Mucinous Histology Is Associated with Resistance to Anti-EGFR Therapy in Patients with Left-Sided RAS/BRAF Wild-Type Metastatic Colorectal Cancer

BackgroundLimited studies have suggested that mucinous histology is associated an attenuated response to anti-epidermal growth factor receptor (EGFR) therapy.MethodsWe conducted a single-institution, retrospective study to review the anti-EGFR response and the molecular profile of patients with left-sided microsatellite stable RAS/BRAF wild-type mucinous metastatic colorectal cancer.ResultsIn comparison to nonmucinous population (n = 98), mucinous histology (n = 20) was associated with a younger age (48 vs 54, P = .02), wild-type APC (80% vs 15.3%, P < .0001), and wild-type TP53 (40% vs 8.2%, P = .001). Guanine nucleotide binding protein, alpha stimulating (GNAS) mutations were exclusively found in mucinous tumors (20% vs 0, P < .0001). Genomic alterations associated with resistance to anti-EGFR therapy, such as ERBB2 amplification, PIK3CA mutation, MAP2K1 mutation, and KRAS amplification, were identified in patients with left-sided RAS/BRAF wild-type mucinous metastatic colorectal cancer. Mucinous histology was not associated with a worse outcome than non-mucinous histology (34.3 vs 42.2 months, P = .85). However, patients with left-sided RAS/BARF wild-type mucinous colorectal cancer treated with first-line anti-EGFR therapy had significantly worse progression-free survival (4 vs 6.5 months, hazard ratio [HR] = 5.3, 95% confidence interval [CI] 1.3-21.7, P = .01) than patients treated with the first-line vascular endothelial growth factor A antibody, bevacizumab. Anti-EGFR therapy was associated with limited responses and a short PFS across all lines of therapy in 12 patients with left-sided RAS/BRAF wild-type mucinous colorectal cancer.ConclusionsMucinous histology is associated with diminished benefits from anti-EGFR therapy in patients with left-sided RAS/BRAF wild-type colorectal cancer. These patients should be considered for bevacizumab-based therapy in the first- and second-line settings.     

Reinduction of an Anti-EGFR-based First-line Regimen in Patients with RAS Wild-type Metastatic Colorectal Cancer Enrolled in the Valentino Study

BackgroundIn patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC), growing evidence supports anti-epidermal growth factor receptor (EGFR) retreatment, whereas little is known on the outcomes of anti-EGFR-based reinduction therapy during the upfront strategy.MethodsWe included patients enrolled in the Valentino study who had disease progression and received at least one dose of post-progression therapy. The Kaplan–Meier method and Cox proportional hazards regression were used for the survival analysis. When comparing the outcomes of anti-EGFR-based reinduction versus any second line, a propensity score–based matching was used.ResultsLiver-limited/single site of disease (P < .001 and P = .002), left-sidedness (P = .029), surgery of metastases (P = .003), early tumor shrinkage, and deeper responses (P = .018 and P = .036) were associated with the use of anti-EGFR-based reinduction versus any other second line. All patients treated with reinduction had an anti-EGFR-free interval of at least 3 months. In the propensity score–matched population, progression-free survival (PFS) was similar in the 2 treatment groups, the overall survival (OS) was significantly longer for patients treated with reinduction (P = .029), and the response rate was higher in patients treated with reinduction (P = .033). An oxaliplatin-free interval ≥12 months, left-sidedness, and molecular hyperselection beyond RAS/BRAF were associated with significantly better outcomes after anti-EGFR-based reinduction.ConclusionsReinduction strategies with anti-EGFR-based regimens are commonly used in clinical practice. Our data highlight the importance of clinical–molecular selection for re-treatments and the need for prospective strategy trials in selected populations.     

MicroRNA Signature in Metastatic Colorectal Cancer Patients Treated With Anti-EGFR Monoclonal Antibodies

BackgroundTo investigate whether microRNAs are predictive of sensitivity to anti–epidermal growth factor receptor (EGFR) monoclonal antibodies in patients with metastatic colorectal cancer (mCRC).MethodsA total of 183 mCRC cases from 2 independent cohorts (cohort 1: 74 cases; validation cohort: 109 cases) treated with cetuximab or panitumumab were included in the study. MiRNA arrays were analyzed using Agilent's miRNA platform.ResultsThe study identified the cluster Let-7c/miR-99a/miR-125b as a signature associated with an outcome different from that of anti-EGFR therapies. In the first cohort, patients with high-intensity signatures had a significantly longer progression-free survival (PFS) (6.1 vs. 2.3 mo; P = .02) and longer overall survival (OS) ( 29.8 vs. 7.0 mo, P = .08) than patients with low-intensity signatures. In the validation cohort, patients with high signature had significantly longer PFS and OS than individuals with low-intensity signatures (PFS 7.8 vs. 4.3 mo, P = .02; OS 12.8 vs. 7.5 mo, P = .02). In the KRAS wild-type population (n = 120), high-intensity signature patients had a significantly longer PFS (7.8 vs. 4.6 mo, P = .016) and longer OS (16.1 vs. 10.9 mo, P = .09) than low-signature individuals, with no difference in KRAS mutated patients.ConclusionThe MiR-99a/Let-7c/miR-125b signature may improve the selection of patients with KRAS wild-type mCRC as good candidates for anti-EGFR therapy.     

Plasma Dynamics of RAS/RAF Mutations in Patients With Metastatic Colorectal Cancer Receiving Chemotherapy and Anti-EGFR Treatment

Background

RAS and RAF mutations in colorectal cancer (CRC) hold value in precision medicine. Liquid biopsy is an alternative to tumor tissue biopsy, and circulating tumor DNA (ctDNA) has been intensively investigated, but the clinical relevance of RAS and RAF mutations in plasma is yet to be determined. This study aimed to investigate the clinical aspects of RAS/RAF mutations during combination treatment.

Parallel Evaluation of Circulating Tumor DNA and Circulating Tumor Cells in Metastatic Colorectal Cancer

Background

Tissue biopsy is the gold standard for tumor genotyping, but it is an invasive procedure providing a single snapshot into tumor heterogeneity. Liquid biopsy approaches, encompassing the analysis of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs), have been proposed as an alternative, with the potential of providing a comprehensive portrait of the tumor molecular landscape. In metastatic colorectal cancer (mCRC), both CTCs and ctDNA analysis have been investigated, but comparative analyses are limited.

Cetuximab in the Treatment of Metastatic Colorectal Cancer: a Model-Based Cost-Effectiveness Analysis

Abstract

Cetuximab (Erbitux^®) has shown activity in patients with metastatic colorectal cancer (mCRC). To evaluate the cost-effectiveness of this drug combined with irinotecan in mCRC, a model-based cost-effectiveness analysis (CEA) was performed. Data on cetuximab obtained from Medline in December 2004 and from the 2004 ASCO-meeting were analyzed for life years gained (LYG) with regard to the use of this monoclonal antibody (MAb). Norwegian prices as of January 2005 were employed. The LYG ranged between 1.7 and 2.0 years. The median cost per patient treated was calculated to €34,256 to € 45,764 yielding a cost per LYG in the range between € 205,536 and € 323,040. Sensitivity analysis documented price of cetuximab and survival gain to be the major factors influencing the cost-effectiveness ratio. In conclusion, the analysis indicates cetuximab to be a promising, but very expensive antibody.     

Efficacy and Safety of Bevacizumab in Chinese Patients with Metastatic Colorectal Cancer

Objective: To evaluate the efficacy and safety of bevacizumab in the treatment of patients with metastatic colorectal cancer (mCRC). Methods: In a single-center, observational study of 91 Chinese patients with mCRC who received bevacizumab in combination with chemotherapy was conducted. Objective response rates (ORRs), progression-free survival (PFS), overall survival (OS) and adverse events were recorded, and the relationships between various clinical factors and PFS or OS were evaluated by Cox proportional hazards models. Results: Treatment with bevacizumab and chemotherapy was effective and tolerable. Univariate analysis showed that PFS and OS were significantly associated with the Eastern Cooperative Oncology Group performance status (ECOGPS) score, duration of bevacizumab exposure, and whether chemotherapy was continued after discontinuation of bevacizumab treatment. A multivariate analysis showed that the duration of bevacizumab exposure and whetherchemotherapy was continued after discontinuation of bevacizumab were independent prognostic factors for PFS and OS. Conclusion: In Chinese mCRC population, the shorter the duration of exposure to bevacizumab and chemotherapy, the worse the prognosis is.     

Economic Evaluation of Adding Bevacizumab to Chemotherapy for Metastatic Colorectal Cancer (mCRC) Patients in Indonesia

Objective: Since 2016, bevacizumab has been widely used to treat metastatic colorectal cancer (mCRC) in Indonesia. Nevertheless, the high cost of bevacizumab has raised the question of whether the therapy is considered cost-effective and should be included in the national health insurance system. This study aimed to assess the cost-effectiveness of bevacizumab plus chemotherapy versus chemotherapy alone for the treatment of mCRC patients. Methods: A Markov model was applied using the perspective of the Indonesian healthcare system to assess cost-effectiveness. The health outcomes were expressed in terms of quality-adjusted life years (QALY) using the validated EuroQoL-5D-5L instrument. Data for medical costs were collected from hospital billings in four hospitals located in three different cities in Indonesia. Meanwhile, data for utility were obtained from interviewing 90 patients who came to the hospital. We compared those mCRC patients who received chemotherapy alone either with FOLFOX or FOLFIRI, versus patients who received the addition of bevacizumab. Results: With the perspective of societal, the incremental cost-effectiveness ratio (ICER) of adding bevacizumab was USD 49,312 per QALY gained using secondary data and USD 28,446 per QALY using real world data. Conclusion: Using either a healthcare or societal perspective, the addition of bevacizumab for mCRC treatment was considered not cost-effective.     

Prognostic Value of the Combination of Circulating Tumor Cells Plus KRAS in Patients With Metastatic Colorectal Cancer Treated With Chemotherapy Plus Bevacizumab

ObjectiveCirculating tumor cells (CTCs) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) status were identified as prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer treated with chemotherapy and bevacizumab in analyses of the MACRO (Maintenance Treatment in Advanced Colorectal Cancer) trial. In this post hoc analysis of the MACRO trial, the potential additive effect of these 2 factors on patient outcomes was explored.MethodsA total of 158 of the 480 patients involved in the MACRO trial were included in the biological marker substudy. CTC isolation and enumeration were centralized and performed using the CellSearch System (Veridex LLC, Raritan, NJ) in 7.5 mL of whole blood. Evaluation of KRAS status was performed retrospectively by the standard method used at each center. PFS and OS were analyzed by the Kaplan–Meier method according to CTC count and KRAS status.ResultsPatients with < 3 CTC per 7.5 mL blood at baseline and KRAS wild-type tumors had a median PFS of 14.2 months compared with 6.2 months in patients with ≥ 3 CTCs and KRAS mutated tumors (P < .0001; hazard ratio, 3.0; 95% confidence interval, 1.8-5.2). Similar findings were observed for OS (28.9 and 13.7 months, respectively, P = .0004; hazard ratio 2.8; 95% confidence interval, 1.6-4.9). Multivariate analyses showed that CTC count ≥ 3 and KRAS status were the only independent prognostic factors for both PFS and OS.ConclusionsThis post hoc analysis showed that CTC count and KRAS status were independent prognostic factors for outcomes in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy. These factors should be taken into account in the design of future phase III trials.     

液体活检及其在非小细胞肺癌诊治中的研究进展

随着近几年科学技术的进步,液体活检技术也有了长足的发展,并在肿瘤的早期诊断及后期治疗中扮演着越来越重要的角色。相比于传统的组织活检,液体活检以其独有的无创性、便捷性、高重复性等特点在临床上得到更多的青睐,在未来有着巨大的发展潜力。本文重点探讨了循环肿瘤细胞（circulating tumor cells, CTCs）和循环肿瘤DNA（circulating tumor DNA, ctDNA）,作为液体活检最重要的两个检测对象,其历史、生物学特性,检测手段,局限性及其在非小细胞肺癌诊治中的应用。     

Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Non–Small Cell Lung Cancer

Introduction

Genomic profiling informs selection of matched targeted therapies as part of routine clinical care in NSCLC. Tissue biopsy is the criterion standard; however, genomic profiling of blood-derived circulating tumor DNA (ctDNA) has emerged as a minimally invasive alternative.

Factors Affecting Prognosis in Metastatic Colorectal Cancer Patients

Background: Colorectal cancer (CRC) is a major cause of mortality in developed countries, and it is the thirdmost frequent malignancy in Turkey. There are many biological, genetic, molecular, and tissue-derived prognosticfactors for CRCs. In this study, we evaluated prognostic factors in patients who were metastatic at diagnosis orprogressed to metastatic disease during follow-up. Patients and Methods: This study included 116 patients withmalignancies either in the colon or rectum. Of these, 65 had metastatic disease at diagnosis, and 51 progressedto metastatic disease during the course of the disease. The parameters evaluated were age, gender, comorbidity,performance status and stage of the disease at the beginning, localization, history of surgery, chemotherapyregimen, response to first-line treatment, K-RAS status, site and number of metastases, expression of tumorpredictors (CEA, CA19-9), and survival times. A multivariate analysis conducted with factors that consideredstatistically significant in the univariate analysis. Findings: Median age was 56 (32-82) years and the male/female ratio was 80/36. Eleven patients were at stage II, 40 at stage III, and 65 at stage IV at diagnosis. Twentythree patients had tumor in the right colon, 48 in the left colon, and 45 in the rectum. Ninety seven patients wereoperated, and 27 had surgical metastasectomy. Ninety three patients received targeted therapy. At the end offollow-up, 61 patients had died, and 55 survived. Metastatic period survival times were longer in the adjuvantgroup, but the difference did not reach the level of statistical significance (adjuvant group: median 29 months,metastatic group: median 22 months; p=0.285). In the adjuvant group before the metastatic first-line therapy,CEA and CA 19-9 levels were significiantly lower compared to the metastatic group (p<0.005). We also foundthat patients with elevated tumor predictor (CEA, CA 19-9) levels before the first-line therapy had significiantlypoorer prognosis and shorter survival time. Survival was significiantly better with the patients who were youngerthan 65 years of age, had better initial performance status, a history of primary surgery and metastatectomy,and single site of metastasis. Those who benefitted from the first-line therapy were K-RAS wild type and whosetumor markers (CEA, CA 19-9) were not elevated before the first line therapy. Conclusions: Among the patientswith metastatic CRC, those who benefited from first-line therapy, had history of metastasectomy, were K-RASwild type and had low CA 19-9 levels before the first-line therapy, showed better prognosis independent of otherfactors.     

Lack of Benefit From Anti-EGFR Treatment in RAS and BRAF Wild-type Metastatic Colorectal Cancer With Mucinous Histology or Mucinous Component

BackgroundAdenocarcinoma with mucinous histology or mucinous component are histologic subtypes of metastatic colorectal cancers (mCRCs) with limited benefit from cytotoxic agents. Their sensitivity to anti-epithelial growth factor receptors (EGFRs) is not clear.Patients and MethodsThe activity and efficacy of anti-EGFRs was retrospectively evaluated among patients with RAS and BRAF wild-type mCRC with or without mucinous histology or mucinous component. Subgroup analyses according to primary tumor location were conducted.ResultsOverall, the study population included 22 mucinous or with mucinous component tumors (11 right- and 11 left-sided tumors) and 83 not mucinous tumors. One patient experienced partial response among mucinous tumors, whereas in the not mucinous group, 42 patients experienced partial response, with an overall response rate of 4% and 51%, respectively (P = .003). The median progression-free survival was 2.8 versus 6.7 months (hazard ratio, 0.28; 95% confidence interval, 0.13-0.59; P < .001), and the median overall survival was 6.5 and 16.7 months (hazard ratio, 0.58; 95% confidence interval, 0.33-1.00; P = .022), for the mucinous and not mucinous groups, respectively. Similar results were observed in subgroup analysis according to primary tumor location.ConclusionAnti-EGFRs may not provide clinically meaningful benefit in mCRCs with mucinous histology or mucinous component compared with those without mucinous component, irrespective of sidedness.     

Identification of Somatic Mutations in Thirty-year-old Serum Cell-free DNA From Patients With Breast Cancer: A Feasibility Study

IntroductionThe aim of this study was to assess the feasibility of cell-free DNA (cfDNA) extraction and circulating tumor DNA sequencing in 30-year-old serum samples.Materials and MethodsWe evaluated serum samples from 52 patients with breast cancer, which were collected between 1983 and 1991, with correlating clinicopathologic data. cfDNA was extracted by using the QIAamp Circulating Nucleic Acid Extraction Kit (Qiagen). Of these 52 cfDNA samples, 10 were randomly selected and sequenced with the Oncomine Breast cfDNA Assay (A31183). In a second step, high-depth targeted sequencing of 15 additional cfDNA samples was performed using a custom Ampliseq Ion Torrent panel targeting breast cancer-related genes.ResultscfDNA extraction was successful in 52 (100%) of 52 patients with a total concentration of 0.2 to 54 ng/uL. A total of 24 cancer-specific mutations were found in 22 (88%) of the 25 samples undergoing sequencing. Of the 52 patients, 32 (62%) had died from breast cancer after a median follow-up of 7.9 years (interquartile range, 3.7-15.5 years).ConclusionThe present study shows that current next generation sequencing technology is sufficiently robust and specific to analyze 30-year-old serum. Therefore, longitudinal studies can be designed with storage of serum samples over many years, thereby obviating the need for timely and continuous cfDNA extraction and sequencing. The samples can be pooled and processed at once with the most modern technology available at the end of the study, when accumulation of events allows correlation of clinical outcomes with adequate power.     

Dynamics of EGFR Mutation Load in Plasma for Prediction of Treatment Response and Disease Progression in Patients With EGFR-Mutant Lung Adenocarcinoma

Background

The assessment of epidermal growth factor receptor (EGFR) mutations is crucial for the management of patients with lung adenocarcinoma. Circulating tumor DNA (ctDNA)-based assessment offers advantages over tumor as a minimally invasive method able to capture tumor heterogeneity.

Antiangiogenic Drug-Induced Proteinuria as a Prognostic Factor in Metastatic Colorectal Cancer

Treatment with bevacizumab is known to cause adverse events such as proteinuria and hypertension, amongst others. However, while bevacizumab-induced hypertension has been linked to increased overall survival (OS), data on proteinuria are controversial. We performed a retrospective analysis to observe the influence of adverse events developed during treatment with bevacizumab and chemotherapy on the OS in patients with metastatic colorectal cancer (mCRC). Kaplan–Meier and log-rank analyses were used to assess differences in OS, and hazard ratios (HR) were estimated using Cox models. Out of the 3497 mCRC patients admitted to our center between 2014 and 2019, 150 met the criteria for inclusion in our analysis. Out of these, 50.7% experienced proteinuria and had reached a longer OS (40 versus 25 months, p = 0.015) and progression-free survival (15 versus 12 months, p = 0.039). The following groups were identified as having a lower risk of death: patients with proteinuria (HR 0.589; 95% CI 0.402–0.863; p = 0.007), one metastatic site (HR 0.533; 95% CI 0.363–0.783; p = 0.001), and non-metastatic stage at diagnosis (HR 0.459; 95% CI 0.293–0.720; p = 0.001). Patients with anemia and diabetes had an increased risk of death. Proteinuria emerges as a useful prognostic factor in mCRC patients undergoing bevacizumab-based systemic therapy, and it could be easily integrated into the decision-making process, thus allowing physicians to further individualize systemic treatments.     

Circulating Tumor Cells as a Biomarker of Survival and Response to Radium-223 Therapy: Experience in a Cohort of Patients With Metastatic Castration-Resistant Prostate Cancer

Introduction

Although increasing numbers of therapies with proven survival benefits have become available for metastatic castration-resistant prostate cancer (mCRPC), including radium-223, there is still a need for reliable biomarkers that provide information about clinically meaningful outcomes and treatment responses.