Revisiting Luteolin Against the Mediators of Human Metastatic Colorectal Carcinoma: A Biomolecular Approach.

Metastatic colorectal carcinoma (mCRC) is one of the prevalent subtypes of human cancers and is caused by the alterations of various lifestyle and diet-associated factors. ß-catenin, GSK-3ß, PI3K-α, AKT1, and NF-κB p50 are known to be the critical regulators of tumorigenesis and immunopathogenesis of mCRC. Unfortunately, current drugs have limited efficacy, side effects and can lead to chemoresistance. Therefore, searching for a nontoxic, efficacious anti-mCRC agent is crucial and of utmost interest. The present study demonstrates the identification of a productive and nontoxic anti-mCRC agent through a five-targets (ß-catenin, GSK-3ß, PI3K-α, AKT1, and p50)-based and three-tier (binding affinity, pharmacokinetics, and pharmacophore) screening strategy involving a series of 30 phytocompounds having a background of anti-inflammatory/anti-mCRC efficacy alongside 5-fluorouracil (FU), a reference drug. Luteolin (a phyto-flavonoid) was eventually rendered as the most potent and safe phytocompound. This inference was verified through three rounds of validation. Firstly, luteolin was found to be effective against the different mCRC cell lines (HCT-15, HCT-116, DLD-1, and HT-29) without hampering the viability of non-tumorigenic ones (RWPE-1). Secondly, luteolin was found to curtail the clonogenicity of CRC cells, and finally, it also disrupted the formation of colospheroids, a characteristic of metastasis. While studying the mechanistic insights, luteolin was found to inhibit ß-catenin activity (a key regulator of mCRC) through direct physical interactions, promoting its degradation by activating GSK3-ß and ceasing its activation by inactivating AKT1 and PI3K-α. Luteolin also inhibited p50 activity, which could be useful in mitigating mCRC-associated proinflammatory milieu. In conclusion, our study provides evidence on the efficacy of luteolin against the critical key regulators of immunopathogenesis of mCRC and recommends further studies in animal models to determine the effectiveness efficacy of this natural compound for treating mCRC in the future.

Prevalence of hypoxia and correlation with glycolytic metabolism and angiogenic biomarkers in metastatic colorectal carcinoma.

PURPOSE: Hypoxia is associated with aggressive tumour behaviour and can influence response to systemic therapy and radiotherapy. The prevalence of hypoxia in metastatic colorectal cancer is poorly understood, and the relationship of hypoxia to patient outcomes has not been clearly established. The aims of the study were to evaluate hypoxia in metastatic colorectal cancer with [18F]Fluoromisonidazole ([18F]FMISO PET) and correlate these findings with glycolytic metabolism ([18F]FDG PET) and angiogenic blood biomarkers and patient outcomes. METHODS: Patients with metastatic colorectal cancer received routine staging investigations and both [18F] FMISO PET and [18F] FDG PET scans. Correlative blood specimens were also obtained at the time of the [18F] FMISO PET scan. Patient follow-up was performed to establish progression-free survival. RESULTS: A total of 40 patients were recruited into the trial. [18F]FMISO and [18F]FDG PET scans showed a significant correlation of SUVmax (p = 0.003). A significant correlation of progression-free survival and [18F] FMISO TNR (p = 0.02) and overall survival with [18F]FMISO TNR (p = 0.003) and [18F]FDG TGV (p = 0.02) was observed. Serum levels of osteopontin, but not VEGF, correlated with [18F] FMISO and [18F]FDG PET scan parameters. CONCLUSION: [18F]FMISO PET uptake in metastatic colorectal cancer significantly correlates with glycolytic metabolism and is predictive of progression-free and overall survival. These findings have implications for the assessment and treatment of metastatic colorectal cancer patients with novel therapies which affect tumour angiogenesis and hypoxia.

Durable complete remission following anti-EGFR antibodies in recurrent metastatic colorectal cancer.

In this case report, we describe a patient who remains in complete remission two years after the discontinuation of anti-EGFR monotherapy as a third-line treatment, accompanied by persistent severe hypomagnesemia. A 45-year-old Caucasian woman with mCRC started chemotherapy with weekly cetuximab. After ten months of treatment, the therapy was stopped because the patient had persistent grade III hypomagnesemia despite amiloride, oral, and intravenous magnesium. A month later, the patient was switched to panitumumab 6 mg/kg every two weeks for four additional months to avoid weekly visits to the clinic. Following discontinuation of panitumumab, PET scans remain negative to this day, two years after anti-EGFR therapy discontinuation. No factor has been identified to explain the complete and sustained response experienced by this patient. Hypomagnesemia is a common adverse effect of anti-EGFR therapy that can lead to treatment interruption and discontinuation if severe. This case highlights the importance of pursuing anti-EGFR therapy when a response is observed in spite of severe hypomagnesemia. It also provides preliminary information that anti-EGFR therapy could be stopped after a complete response is obtained.

Safety profile of trifluridine/tipiracil monotherapy in clinical practice: results of the German compassionate-use program for patients with metastatic colorectal cancer.

BACKGROUND: Trifluridine/tipiracil (TAS-102, Lonsurf®), a novel oral anti-tumor agent combining an anti-neoplastic thymidine-based nucleoside analogue (trifluridine, FTD) with a thymidine phosphorylase inhibitor (tipiracil hydrochloride, TPI) presents a new treatment option for metastatic colorectal cancer (mCRC) patients refractory or intolerant to standard therapies. FTD/TPI was approved in the European Union (EU) in April 2016 and launched on the German market in August 15, 2016. METHODS: We investigated the characteristics of patients (pts) with mCRC treated with FTD/TPI at 118 centers in Germany from January 12 to August 14, 2016 and analyzed the safety in a clinical real-world setting. RESULTS: In Germany, a total of 226 mCRC patients were included into a compassionate-use-program (CUP) and received FTD/TPI. For 45.5% of patients (n = 101), 253 adverse events (AE) were documented, most of them drug-related (n = 135). From January 12 (2016) to March 2 (2017), 124 serious adverse events (SAE) were reported (74 drug related). The most common serious adverse drug reactions (SADR) were leukopenia (12 events), neutropenia (8 events), anemia (7 events), diarrhea and nausea (5 events each) (observation period January 12 2016 to October 7 2016). In total, 122 patients (54%) discontinued FTD/TPI treatment, mostly due to progression (n = 75) followed by AEs (n = 21), deaths (n = 16), and non-specified reasons (n = 16). Interestingly, 12 patients with ECOG PS ≥2 achieved up to 3 cycles of FTD/TPI and in this patient population only 3 treatment discontinuations due to AEs were documented and the safety profile was comparable to the entire population. CONCLUSION: The patient characteristics as well as the safety profile of FTD/TPI documented in the German CUP were consistent with those reported in the pivotal trial RECOURSE without unexpected safety signals.

Carbon dating cancer: defining the chronology of metastatic progression in colorectal cancer.

Background: Patients often ask oncologists how long a cancer has been present before causing symptoms or spreading to other organs. The evolutionary trajectory of cancers can be defined using phylogenetic approaches but lack of chronological references makes dating the exact onset of tumours very challenging. Patients and methods: Here, we describe the case of a colorectal cancer (CRC) patient presenting with synchronous lung metastasis and metachronous thyroid, chest wall and urinary tract metastases over the course of 5 years. The chest wall metastasis was caused by needle tract seeding, implying a known time of onset. Using whole genome sequencing data from primary and metastatic sites we inferred the complete chronology of the cancer by exploiting the time of needle tract seeding as an in vivo 'stopwatch'. This approach allowed us to follow the progression of the disease back in time, dating each ancestral node of the phylogenetic tree in the past history of the tumour. We used a Bayesian phylogenomic approach, which accounts for possible dynamic changes in mutational rate, to reconstruct the phylogenetic tree and effectively 'carbon date' the malignant progression. Results: The primary colon cancer emerged between 5 and 8 years before the clinical diagnosis. The primary tumour metastasized to the lung and the thyroid within a year from its onset. The thyroid lesion presented as a tumour-to-tumour deposit within a benign Hurthle adenoma. Despite rapid metastatic progression from the primary tumour, the patient showed an indolent disease course. Primary cancer and metastases were microsatellite stable and displayed low chromosomal instability. Neo-antigen analysis suggested minimal immunogenicity. Conclusion: Our data provide the first in vivo experimental evidence documenting the timing of metastatic progression in CRC and suggest that genomic instability might be more important than the metastatic potential of the primary cancer in dictating CRC fate.

Clinical performance evaluation of a sensitive, rapid low-throughput test for KRAS mutation analysis using formalin-fixed, paraffin-embedded tissue samples.

BACKGROUND: Testing for KRAS mutations in metastatic colorectal cancer (mCRC) on formalin-fixed, paraffin embedded (FFPE) tumor tissue has become standard of care. Different molecular methods exist to determine hotspot KRAS mutations in exon 2, 3 and 4, but testing is often limited by the sensitivity and the speed of analysis. The aim of this retrospective study was to establish the clinical performance of the Idylla™ KRAS Mutation Test on FFPE tumor samples of patients with mCRC. METHODS: KRAS mutation analysis was performed using the therascreen KRAS on the RotorGene Q platform (CE-IVD; Qiagen) and results were subsequently compared to the Idylla™ KRAS Mutation Test. Discordant result testing was performed with massive parallel sequencing or alternative routine approaches. RESULTS: Data from 182 samples were used to show that the overall agreement between the two methods for mutation characterization was 96.7% [95%CI: 93.0%-98.5%]. Six out of 182 samples (3.3%) showed true discordant results. CONCLUSION: The Idylla™ KRAS Mutation Test allows for a fast and reliable analysis of FFPE samples with a turnaround-time of two hours without the need of molecular infrastructure or expertise in order to guide the personalized treatment of colorectal cancer patients.

Recommendations for SIR-Spheres Y-90 resin microspheres in chemotherapy-refractory/intolerant colorectal liver metastases.

A Spanish expert panel reviewed current evidence for the use of SIR-Spheres Y-90 resin microspheres in patients with chemotherapy refractory/intolerant unresectable colorectal liver metastases. Substantial evidence for its efficacy and safety is available from a randomized controlled study, retrospective comparative studies and several single arm studies. Clinical evidence data obtained from more than 1500 patients have led to the inclusion of selective internal radiation therapy in the 2016 ESMO Clinical Guidelines as third-line treatment. This publication results from an expert panel meeting, where published evidence and author's experiences were shared to position SIR-Spheres Y-90 resin microspheres in Spain for the treatment of chemotherapy refractory/intolerant unresectable colorectal liver metastases, and second, to define the patient subgroup that will benefit the most with this treatment.

Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression.

BACKGROUND: The RAISE phase III clinical trial demonstrated that ramucirumab + FOLFIRI improved overall survival (OS) [hazard ratio (HR) = 0.844, P = 0.0219] and progression-free survival (PFS) (HR = 0.793, P < 0.0005) compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Since some patient or disease characteristics could be associated with differential efficacy or safety, prespecified subgroup analyses were undertaken. This report focuses on three of the most relevant ones: KRAS status (wild-type versus mutant), age (<65 versus ≥65 years), and time to progression (TTP) on first-line therapy (<6 versus ≥6 months). PATIENTS AND METHODS: OS and PFS were evaluated by the Kaplan-Meier analysis, with HR determined by the Cox proportional hazards model. Treatment-by-subgroup interaction was tested to determine whether treatment effect was consistent between subgroup pairs. RESULTS: Patients with both wild-type and mutant KRAS benefited from ramucirumab + FOLFIRI treatment over placebo + FOLFIRI (interaction P = 0.526); although numerically, wild-type KRAS patients benefited more (wild-type KRAS: median OS = 14.4 versus 11.9 months, HR = 0.82, P = 0.049; mutant KRAS: median OS = 12.7 versus 11.3 months, HR = 0.89, P = 0.263). Patients with both longer and shorter first-line TTP benefited from ramucirumab (interaction P = 0.9434), although TTP <6 months was associated with poorer OS (TTP ≥6 months: median OS = 14.3 versus 12.5 months, HR = 0.86, P = 0.061; TTP <6 months: median OS = 10.4 versus 8.0 months, HR = 0.86, P = 0.276). The subgroups of patients ≥65 versus <65 years also derived a similar ramucirumab survival benefit (interaction P = 0.9521) (≥65 years: median OS = 13.8 versus 11.7 months, HR = 0.85, P = 0.156; <65 years: median OS = 13.1 versus 11.9 months, HR = 0.86, P = 0.098). The safety profile of ramucirumab + FOLFIRI was similar across subgroups. CONCLUSIONS: These analyses revealed similar efficacy and safety among patient subgroups with differing KRAS mutation status, longer or shorter first-line TTP, and age. Ramucirumab is a beneficial addition to second-line FOLFIRI treatment for a wide range of patients with mCRC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01183780.

Palliative surgical intervention in metastatic colorectal carcinoma: a prospective analysis of quality of life.

AIM: Quality of life (QOL) was assessed after palliative surgery for incurable metastatic colorectal cancer (CRC). METHOD: Newly diagnosed patients with incurable metastatic CRC who were offered elective palliative surgical intervention were included. The European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR29 questionnaire was used for the assessment of QOL at baseline and at 3 and 6 months after surgery. Generalized estimating equations were used to estimate the mean change in the QOL score from baseline. RESULTS: Twenty-four patients formed the study group. Sixteen underwent resection of the primary tumour and eight had a proximal diversion or bypass. The Global Health (GH) score and Social Functioning (SF) score improved at 3 and 6 months after intervention respectively (GH +11, P = 0.021; SF +15, P = 0.005). Mean anxiety scores were markedly improved from the baseline of 51 to 71 (P = 0.004, 3 months) and 76 (P = 0.002, 6 months). Weight concerns also improved significantly when compared with baseline (3 months, +20, P < 0.001; 6 months, +14, P = 0.012). Symptoms of diarrhoea (3 months, --17, P = 0.007; 6 months,--16, P = 0.008) and nausea (--8, P = 0.032) improved. CONCLUSION: In patients with incurable metastatic CRC, surgery improved QOL.

Pilot study of angiogenic response to yttrium-90 radioembolization with resin microspheres.

PURPOSE: To investigate the impact of radioembolization with yttrium-90 resin microspheres on the regulation of angiogenesis through observation of serial changes in a spectrum of angiogenic markers and other cytokines after therapy. MATERIALS AND METHODS: This prospective pilot study enrolled 22 patients with liver-dominant disease deriving from biopsy-proven hepatocellular carcinoma (HCC) (n = 7) or metastatic colorectal carcinoma (mCRC) (n = 15). Circulating angiogenic markers were measured from serum samples drawn at baseline and at time points after therapy ranging from 6 hours to 120 days. Using multiplex enzyme-linked immunosorbent assay, several classic angiogenesis factors (vascular endothelial growth factor [VEGF], angiopoietin-2 [Ang-2], basic fibroblast growth factor [bFGF], platelet-derived growth factor subunit BB [PDGF-BB], thrombospondin-1 [Tsp-1]) and nonclassic factors (follistatin, leptin, interleukin [IL]-8) were evaluated. RESULTS: Increases in cytokine levels ≥ 50% over baseline were observed in more than half of all patients studied for many cytokines, including classic angiogenic factors such as VEGF, Ang-2, and Tsp-1 as well as nonclassic factors IL-8 and follistatin (range, 36%-82% for all cytokines). Baseline cytokine levels in patients with overall survival (OS) < 6 months differed significantly from patients with longer survival for Ang-2 (P = .033) and IL-8 (P = .041). Patients with OS ≤ 6 months exhibited transient increases in VEGF and PDGF-BB after therapy compared with patients with OS > 6 months. CONCLUSIONS: Radioembolization is associated with early transient increases in many angiogenic cytokines. In this small sample size, some of these changes were associated with worse OS. This research has important implications for future studies of radioembolization with antiangiogenic therapy performed during and after the procedure.

The Real-Life Impact of Primary Tumor Resection of Synchronous Metastatic Colorectal Cancer-From a Clinical Oncologic Point of View.

AIM: The complex medical care of synchronous metastatic colorectal (smCRC) patients requires prudent multidisciplinary planning and treatments due to various challenges caused by the primary tumor and its metastases. The role of primary tumor resection (PTR) is currently uncertain; strong arguments exist for and against it. We aimed to define its effect and find its best place in our therapeutic methodology. METHOD: We performed retrospective data analysis to investigate the clinical course of 449 smCRC patients, considering treatment modalities and the location of the primary tumor and comparing the clinical results of the patients with or without PTR between 1 January 2013 and 31 December 2018 at the Institute of Oncotherapy of the University of Pécs. RESULTS: A total of 63.5% of the 449 smCRC patients had PTR. Comparing their data to those whose primary tumor remained intact (IPT), we observed significant differences in median progression-free survival with first-line chemotherapy (mPFS1) (301 vs. 259 days; p < 0.0001; 1 y PFS 39.2% vs. 26.6%; OR 0.56 (95% CI 0.36-0.87)) and median overall survival (mOS) (760 vs. 495 days; p < 0.0001; 2 y OS 52.4 vs. 26.9%; OR 0.33 (95% CI 0.33-0.53)), respectively. However, in the PTR group, the average ECOG performance status was significantly better (0.98 vs. 1.1; p = 0.0456), and the use of molecularly targeted agents (MTA) (45.3 vs. 28.7%; p = 0.0005) and rate of metastasis ablation (MA) (21.8 vs. 1.2%; p < 0.0001) were also higher, which might explain the difference partially. Excluding the patients receiving MTA and MA from the comparison, the effect of PTR remained evident, as the mOS differences in the reduced PTR subgroup compared to the reduced IPT subgroup were still strongly significant (675 vs. 459 days; p = 0.0009; 2 y OS 45.9 vs. 24.1%; OR 0.37 (95% CI 0.18-0.79). Further subgroup analysis revealed that the site of the primary tumor also had a major impact on the outcome considering only the IPT patients; shorter mOS was observed in the extrapelvic IPT subgroup in contrast with the intrapelvic IPT group (422 vs. 584 days; p = 0.0026; 2 y OS 18.2 vs. 35.9%; OR 0.39 (95% CI 0.18-0.89)). Finally, as a remarkable finding, it should be emphasized that there were no differences in OS between the smCRC PTR subgroup and metachronous mCRC patients (mOS 760 vs. 710 days, p = 0.7504, 2 y OS OR 0.85 (95% CI 0.58-1.26)). CONCLUSIONS: The role of PTR in smCRC is still not professionally justified. Our survey found that most patients had benefited from PTR. Nevertheless, further prospective trials are needed to clarify the optimal treatment sequence of smCRC patients and understand this cancer disease's inherent biology.

The Real-Life Impact of mFOLFIRI-Based Chemotherapies on Elderly Patients-Should We Let It or Leave It?

AIM: The oncologic treatment of elderly patients is going on with a lack of evidence due to their underrepresentation in clinical trials. Many data suggest that certain groups of elderly patients, like their younger counterparts, may benefit from the systemic treatment of their metastatic colorectal tumors (mCRC). METHOD: We performed retrospective data analysis to investigate the clinical course of care and clinical outcomes of 515 patients who received first-line mFOLFIRI-based chemotherapy for mCRC between 1 January 2013 and 31 December 2018 at the Institute of Oncotherapy of the University of Pécs, focusing on a comparison of patients over and under 70 years of age, defined as the cut-off value. RESULTS: 28.7% of the 515 patients were 70 years old and older (median age 73.5 years). Compared to the data of the elderly patients, the younger group (median age 61.1 years) had a performance status that was significantly better (average ECOG 1.07 vs. 0.83, p < 0.0001), and significantly more patients received molecularly targeted agents (MTA) (21.6% vs. 51.8%, p < 0.0001); nevertheless, mPFS (241 vs. 285 days, p = 0.3960) and mOS (610 vs. 698 days, p = 0.6305) results did not differ significantly. Considering the 1y PFS OR and the 2ys OS OR values (0.94 [95%CI 0.63-1.41] and 0.72 [95%CI 0.47-1.09], respectively), only a non-significant trend was observed in OS favouring the younger population. Additional analysis of our data proved that the survival in patients over 70 years was positively affected by the addition of MTAs to the doublet chemotherapies, and the reasonable modifications/reductions in dose intensity and the addition of local interventions had similar positive effects as observed in the younger patients' group. CONCLUSIONS: Age stratification of mCRC patients is not professionally justified. Patients over 70 years of age with good performance status and controlled co-morbidities benefit from systemic therapy, its modifications and local treatment to the same extent as younger patients. With the increasing incidence of age-related cancers due to the rising average lifespan, prospective randomised clinical trials are needed to determine the real value of systemic therapy in the elderly and the rational, objective methods of patient selection.

Real-Life Effectivity of Dose Intensity Reduction of First-Line mFOLFIRI-Based Treatment of Metastatic Colorectal Cancers: Sometimes Less Is More.

Aim: The key purposes of the treatment of metastatic malignancies are to extend survival and maintain the quality of life. Recently it has been emphasized in the scientific literature that the maintenance of maximal dose intensity is not always beneficial. Method: We examined the effectiveness of first-line mFOLFIRI-based treatments used in mCRC indication in 515 patients, treated between 1 January 2013 and 31 December 2018 at the Department of Oncotherapy of the University of Pécs, on a basis of real-world retrospective data analysis. We studied the effect of decreased dose intensity treatment modifications on patient survival. Results: 45% of all patients achieved the optimal relative dose intensity (RDI) of 85%, and the median progression-free and overall survival (mPFS, mOS) were 199 and 578 days, compared to 322 and 743 days, (mPFS p < 0.0002, 1 y (year) PFS OR (odds ratio) 0.39 (95% CI: 0.26−0.56) and mOS p = 0.0781, 2 yrs OS OR 0.58 (95% CI: 0.39−0.85), respectively) in the group of patients not achieving the RDI of 85%. Conclusions: Decreased dose intensity did not reduce the effectiveness of treatment; in fact, there was a significant improvement in most of the analyzed parameters. The option of reduced dose intensity, which shows the same or even better results with less toxicity, should definitely be considered in the future palliative treatment of mCRC patients.

Current Landscape and Potential Challenges of Immune Checkpoint Inhibitors in Microsatellite Stable Metastatic Colorectal Carcinoma.

Colorectal cancer (CRC) is the third most frequent cancer and the second most common cause of cancer-related death in Europe. High microsatellite instability (MSI-H) due to a deficient DNA mismatch repair (dMMR) system can be found in 5% of metastatic CRC (mCRC) and has been established as a biomarker of response to immunotherapy in these tumors. Therefore, immune checkpoint inhibitors (ICIs) in mCRC with these characteristics were evaluated with results showing remarkable response rates and durations of response. The majority of mCRC cases have high levels of DNA mismatch repair proteins (pMMR) with consequent microsatellite stability or low instability (MSS or MSI-low), associated with an inherent resistance to ICIs. This review aims to provide a comprehensive analysis of the possible approaches to overcome the mechanisms of resistance and evaluates potential biomarkers to establish the role of ICIs in pMMR/MSS/MSI-L (MSS) mCRC.

An Observational Study of Trifluridine/Tipiracil-Containing Regimen Versus Regorafenib-Containing Regimen in Patients With Metastatic Colorectal Cancer.

Background: There are no randomized control trials comparing the efficacy of trifluridine/tipiracil and regorafenib in patients with metastatic colorectal cancer (mCRC). Herein, we conducted an observational study to compare the oncologic outcomes of trifluridine/tipiracil-containing regimen (TAS-102) and regorafenib-containing regimen (REG) in patients with mCRC. Material and method: Patients who were diagnosed to have mCRC in 2015 to 2021 and treated with TAS-102-containing regimen or REG-containing regimen were recruited. Monotherapy or combination therapy were all allowed in this study. Oncologic outcomes were presented with progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and disease control rate (DCR). Results: A total of 125 patients were enrolled into our study, accounting for 50 patients with TAS-102 and 75 patients with REG. Of these patients, 64% were treated with TAS-102 or REG monotherapy, while the remaining were treated with TAS-102 combination or REG combination. In general, the median PFS and OS were 3.7 versus 2.0 months (P = 0.006) and 9.2 versus 6.8 months (P = 0.048) in TAS-102 and REG, respectively. The ORR and DCR were 44% versus 20% (P < 0.001) and 72% versus 43% (P < 0.001) in TAS-102 and REG, respectively. As for treatment strategies, the survival were significantly longer in combination than in monotherapy, no matter in TAS-102 or REG group. Multivariate analysis showed TAS-102 and combination therapy were independent predictor associated with better survival. Conclusions: Our results suggested that TAS-102 had better oncologic outcomes than REG in patients with mCRC, especially in combination. Further prospective trials are warranted to confirm our results.

Metastatic Liver Tumors in Surgical Pathology: Impact of Contemporary Diagnostic and Therapeutic Paradigms in a Tertiary Care Center.

We analyzed metastatic liver tumors received in the department of pathology in a tertiary care center over a 3-year period. There were 509 metastatic liver tumors; counterintuitively, there were as many resections (235 cases) as biopsies (274 cases). This unexpected finding reflects contemporaneous organ-specific paradigms for diagnosis and management of metastatic liver disease in oncologic practice, and the association of our practice with a National Cancer Institute-designated comprehensive cancer center with expertise and specialization in liver surgery. We receive a large number of resections for metastatic liver tumors because metastasectomy from a variety of primary tumors is associated with improved overall, and in many instances, disease-free, long-term survival. Metastatic colorectal carcinomas, metastatic neuroendocrine tumors, and metastatic gastrointestinal stromal tumors constituted 78% of resections because the largest body of literature and cumulative experience exists for these lesions. In contrast, breast carcinomas and pancreatic carcinomas, which are the next common metastatic liver tumors were biopsied but rarely resected, because metastasectomy is not the standard of care for these tumors. Immunohistochemistry was performed in less than a quarter of the total number of cases (23%), because the primary tumor site was known in the vast majority of cases. Of the 42 cases with unknown primary tumor, it was elucidated in 50% of the cases by immunohistochemical and clinical work-up. Of the cases with known primary tumor, immunohistochemistry was performed mostly in metastatic breast, colon, and lung carcinomas. In these cases, biomarker analyses provided additional information relevant to clinical management.

Next-Generation Sequencing of Circulating Tumor DNA Can Optimize Second-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer after Progression on anti-EGFR Therapy: Time to Rethink Our Approach.

BACKGROUND: Management of Ras wild-type colorectal cancer (CRC) patients upon disease progression after the successful use of targeted treatment with anti-EGFR monoclonal antibodies and backbone chemotherapy remains a clinical challenge. SUMMARY: Development of treatment resistance with prevalence of preexisting RAS mutated clones, RAS mutation conversion, truncation of extracellular receptor domains as well as HER2 and MET amplification are molecular events that can be difficult to follow without the use of sophisticated laboratory techniques. The clinical hurdle of re-biopsy and tumor heterogeneity can be overcome by the implementation of next-generation sequencing (NGS) to analyze circulating tumor DNA (ctDNA) and identify druggable mutations or recovery of RAS-wildness. In this opinion paper, we summarize with critical thinking the clinical approach to be followed after the failure of first-line treatment in Ras wild-type CRC tumors with the use of NGS. Rechallenge with anti-EGFR inhibitors, in case of persistent or recovery of RAS-wildness, and targeted approach of specific mutations (BRAF inhibitors), amplifications (anti-Her2 treatment), or fusion proteins (NTRK inhibitors) can by guided by the use of NGS. The use of NGS platforms for serial analysis of ctDNA is an important step to better understand the molecular landscape of metastatic CRC and guide clinical decisions. KEY MESSAGES: NGS should be considered a mainstay in clinical practice for the management of CRC patients and health authorities should consider reimbursing its use in the appropriate clinical settings.

Treatment of Metastatic Colorectal Carcinoma with Bevacizumab in First-Line and beyond First Progression: The KORALLE Non-Interventional Cohort Study.

INTRODUCTION: The non-interventional study (NIS) KORALLE evaluated the effectiveness and safety of bevacizumab in patients with metastatic colorectal carcinoma (mCRC) treated with bevacizumab in combination with fluoropyrimidine-based chemotherapy in the first-line setting and beyond first progression in routine clinical practice. METHODS: This prospective, multicenter NIS observed adult patients with mCRC who started first-line bevacizumab therapy. The planned maximum duration of observation per patient was 21 months. The primary effectiveness variable was progression-free survival in the first-line therapy setting (PFS-1). Secondary effectiveness variables included PFS after first progression as well as overall survival and overall response rate. All analyses were carried out descriptively for the full analysis population set (FAS). Effectiveness analyses were also assessed for predefined subgroups based on therapy goals. RESULTS: Between December 2012 and July 2016, 2,429 eligible patients were observed at 314 sites in Germany. In the first-line setting in the FAS, the median PFS-1 was 10.3 months (95% CI: 9.9; 10.8), the median overall survival was 16.9 months (95% CI: 16.3; 17.5), and the overall response rate (ORR-1) was 44.2% (95% CI: 41.6%; 46.8%). Effectiveness results of all subgroups were similar to the FAS. Overall, 80.9% of patients experienced any adverse events, 36.6% of patients experienced serious adverse events, and 8.8% of patients experienced fatal adverse events. CONCLUSION: The NIS KORALLE provided broad real-world evidence on effectiveness and safety of bevacizumab. Despite different treatment intentions, the combination of bevacizumab plus fluoropyrimidine-based chemotherapy was similarly effective in all subgroups in routine clinical practice. The safety information reported in this study is consistent with the known safety profile of bevacizumab.

Evaluating the value of Amphiregulin, Phosphatase and Tensin Homologue (PTEN) and P21 Expression for Anti-EGFR Treatment in Metastatic Colorectal Carcinoma.

BACKGROUND: Despite the significant progress in target therapy for the treatment of metastatic colorectal carcinoma (mCRC), the overall survival isn't satisfactory. METHODS: We assessed the expression of Amphiregulin, PTEN, and P21 in sections from 23 paraffin blocks prepared from 23 patients with left-sided mCRC using immunohistochemistry (IHC). The relationship between their level of expressions, clinicopathological parameters, response to anti-EGFR, and prognosis were analyzed. RESULTS: High Amphiregulin, PTEN and low P21 expression levels were associated with low tumor grade (p= 0.038 and 0.025 respectively), better response to anti-EGFR treatment (p <0.001), and favorable outcome {progression-free survival (PFS) and overall survival (OS)} (p <0.05). There was a direct relation between Amphiregulin and PTEN expressions (phi coefficient=+0.840), while there was an inverse relation between P21expression and both Amphiregulin (phi coefficient= -0.840) and PTEN expressions (phi coefficient = -1.000), which was statistically significant (P <0.001). CONCLUSION: High Amphiregulin and PTEN expression levels and low P21 expression levels were associated with better response to anti-EGFR therapy and improved survival outcome. They might be considered predictive markers of response to anti-EGFR therapy in mCRC.

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Evaluation of 18F-FMISO PET and 18F-FDG PET Scans in Assessing the Therapeutic Response of Patients With Metastatic Colorectal Cancer Treated With Anti-Angiogenic Therapy.

INTRODUCTION: Tumor hypoxia and angiogenesis are implicated in tumor growth and metastases, and anti-angiogenic therapies have an important role in treating patients with metastatic colorectal cancer. However, the prevalence of hypoxia has not been fully evaluated in colorectal liver metastases, and hypoxic response to anti-angiogenic therapy has not been clearly established. The aims of the study were to evaluate the changes seen on 18F-FMISO and 18F-FDG PET scans in patients treated with anti-angiogenic therapy, and to correlate these measures of hypoxia and metabolism with clinical outcomes, and blood biomarkers of angiogenesis. METHODS: Patients with metastatic colorectal carcinoma planned for treatment with bevacizumab and chemotherapy received routine staging investigations prior to any treatment, including a FDG PET scan. A FMISO PET scan was performed within 4 weeks of staging tests, with blood specimens collected at that time for serum VEGF and osteopontin measurement. Follow-up FDG and FMISO scans were performed after 1 cycle of treatment. Results were compared to response (RECIST), progression free survival (PFS), and overall survival (OS). RESULTS: A total of 15 patients were recruited into this prospective trial, of which 13 patients were evaluable for assessment of treatment follow-up. Baseline FDG uptake was higher than FMISO uptake, and there was a significant decrease in FDG uptake (SUVmax and TGV) but not FMISO uptake (SUVmax and TNR) after treatment. There was a positive correlation between FDG and FMISO SUVmax on both baseline and post-treatment PET scans. Blood biomarkers of serum VEGF and osteopontin were significantly correlated with the FDG and FMISO PET parameters. CONCLUSIONS: This study shows that hypoxia in metastatic colorectal cancer, assessed by FMISO PET, shows minor changes following initial treatment with anti-angiogenic therapy, but is associated with therapeutic response. FDG PET uptake changes (SUVmax, TLG) are also associated with response to anti-angiogenic therapy. These findings demonstrate the interplay between tumor metabolism and hypoxic regulation following anti-angiogenic treatment of metastatic colorectal cancer.