for future trials in metastatic colorectal cancer. Table. Adjusted Associations of Plant-Based Diet with Survival in Metastatic Colorectal Cancer Q1 Q2 Q3 Q4 Q5 P for trend Overall Survival PDI 1.00 0.96 (0.80-1.16) 0.93 (0.77-1.14) 0.82 (0.67-0.99) 0.80 (0.65-0.99) 0.01 hPDI 1.00 0.95 (0.78-1.14) 0.94 (0.77-1.15) 0.86 (0.70-1.04) 0.84 (0.68-1.03) 0.07 uPDI 1.00 1.14 (0.95-1.39) 1.07 (0.87-1.31) 1.18 (0.97-1.45) 1.17 (0.95-1.45) 0.15 Progression-free Survival PDI 1.00 0.84 (0.70-1.01) 0.94 (0.78-1.14) 0.93 (0.77-1.12) 0.80 (0.65-0.98) 0.10 hPDI 1.00 0.86 (0.72-1.03) 0.83 (0.69-1.01) 0.80 (0.67-0.97) 0.80 (0.66-0.97) 0.03 uPDI 1.00 1.12 (0.94-1.34) 1.11 (0.91-1.34) 1.10 (0.91-1.34) 1.15 (0.94-1.41) 0.23 Citation Format: En Cheng, Fang-Shu Ou, Chao Ma, Alan P. Venook, Heinz-Josef Lenz, Eileen M. O’Reilly, Peter T. Campbell, Chaoyuan Kuang, Bette J. Caan, Kimmie Ng, Jeffrey A. Meyerhardt. Plant-based diet and survival among patients with metastatic colorectal cancer: Findings from CALGB/SWOG 80405 (Alliance) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2200.

Effect of Hospital Cancer Designation on use of Multimodal Therapy and Survival of Metastatic Colorectal Cancer: A State-Wide Analysis.

Stage IV colorectal cancer (CRC) often requires multidisciplinary approach. However, multimodal treatment options (receipt of >1 type of treatment) may not be uniformly delivered across health systems. We characterized the association between center-level cancer center designation and receipt of multimodal treatment and survival. The Texas Cancer Registry was used to identify patients diagnosed with stage IV CRC from 2004-2017. We identified those who received care at either: a National Cancer Institute-designated (NCI-D), an American College of Surgeons-Commission on Cancer-designated (ACS-D), or an undesignated facility. We used multivariable logistic regression and Cox regression for analysis to assess receipt of one or more treatment modality and 5-year overall survival. Of 19,355 patients with stage IV CRC, 2955 (15%) received care at an NCI-D facility and 5871 (30%) received multimodal therapy. Both NCI-D (odds ratio [OR] 1.64; 95% confidence interval [CI] 1.49-1.81) and ACS-D (OR 1.37; 95% CI 1.27-1.48) were associated with increased likelihood of multimodal therapy compared with undesignated centers. NCI-D also was associated with significantly improved survival (hazard ratio [HR] 0.74; 95% CI 0.70-0.78), although ACS-D was associated with a modest improvement in survival (HR 0.95; 95% CI 0.92-0.99). Receipt of multimodal therapy was strongly associated with improved survival (HR 0.61; 95% CI 0.59-0.63). In patients with stage IV CRC, treatment at ACS-D and NCI-D facilities was associated with increased use of multimodality therapy and improved survival. However, only a small proportion of patients have access to these specialized centers, highlighting a need for expanded access to multimodal therapies at other centers.

Is Older Age an Independent Prognostic Factor of Survival in Metastatic Colorectal Cancer?

Plain Language SummaryOlder patients with advanced CRC constitute a heterogeneous population, including patients with excellent health status and others with multiple comorbidities, functional dependence, or limited life expectancy. Furthermore, the definition of an “elderly” or “older” patient is not widely accepted and may vary between studies, although 75 years may be an appropriate cut-off point, as confirmed in our study. At present, there are few prospective and randomized studies focused on the progression and treatment of advanced colorectal cancer in elderly patients, so understanding the factors that influence its clinical course is a difficult challenge. In this retrospective real-world study, we analyze the influence of advanced age on the survival of patients with advanced colorectal cancer. The analysis of eighteen characteristics that were grouped in three subcategories: characteristic related to the patient (age, sex, comorbidities, polypharmacy, ECOG, and nutritional status [albumin levels at diagnosis]), to the tumor (stage at diagnosis, tumor side, molecular profile, tumor burden [CEA levels at diagnosis], location and number of metastasis), and to the treatment administrated (systemic treatment for advanced disease, chemotherapy schedule and number of lines, severe adverse events and dose reductions, and surgery of liver metastasis) showed that older age at diagnosis is not an independent prognostic factor of overall survival in patients with metastatic colorectal cancer. However, tumor burden, nutritional status, systemic treatment of advanced disease, or surgery of liver metastases are independent predictors of survival.

A commentary on 'Nomogram of conditional survival probability of long-term survival for metastatic colorectal cancer: a real-world data retrospective cohort study from SEER database'.

A commentary on 'Nomogram of conditional survival probability of long-term survival for metastatic colorectal cancer: a real-world data retrospective cohort study from SEER database'.

Assessment of exposure-response relationship for cetuximab in patients with metastatic colorectal cancer and head and neck cancer

ObjectiveThere is limited scientific evidence on the cetuximab exposure-response relationship and no concentration threshold has been associated with optimal disease control. The aims were to assess, in a real-life setting, the relationship between steady state cetuximab concentrations (Ctrough, ss) and disease control. MethodA prospective observational study in patients with metastatic colorectal cancer or head and neck cancer treated with cetuximab. Steady state trough concentrations were compared with the results of radiological assessment of response (progression or clinical benefit). Generalized estimating equations analysis was performed. To test the association between steady state concentrations and overall survival and progression-free survival, Cox proportional hazard models were developed. An optimal cut-off point was searched using the area under the receiver operating characteristic curve. ResultsA total of 30 steady state cetuximab concentrations from 16 patients were analysed. Median Ctrough, ss was 26.86 mg/L and there was marked inter- and intraindividual variability (standard deviation 32.4 mg/L and 16.9 mg/L, respectively). A positive association was found between cetuximab Ctrough, ss and clinical benefit (odds ratio 1.24, 95% confidence interval: 0.95-1.63, p = 0.113), although without reaching statistical significance. The area under the receiver operating characteristic curve (n = 30) had moderate discrimination power (0.71; 95% confidence interval 0.49-0.93), and the empirical optimal cutoff point was 19.12 mg/L. However, no association was observed between cetuximab Ctrough, SS and survival in metastatic colorectal cancer or neck cancer patients. ConclusionsWe cannot confirm a relationship between cetuximab Ctrough, SS and disease control despite a positive association. This study was conducted with a small sample, which reduces the power analysis. Further controlled randomised studies with a sufficient number of patients are needed.

Prognostic significance of prognostic nutritional index and hemoglobin to red cell distribution width ratio in metastatic colorectal cancer patients

Aims: Malnutrition and systemic inflammation are poor prognostic factors in cancer. Prognostic nutritional index (PNI) and Hemoglobin to red blood cell distribution witdh (HRR) are considered indicators of malnutrition and systemic inflammation. We aimed to investigate the prognostic importance of PNI and HRR on metastatic colorectal cancer survival.
 Methods: We retrospectively reviewed all patients diagnosed with metastatic colorectal cancer treated at Kayseri City Training and Research Hospital and Erciyes University Medical School. PNI is calculated as (serum albumin (g/L) +5 x total lymphocyte count (10⁹/L)). And HRR was calculated as the ratio of hemoglobin (g/dl) and RDW (%). PNI was divided into two groups based on the cut off points 46.175 as PNI high and low. And we compared these two groups according to general characteristics and overall survival. We performed another comparision between HRR low and high groups based on the cut off points 0.8675 according to general characteristics and overall survival. Kaplan Meier method was used to analyse overall survival and compared survival rates with the log-rank test.
 Results: We reviewed 346 metastatic colorectal cancer patients and we included 145 of them who fit to inclusion criteria to the study. Univariate analysis revealed that presence of initially metastatic disease, right located tumor, low HRR, low PNI were independent prognostic markers of poor overall survival. In multivariate analysis, presence of initially metastatic disease and low PNI remain statistically significant independent prognostic markers of poor survival. The median overall survival was statistically longer in HRR and PNI low groups than high groups.
 Conclusion: Both PNI and HRR are associated with poor overall survival in metastatic colorectal cancer.

Baseline Expression of Exosomal miR-92a-3p and miR-221-3p Could Predict the Response to First-Line Chemotherapy and Survival in Metastatic Colorectal Cancer.

The status of predictive biomarkers in metastatic colorectal cancer is currently underdeveloped. Our study aimed to investigate the predictive value of six circulating exosomal miRNAs derived from plasma (miR-92a-3p, miR-143-3p, miR-146a-5p, miR-221-3p, miR-484, and miR-486-5p) for chemosensitivity, resistance patterns, and survival. Thirty-one metastatic colorectal cancer patients were selected before receiving first-line irinotecan- or oxaliplatin-based chemotherapy. Blood samples were harvested at baseline and 4-6 months after the initiation of chemotherapy. The levels of exosomal expression for each miRNA were analyzed by qPCR. Our results for patients receiving first-line FOLFOX showed significantly higher baseline levels of miR-92a-3p (p = 0.007 **), miR-146a-5p (p = 0.036 *), miR-221-3p (p = 0.047 *), and miR-484 (p = 0.009 **) in non-responders (NR) vs. responders (R). Of these, miR-92a-3p (AUC = 0.735), miR-221-3p (AUC = 0.774), and miR-484 (AUC = 0.725) demonstrated a predictive ability to discriminate responses from non-responses, regardless of the therapy used. Moreover, Cox regression analysis indicated that higher expression levels of miR-92a-3p (p = 0.008 **), miR-143-3p (p = 0.009 **), miR-221-3p (p = 0.016 *), and miR-486-5p (p = 0.019 *) at baseline were associated with worse overall survival, while patients expressing higher baseline miR-92a-3p (p = 0.003 **) and miR-486-5p (p = 0.003 **) had lower rates of progression-free survival. No predictive values for candidate microRNAs were found for the post-chemotherapy period. In line with these findings, we conclude that the increased baseline exosomal expression of miR-92a-3p and miR-221-3p seems to predict a lack of response to chemotherapy and lower OS. However, further prospective studies on more patients are needed before drawing practice-changing conclusions.

Plasma-based methylated SEPTIN9 circulating tumor DNA to predict progression-free and overall survival in metastatic colorectal cancer.

e15615 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths, as about half of cases develop incurable metastatic disease. Recent studies have shown circulating tumor DNA (ctDNA) markers reflect disease burden and responses to neoadjuvant therapy in metastatic CRC more accurately than carcinoembryonic antigen (CEA). We aimed to determine if a semi-quantitative evaluation of the methylated SEPTIN9 (mSEPT9) ctDNA marker, used in a CRC screening test, is capable of predicting progression free survival (PFS) and overall survival (OS) in a longitudinal cohort of metastatic CRC cases. Methods: A longitudinal cohort of 70 CRC cases who presented with stage IV disease, or experienced recurrent disease, was prospectively assembled from patients undergoing treatment at Cedars-Sinai Medical Center. Blood samples were drawn either prior to, or within 2 weeks following, treatment initiation, and 1-2 monthly thereafter for two years or until death. mSEPT9 ctDNA levels were measured in 1 mL plasma using a modified Epi-proColon V2.0 (Epigenomics) protocol. Univariate and multivariate analyses of clinical endpoints, PFS and OS, were conducted using a Cox regression model with CEA and mSEPT9 ctDNA as time-dependent covariates, with and without adjustments for multiple confounding factors (sex, age, race, organ of metastasis, neo- and adjuvant chemotherapy, immunotherapy, surgery, mismatch repair, KRAS and BRAF mutation status). Results: In univariate analysis, higher level of ctDNA, peritoneal metastasis, gynecologic metastasis, and additional liver metastasis, were associated with poor PFS. Elevated CEA was not associated with PFS either as a continuous variable or as a categorical variable (threshold 10ng/mL). In multivariable analysis, higher level of ctDNA (HR: 1.41; 95% CI: 1.17-1.71; P< 0.001) remained associated with poor PFS after adjusting for adjuvant chemotherapy and peritoneal metastasis. CEA remained not associated with PFS. In univariate analyses, high level of CEA, high level of mSEPT9 ctDNA, neoadjuvant chemotherapy, male sex, and peritoneal metastasis were associated with poor OS. In multivariable analysis, higher level of CEA (HR: 1.63; 95% CI: 1.12-2.36; P= 0.011) and mSEPT9 ctDNA (HR: 1.50; 95% CI: 1.22-1.84; P< 0.001) remained associated with poor OS after adjusting for sex and peritoneal metastasis. Conclusions: Semi-quantification of the single ctDNA marker, mSEPT9, a prevalent biomarker of CRC, was an independent predictor of PFS whereas CEA was not. High levels of both CEA and mSEPT9 ctDNA were independent predictors of OS, showing that mSEPT9 ctDNA added value to CEA in evaluation of OS. The mSEPT9 ctDNA test is rapid turn-around and easy to perform in molecular diagnostic pathology laboratories, thus may serve as a valuable adjunct to CEA for frequent testing in the setting of metastatic CRC.

Abstract 2584: Overcoming cetuximab resistance in colorectal cancer through inhibition of HGF processing

Abstract Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR) and can prolong survival in metastatic colorectal cancer (CRC) patients. However, therapeutic resistance can limit its efficiency and use. Our lab has previously identified that the activation of receptor tyrosine kinases (RTKs) MET and RON contributed to cetuximab resistance. In the absence of activating mutations of MET and RON, the activity of these RTKs depends on the availability of their ligands, hepatocyte growth factor (HGF) and hepatocyte growth factor-like (HGFL), respectively. To become biologically active, the inactive precursors of HGF and HGFL must be processed by serine proteases (HGFA, matriptase, and hepsin). A survey of TCGA datasets indicated that MET and HGF were overexpressed in several CRC CMS subtypes. However, we did not observe any significant overexpression of the serine proteases. Hepatocyte growth factor activator inhibitor type 1 and 2 (HAI-1/2) are two Kunitz-type serine protease inhibitors that displayed reduced expression in TCGA datasets. The addition of recombinant human HGF conferred cetuximab resistance to cetuximab-sensitive cells and cetuximab-sensitive cells engineered to overexpress HGF also exhibited cetuximab-resistant phenotype. Cetuximab resistance induced by HGF addition or overexpression could be overcome by downstream inhibition with crizotinib, a multi-targeted RTK inhibitor. ZFH7116 is a small molecule inhibitor of the serine proteases that mimics HAI-1 activity. ZFH7116 suppressed HGF cleavage and maturation in our cetuximab-resistant SC cells. We observed cooperative effect of ZFH7116 with cetuximab to reduce SC cell growth in 3D collagen cultures. We are currently testing if upstream inhibition with recombinant human HAI-1 addition can suppress HGF cleavage and overcome cetuximab resistance induced by HGF overexpression. Collectively, our findings suggest that inhibiting HGF cleavage and processing may be a unique strategy for overcoming EGFR-targeted therapy resistance in colorectal cancer. Citation Format: Vivian Truong Jones, Ramona Graves-Deal, Galina Bogatcheva, Zheng Cao, James Higginbotham, Sarah Harmych, Gregory Ayers, Marisol Ramirez, Qi Liu, James Janetka, Bhuminder Singh. Overcoming cetuximab resistance in colorectal cancer through inhibition of HGF processing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2584.

Baseline Quality of Life is a Strong and Independent Prognostic Factor for Overall Survival in Metastatic Colorectal Cancer.

Previous studies have established that higher baseline quality of life (QOL) scores are associated with improved survival in patients with metastatic colorectal cancer (mCRC). We examined the relationship between overall survival (OS) and baseline QOL. A total of 1 247 patients with mCRC participating in N9741 (comparing bolus 5-FU/LV, irinotecan [IFL] vs infusional 5-FU/leucovorin [LV]/oxaliplatin [FOLFOX] vs. irinotecan/oxaliplatin [IROX]) provided data at baseline on overall QOL using a single-item linear analogue self-assessment (LASA) 0-100 point scale. The association of OS according to clinically deficient (defined as CD-QOL, score 0-50) vs not clinically deficient (nCD-QOL, score 51-100) baseline QOL scores was tested. A multivariable analysis using Cox proportional hazards modeling was performed to adjust for the effects of multiple baseline factors. An exploratory analysis was performed evaluating OS according to baseline QOL status among patients who did or did not receive second-line therapy. Baseline QOL was a strong predictor of OS for the whole cohort (CD-QOL vs nCD-QOL: 11.2months vs 18.4months, P < .0001), and in each arm IFL 12.4 vs 15.1months, FOLFOX 11.1 months vs 20.6months, and IROX 8.9months vs 18.1months. Baseline QOL was associated with baseline performance status (PS) (P < .0001). After adjusting for PS and treatment arm, baseline QOL was still associated with OS (P = .017). Baseline QOL is an independent prognostic factor for OS in patients with mCRC. The demonstration that patient-assessed QOL and PS are independent prognostic indicators suggests that these assessments provide important complementary prognostic information.

New Horizons in Metastatic Colorectal Cancer: Prognostic Role of CD44 Expression

The transmembrane glycoprotein CD44, the major hyaluronan (HA) receptor, has been proven to regulate cell growth, survival, differentiation, and migration. It is therefore widely considered to be involved in carcinogenesis. Its role as a new therapeutic target in solid tumors is under evaluation in clinical trials. The prognostic value remains controversial. Here, we aimed to investigate the correlation between CD44 expression and the clinicopathological features and survival in metastatic colorectal cancer (mCRC) patients. Data from 65 mCRC patients of the Medical Oncology Unit, University Hospital and University of Cagliari were retrospectively collected from 2008 to 2021. Immunohistochemical analysis was performed at the Pathology Division, University Hospital of Cagliari on 3 μm thick sections obtained from paraffin blocks. The intensity of immunohistochemical staining was subclassified into four groups: score 0 if negative or weak membrane staining in less than 10% of tumor cells; score 1+ if weak membrane staining in at least 10% of tumor cells or moderate membrane staining in less than 10% of tumor cells; score 2+ if moderate membrane staining in at least 10% of tumor cells or intensive membrane staining in less than 10% of tumor cells; score 3+ if intense membrane staining in at least 10% of tumor cells. Based on this score, we distinguished patients into low CD44 expression (score 0, 1+, 2+) and high CD44 expression (score 3+). Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; association between categorical variables: Fisher's exact test). Patients' median age was 66 years (range 49-85). Regarding CD44 expression, score was 0 in 18 patients, 1+ in 15 patients, 2+ in 18 patients, and 3+ in 14 patients. Median overall survival (mOS) was 28.1 months (95%CI: 21.3-101). CD44 overexpression (3+) was correlated with poor prognosis (p = 0.0011; HR = 0.2), with a mOS of 14.5 months (95%CI 11.7 to 35.9) versus 30.7 months (95%CI 27.8 to 101) in lower CD44 expression. Higher CD44 expression was associated with clinically poor prognostic features: age ≥ 70 years (p = 0.0166); inoperable disease (p = 0.0008); stage IV at diagnosis (p = 0.0241); BRAF mutated (p = 0.0111), high-grade tumor (p = 0.0084). CD44 markedly correlated with aggressive tumor behavior and contributed to the earlier progression of disease, thus suggesting its role as a novel prognostic marker and potential therapeutic target for mCRC patients.

Cell-free circulatingRAS mutation concentrationssignificantly impact the survival of metastatic colorectal cancer patients.

RAS mutations are predictors of an adverse outcome in EGFR-targeted therapies and have been proposed as prognostic biomarkers of survival in metastatic colorectal cancer (mCRC). The analysis of circulating tumor DNA from plasma samples, known as liquid biopsies, has indicated that the RAS mutation status may change over time, potentially affecting patients' prognosis. To further evaluate the clinical validity of RAS mutation retesting using liquid biopsies, we prospectively investigated the impact of the circulating quantitative RAS mutation status on the course of mCRC. The present study included 81 consecutively recruited patients with mCRC. We used targeted next-generation sequencing of circulating cell-free DNA to determine and quantify plasma RAS mutation status. Patients with a RAS mutation detected by liquid biopsy (37%; n = 30) were at increased risk of death during the follow-up period compared to RAS wild-type patients. Patients with evidence of a RAS mutation in the primary tumor but a putative RAS mutation loss in plasma (28%; n = 11) showed a prolonged survival compared to patients with a preserved RAS mutation status. Also, circulating RAS mutation concentrations significantly affected the outcome: The mortality risk of patients with a high RAS mutation concentration increased fivefold compared to subjects with a putative RAS mutation loss or low RAS mutation concentration. Our results emphasize the clinical value of circulating RAS mutations in managing mCRC.

Time trends in treatment patterns and survival of older patients with synchronous metastatic colorectal cancer in the Netherlands: A population-based study.

New treatment strategies have improved survival of metastatic colorectal cancer in trials. However, it is not clear whether older patients benefit from these novel therapies, as they are often not included in pivotal trials. Therefore, we investigated treatment patterns and overall survival over time in older patients with metastatic colorectal cancer in a population-based study. We identified 22.192 Dutch patients aged ≥70 years diagnosed with synchronous metastatic colorectal cancer between 2005 and 2020 from the Netherlands Cancer Registry. Changes in treatment over time were assessed with logistic regression models. Survival was assessed by Cox proportional hazard ratios (HR). Results showed that chemotherapy use increased between 2005 and 2015, but declined from 2015 onwards, while more patients received best supportive care. Over time, fewer patients underwent primary tumor resection alone. Although survival of both metastatic colon and rectal cancer improved until 2014, survival of colon cancer decreased from 2014 onwards (HR 1.04, 95% confidence interval [CI] 1.01-1.05), which was seen in all age groups. Survival of metastatic rectal cancer patients remained unchanged from 2014 onwards (HR 1.00, 95% CI 0.98-1.03) in all age groups. In conclusion, treatment patterns of Dutch older patients with synchronous metastatic colorectal cancer rapidly changed from 2005 to 2020, with increasing percentages of patients receiving best supportive care. Survival of metastatic colon cancer decreased from 2014 onwards. The implementation of a colorectal cancer screening program and patient selection might explain why only a subset of older patients seem to benefit from the availability of novel treatment options.

MSR21 Exploration of the Impact of the Treatment Mechanism of Action on the Surrogate Relationship Between Progression Free Survival and Overall Survival in Metastatic Colorectal Cancer

To determine whether treatment’s mechanism of action affects the surrogate relationship between progression free survival (PFS) and overall survival (OS) for metastatic colorectal cancer (mCRC) patients.

Sequenced treatment after regorafenib and survival in metastatic colorectal cancer: a qualitative clinical review

There is limited evidence-based guidance regarding treatment sequencing and outcomes following regorafenib in patients with refractory metastatic colorectal cancer (mCRC). A targeted literature review was conducted to identify studies with clinical outcomes associated with regorafenib therapy and subsequent treatment following regorafenib therapy. The median overall survival range of the nine studies with sequenced-based survival data was 2.1–19.3 months for regorafenib prior to subsequent therapy in refractory mCRC. Safety outcomes in patients treated with regorafenib prior to other therapies in mCRC were generally comparable to reported adverse events in clinical trials for subsequent agents. Data from this review demonstrate a potential correlation between survival and the use of regorafenib prior to subsequent chemotherapy or targeted therapy in patients with refractory mCRC.

Trajectories of body weight change and survival among patients with mCRC treated with systemic therapy: Pooled analysis from the ARCAD database

BackgroundHigher body mass index is associated with a higher incidence of colorectal cancer (CRC) but also with improved survival in metastatic CRC (mCRC). Whether weight change after mCRC diagnosis is associated with survival remains largely unknown. MethodsWe analysed individual patient data for previously untreated patients enrolled in five phase 3 randomised trials conducted between 1998 and 2006. Weight measurements were prospectively collected at baseline and up to 59.4 months after diagnosis. We used stratified multivariable Cox models to assess the prognostic associations of weight loss with overall and progression-free survival, adjusting for other factors. The primary end-point was a difference in overall survival (OS) between populations with weight loss and stable or increasing weight. FindingsData were available for 3504 patients. The median weight change at 3 months was −0.54% (IQR −3.9 … +1.5%). We identified a linear trend of increasing risk of death associated with progressive weight loss. Unstratified median OS was 20.5, 18.0, and 11.9 months (p < 0.001) for stable weight or gain, <5% weight loss, and ≥5% weight loss at 3 months, respectively. Weight loss was associated with a higher risk of death (<5% loss: aHR 1.18 [1.06–1.30], p < 0.002; ≥5% loss: aHR 1.87 [1.67–2.1], p < 0.001) as compared to stable or increasing weight at 3 months post-baseline (reference), while adjusting for age, sex, performance, and a number of metastatic sites. InterpretationPatients losing weight during systemic therapy for metastatic colorectal cancer have significantly shorter OS. The degree of weight loss is proportional to the observed increased risk of death and remains evident among underweight, normal weight, and obese individuals. On-treatment weight change could be used as an intermediate end-point. FundingThe creation and management of the database containing the individual patient data from the original randomised trials is supported by the Aide et Recherche en Cancérologie Digestive Foundation.

Time to treatment initiation and its impact on real-world survival in metastatic colorectal cancer and pancreatic cancer.

Given the dearth of data regarding the time to treatment initiation (TTI) in the palliative setting, and its impact on survival outcomes, we sought to determine TTI in a real-world cohort of metastatic colorectal cancer (mCRC) and metastatic pancreatic cancer (mPC) patients and evaluate the impact of TTI on real-world survival outcomes. We collected survival and treatment data for mCRC and mPC from the Flatiron Health electronic health records (EHR) derived database. We divided TTI into 3 categories: < 2 weeks, 2-< 4 weeks, and 4-8 weeks, from diagnosis to first-line therapy. Outcome measures were median TTI, real-world overall survival (RW-OS) based on TTI categories by Kaplan-Meier method, and impact of TTI on survival using cox proportional hazard models. Among 7108 and 3231 patients with mCRC and mPC treated within 8 weeks of diagnosis, the median TTI were 28 days and 20 days. Median RW-OS for mCRC was 24 months; 26.9months versus 22.6 and 18.05 months in the 4-8-week, 2-< 4week (control) and < 2-week groups, respectively (p < 0.0001). For mPC, median RW-OS was 8months, without significant difference in RW-OS among the groups (p=0.05). The 4-8-week group was associated with lower hazard of death (HR 0.782, 95% CI 0.73-0.84, p < 0.0001) and the < 2-week group was associated with a higher hazard of death (HR 1.26, 95% CI 1.15-1.38, p < 0.0001) in mCRC. The 4-8-week group was associated with lower hazard of death for mPC (HR 0.88, 95% CI 0.8-0.97, p=0.0094). In a real-world cohort of patients treated within 8 weeks of diagnosis, and with the limitations of a retrospective study, later TTI did not have a negative impact on survival outcomes in mCRC and mPC.

Standard diametric versus volumetric early tumor shrinkage as a predictor of survival in metastatic colorectal cancer: subgroup findings of the randomized, open-label phase III trial FIRE-3 / AIO KRK-0306

ObjectivesEarly tumor shrinkage (ETS) quantifies the objective response at the first assessment during systemic treatment. In metastatic colorectal cancer (mCRC), ETS gains relevance as an early available surrogate for patient survival. The aim of this study was to increase the predictive accuracy of ETS by using semi-automated volumetry instead of standard diametric measurements.MethodsDiametric and volumetric ETS were retrospectively calculated in 253 mCRC patients who received 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) combined with either cetuximab or bevacizumab. The association of diametric and volumetric ETS with overall survival (OS) and progression-free survival (PFS) was compared.ResultsContinuous diametric and volumetric ETS predicted survival similarly regarding concordance indices (p > .05). In receiver operating characteristics, a volumetric threshold of 45% optimally identified short-term survivors. For patients with volumetric ETS ≥ 45% (vs < 45%), median OS was longer (32.5 vs 19.0 months, p < .001) and the risk of death reduced for the first and second year (hazard ratio [HR] = 0.25, p < .001, and HR = 0.39, p < .001). Patients with ETS ≥ 45% had a reduced risk of progressive disease only for the first 6 months (HR = 0.26, p < .001). These survival times and risks were comparable to those of diametric ETS ≥ 20% (vs < 20%).ConclusionsThe accuracy of ETS in predicting survival was not increased by volumetric instead of diametric measurements. Continuous diametric and volumetric ETS similarly predicted survival, regardless of whether patients received cetuximab or bevacizumab. A volumetric ETS threshold of 45% and a diametric ETS threshold of 20% equally identified short-term survivors.Key Points• ETS based on volumetric measurements did not predict survival more accurately than ETS based on standard diametric measurements.• Continuous diametric and volumetric ETS predicted survival similarly in patients receiving FOLFIRI with cetuximab or bevacizumab.• A volumetric ETS threshold of 45% and a diametric ETS threshold of 20% equally identified short-term survivors.