Current and Emerging Treatment Paradigms in Colorectal Cancer: Integrating Hallmarks of Cancer.

The treatment of unresectable metastatic colorectal cancer has evolved over the last two decades, as knowledge of cancer biology has broadened and new targets have emerged. 'The Hallmarks of Cancer' illustrate the crucial capabilities acquired by cells to become malignant and represent the evolution of knowledge of tumor biology. This review integrates these novel targets and therapies into selected hallmarks: sustaining proliferative signaling, inducing vasculature, avoiding immune destruction, genome instability and mutation, reprogramming cellular metabolism, and resisting cell death. The different strategies and combinations under study are based on treatments with anti-EGFR, anti-VEGF, and anti-HER2 agents, KRAS G12C inhibitors, BRAF and MEK inhibitors, and immune checkpoint inhibitors. However, new approaches are emerging, including vaccines, WEE1 inhibitors, and PARP inhibitors, among others. The further deciphering of cancer biology will unravel new targets, develop novel therapies, and improve patients' outcomes.

Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver.

Kirsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), KRAS mutations are present in more than 50% of cases, and the KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in up to 4% of patients. This mutation is associated with short responses to standard chemotherapy and worse overall survival compared to non-G12C mutations. In recent years, several KRAS G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification of negative feedback through the EGFR receptor has led to the development of KRAS inhibitors plus an anti-EGFR combination, thus boosting antitumor activity. Currently, several KRAS G12C inhibitors are under development, and results from phase I and phase II clinical trials are promising. Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation. Nonetheless, most of these patients will eventually relapse. In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.

Liver transplantation in metastatic colorectal cancer: are we ready for it?

Colorectal cancer (CRC) is a prevalent disease worldwide, with more than 50% of patients developing metastases to the liver. Five-year overall survival remains modest among patients with metastatic CRC (mCRC) treated with conventional therapies however, liver transplantation in a highly selected population can improve clinical outcomes with an impressive 5-year overall survival of 83%. Despite liver transplantation appearing to be a promising therapeutical option for well-selected patients with mCRC with the liver-limited disease, these data come from small monocentric trials which included a heterogeneous population. Currently, several clinical trials are evaluating liver transplantation in this scenario, aiming for a more accurate patient selection by integrating liquid biopsy, tissue profiling, and nuclear medicine to the already known clinical biomarkers that eventually may lead to a survival improvement. In this paper, the clinical outcomes and inclusion criteria from the most relevant clinical trials and clinical series involving liver transplantation in patients with liver-limited disease colorectal cancer are reviewed as well as the trials currently recruiting.

Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor induced myositis.

OBJECTIVES: Inflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis. METHODS: Bulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM). RESULTS: Unsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway. CONCLUSIONS: We identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.

Paeniclostridium sordellii-associated peripartum metritis in goats.

Paeniclostridium sordellii is involved in enteric and histotoxic infections in several animal species. In humans, P. sordellii has been linked to gynecological disease, an association not previously investigated in animals. To unveil a potential association of P. sordellii with veterinary reproductive disease, a retrospective search of the database of the California Animal Health and Food Safety Laboratory System (1990-2020) was conducted and identified 9 cases of goats with P. sordellii-associated metritis or endometritis that were confirmed by immunofluorescence antibody test and/or bacterial isolation, and often co-colonized by Escherichia coli. Six of 9 does were also copper deficient. Polymerase chain reaction (PCR) on formalin-fixed, paraffin-embedded uterine tissue identified the sordellilysin gene in all 9 cases, and the lethal toxin gene in 4. Our findings suggest goats could be predisposed to P. sordellii-associated endometritis/metritis and toxemia when co-infected with E. coli. The role of mineral deficiencies influencing vulnerability to puerperal bacterial infections in goats is possible but remains undetermined. To our knowledge, this is the first report documenting the association of P. sordellii with veterinary gynecological disease.

A Comprehensive Biomarker Analysis of Microsatellite Unstable/Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy.

The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial.

The Evolving Role of Consensus Molecular Subtypes: a Step Beyond Inpatient Selection for Treatment of Colorectal Cancer.

OPINION STATEMENT: The heterogenous nature of colorectal cancer (CRC) renders it a major clinical challenge. Increasing genomic understanding of CRC has improved our knowledge of this heterogeneity and the main cancer drivers, with significant improvements in clinical outcomes. Comprehensive molecular characterization has allowed clinicians a more precise range of treatment options based on biomarker selection. Furthermore, this deep molecular understanding likely extends therapeutic options to a larger number of patients. The biological associations of consensus molecular subtypes (CMS) with clinical outcomes in localized CRC have been validated in retrospective clinical trials. The prognostic role of CMS has also been confirmed in the metastatic setting, with CMS2 having the best prognosis, whereas CMS1 tumors are associated with a higher risk of progression and death after chemotherapy. Similarly, according to mesenchymal features and immunosuppressive molecules, CMS1 responds to immunotherapy, whereas CMS4 has a poorer prognosis, suggesting that a CMS1 signature could identify patients who may benefit from immune checkpoint inhibitors regardless of microsatellite instability (MSI) status. The main goal of these comprehensive analyses is to switch from "one marker-one drug" to "multi-marker drug combinations" allowing oncologists to give "the right drug to the right patient." Despite the revealing data from transcriptomic analyses, the high rate of intra-tumoral heterogeneity across the different CMS subgroups limits its incorporation as a predictive biomarker. In clinical practice, when feasible, comprehensive genomic tests should be performed to identify potentially targetable alterations, particularly in RAS/BRAF wild-type, MSI, and right-sided tumors. Furthermore, CMS has not only been associated with clinical outcomes and specific tumor and patient phenotypes but also with specific microbiome patterns. Future steps will include the integration of clinical features, genomics, transcriptomics, and microbiota to select the most accurate biomarkers to identify optimal treatments, improving individual clinical outcomes. In summary, CMS is context specific, identifies a level of heterogeneity beyond standard genomic biomarkers, and offers a means of maximizing personalized therapy.

Infected bone defects in the lower limb. Management by means of a two-stage distraction osteogenesis protocol.

INTRODUCTION: Although bone transport is generally accepted as the gold standard for the treatment of segmental septic bone defects, some aspects of its practical application are still open to debate. We present our results in this field and compare them with the series published so far. MATERIAL AND METHODS: We reviewed all our patients (2010-2018) that underwent a bone transport procedure in the lower limb due to a septic bone defect. We calculated the bone healing index (BHI), the external fixation index (EFI), the rate of complications and the clinical results. We statistically compared our results with 63 publications with a similar scope. RESULTS: Thirty-five patients (30 M/5F) with a mean age of 40 years and a mean follow-up of 45 months were included. Bone segment was 24 T/11F and mean defect was 8.4 cm (7.34 T/ 10.73F). Mean global BHI was 45.62 days/cm (48.16 T/40.09F). Mean EFI was 2.37 months/cm. Results were excellent in 9 patients, good in 23 and bad in 3. Bone graft was used in 60% of the cases. DISCUSSION: The size of our series is similar to previously published ones, although the mean age of our patients is higher and they present a larger bone defect. BHI of our series is similar to that of other series, although EFI is significantly higher. The number of complications is also in line with the existing literature. CONCLUSION: The use of a two-stage technique for managing segmental bone defects of septic origin in the lower extremity is a valid alternative. Our series shows results comparable to the current literature.

A Scoring System to Determine Risk of Delayed Bleeding After Endoscopic Mucosal Resection of Large Colorectal Lesions.

BACKGROUND & AIMS: After endoscopic mucosal resection (EMR) of colorectal lesions, delayed bleeding is the most common serious complication, but there are no guidelines for its prevention. We aimed to identify risk factors associated with delayed bleeding that required medical attention after discharge until day 15 and develop a scoring system to identify patients at risk. METHODS: We performed a prospective study of 1214 consecutive patients with nonpedunculated colorectal lesions 20 mm or larger treated by EMR (n = 1255) at 23 hospitals in Spain, from February 2013 through February 2015. Patients were examined 15 days after the procedure, and medical data were collected. We used the data to create a delayed bleeding scoring system, and assigned a weight to each risk factor based on the ß parameter from multivariate logistic regression analysis. Patients were classified as being at low, average, or high risk for delayed bleeding. RESULTS: Delayed bleeding occurred in 46 cases (3.7%, 95% confidence interval, 2.7%-4.9%). In multivariate analysis, factors associated with delayed bleeding included age ≥75 years (odds ratio [OR], 2.36; P < .01), American Society of Anesthesiologist classification scores of III or IV (OR, 1.90; P ≤ .05), aspirin use during EMR (OR, 3.16; P < .05), right-sided lesions (OR, 4.86; P < .01), lesion size ≥40 mm (OR, 1.91; P ≤ .05), and a mucosal gap not closed by hemoclips (OR, 3.63; P ≤ .01). We developed a risk scoring system based on these 6 variables that assigned patients to the low-risk (score, 0-3), average-risk (score, 4-7), or high-risk (score, 8-10) categories with a receiver operating characteristic curve of 0.77 (95% confidence interval, 0.70-0.83). In these groups, the probabilities of delayed bleeding were 0.6%, 5.5%, and 40%, respectively. CONCLUSIONS: The risk of delayed bleeding after EMR of large colorectal lesions is 3.7%. We developed a risk scoring system based on 6 factors that determined the risk for delayed bleeding (receiver operating characteristic curve, 0.77). The factors most strongly associated with delayed bleeding were right-sided lesions, aspirin use, and mucosal defects not closed by hemoclips. Patients considered to be high risk (score, 8-10) had a 40% probability of delayed bleeding.

Determinants of Metastatic Colorectal Cancer With Permanent Liver- Limited Disease.

Colorectal cancer (CRC) is a complex and genetically heterogeneous disease presenting a specific metastatic pattern, with the liver being the most common site of metastasis. Around 20%-25% of patients with CRC will develop exclusively hepatic metastatic disease throughout their disease history. With its specific characteristics and therapeutic options, liver-limited disease (LLD) should be considered as a specific entity. The identification of these patients is particularly relevant in view of the growing interest in liver transplantation in selected patients with advanced CRC. Identifying why some patients will develop only LLD remains a challenge, mainly because of a lack of a systemic understanding of this complex and interlinked phenomenon given that cancer has traditionally been investigated according to distinct physiological compartments. Recently, multidisciplinary efforts and new diagnostic tools have made it possible to study some of these complex issues in greater depth and may help identify targets and specific treatment strategies to benefit these patients. In this review we analyze the underlying biology and available tools to help clinicians better understand this increasingly common and specific disease.

Cetuximab as a Key Partner in Personalized Targeted Therapy for Metastatic Colorectal Cancer.

Cetuximab, a chimeric IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has revolutionized personalized treatment of metastatic colorectal cancer (mCRC) patients. This review highlights the mechanism of action, characteristics, and optimal indications for cetuximab in mCRC. Cetuximab has emerged as a pivotal partner for novel therapies in specific molecular subgroups, including BRAF V600E, KRAS G12C, and HER2-altered mCRC. Combining cetuximab with immunotherapy and other targeted agents further expands the therapeutic landscape, offering renewed hope for mCRC patients who face the development of resistance to conventional therapies. Ongoing clinical trials have continued to uncover innovative cetuximab-based treatment strategies, promising a brighter future for mCRC patients. This review provides a comprehensive overview of cetuximab's role and its evolving importance in personalized targeted therapy of mCRC patients, offering valuable insights into the evolving landscape of colorectal cancer treatment.

Epidermal growth factor receptor antagonists in colorectal cancer: emerging strategies for precision therapy.

INTRODUCTION: The global prevalence of colorectal cancer highlights the need to enhance treatment strategies for improved patient outcomes. The pivotal role of epidermal growth factor receptor (EGFR) signaling in regulating cellular processes for this disease pinpoints its value as a therapeutic target, despite the emergence of resistance mechanisms over time. AREAS COVERED: This review discusses the clinical evidence supporting the use of EGFR inhibitors in molecularly-selected patients based on molecular characteristics (notably BRAF V600E and KRAS G12C) including combination approaches targeting different points in in the signaling pathway, as well as strategies such as EGFR inhibitor rechallenge. The role of HER2 inhibitors and emerging approaches such as bispecific antibodies are also reviewed. EXPERT OPINION: Recently, inhibitors targeting the KRAS G12C variant have emerged, albeit with modest monotherapy activity compared to other tumor types, emphasizing the influence of histologic origins on the EGFR signaling pathway. Integration of EGFR inhibitors into precision medicine has facilitated tailored therapies addressing resistance mechanisms. Patient selection for EGFR inhibitor rechallenge guided by ctDNA findings is crucial, with ongoing investigations exploring novel combinations to enhance EGFR blockade, highlighting the transformative potential of precision medicine in shaping the future of mCRC treatment toward personalized and targeted approaches.

Pseudoaneurysm as an unusual complication in bone lengthening.

One of the risks of distraction osteogenesis-based techniques is the development of vascular complications, such as pseudoaneurysms associated with the osteotomies performed or the fixation elements of the external fixator used in the procedure. Pseudoaneurysm are formed when the tunica adventitia of the artery is injured, resulting in a gradual and persistent blood extravasation into the surrounding tissues that is encapsulated and connected to the arterial lumen. This report describes a rare case of a late-presentation pseudoaneurysm in the anterior tibial artery resulting from a tibial lengthening procedure aimed at addressing a leg length discrepancy in a 57-year-old female with severe peripheral neuropathy resulting from long-standing poorly controlled diabetes mellitus. We describe the diagnostic process, the treatment options and confirm how the shape of the bony callus can be a reliable indicator of this pathology, as has already been described in the literature.

Treatment of Schatzker Type VI Tibia Fractures Using Circular External Fixation: State of the Art, Surgical Technique and Results.

BACKGROUND: Schatzker type VI tibia fractures are usually associated with infection and surgical wound-related problems. Circular external fixation (CEF) has been shown to minimize such complications. METHODS: We pose a retrospective study of patients with Schatzker type VI fractures treated with CEF. RESULTS: Twenty-two (22) patients were included (11M/11F) with a mean age of 60.1 ± 14.9 years. According to the AO/OTA classification, two fractures (9.1%) were A2, three (13.6%) were A3, and seventeen (77.3%) were C3. Three (13.6%) of them were open. The tissue damage observed in the nineteen (86.4%) closed fractures was classified according to Tscherne (four grade I, twelve grade II, and three grade III). The mean ex-fix time was 24.1 ± 5.1 weeks. None of the patients experienced deep infections, nonunion, or malunion. The mean ROM was 111.4 ± 17.8 degrees. Although stability was achieved in all cases, 50% of them suffered osteoarthritic degeneration. Four knees required TKR at a mean of 8.77 ± 5.58 years from trauma. The mean HHS knee score was 84.2 ± 10.3 points (excellent in fifteen (68.2%) cases, good in four (18.2%), and acceptable in three (13.6%)). The mean Rasmussen radiological score was 13.3 ± 3.5 (excellent in three (13.6%) cases, good in fifteen (68.2%), and acceptable in four (18.2%)). The mean SF-12 score was 35.1 ± 10.4 points on the physical scale and 53.0 ± 10.6 points on the mental scale. CONCLUSIONS: CEF has shown itself to be a valid treatment for patients with Schatzker type VI fractures, particularly for those where the fracture is comminuted, severely displaced, open, or associated with severe soft tissue damage.

Negative Hyperselection of Patients with HER2+ and RAS Wild-Type Metastatic Colorectal Cancer Receiving Dual HER2 Blockade: the PRESSING-HER2 Study.

PURPOSE: To demonstrate the negative prognostic impact of a panel of genomic alterations (PRESSING-HER2 panel) and lack of HER2 amplification by next-generation sequencing (NGS) in patients with HER2+, RAS wild-type metastatic colorectal cancer receiving dual HER2 blockade. EXPERIMENTAL DESIGN: The PRESSING-HER2 panel of HER2 mutations/rearrangements and RTK/MAPK mutations/amplifications was assessed by NGS. HER2 amplification was confirmed by NGS if copy-number variation (CNV) was ≥ 6. With a case-control design, hypothesizing 30% and 5% PRESSING-HER2 positivity in resistant [progression-free survival (PFS) <4 months and no RECIST response] versus sensitive cohorts, respectively, 35 patients were needed per group. RESULTS: PRESSING-HER2 alterations included HER2 mutations/rearrangements, EGFR amplification, and BRAF mutations and had a prevalence of 27% (9/33) and 3% (1/35) in resistant versus sensitive patients (P = 0.005) and 63% predictive accuracy. Overall, HER2 nonamplified status by NGS had 10% prevalence. Median PFS and overall survival (OS) were worse in PRESSING-HER2+ versus negative (2.2 vs. 5.3 months, P < 0.001; 5.4 vs. 14.9 months, P = 0.001) and in HER2 nonamplified versus amplified (1.6 vs. 5.2 months, P < 0.001; 7.4 vs. 12.4 months, P = 0.157). These results were confirmed in multivariable analyses [PRESSING-HER2 positivity: PFS HR = 3.06, 95% confidence interval (CI), 1.40-6.69, P = 0.005; OS HR = 2.93, 95% CI, 1.32-6.48, P = 0.007]. Combining PRESSING-HER2 and HER2 CNV increased the predictive accuracy to 75%. CONCLUSIONS: PRESSING-HER2 panel and HER2 nonamplified status by NGS warrant validation as potential predictive markers in this setting. See related commentary by Raghav et al., p. 260.

Precision oncology and systemic targeted therapy in Pseudomyxoma Peritonei.

PURPOSE: Pseudomyxoma peritonei (PMP) is a rare and poorly understood malignant condition characterized by the accumulation of intra-abdominal mucin produced from peritoneal metastases. Currently, cytoreductive surgery remains the mainstay of treatment but disease recurrence and death after relapse frequently occur in PMP patients. New therapeutic strategies are therefore urgently needed for these patients. EXPERIMENTAL DESIGN: A total of 120 PMP samples from 50 patients were processed to generate a collection of 50 patient-derived organoids (PDO) and xenograft (PDX) models. Whole exome sequencing (WES), immunohistochemistry analyses and in vitro and in vivo drug efficacy studies were performed. RESULTS: In this study, we have generated a collection of PMP preclinical models and identified druggable targets, including BRAFV600E, KRASG12C and KRASG12D,that could also be detected in intra-abdominal mucin biopsies of PMP patients using droplet digital PCR. Preclinical models preserved the histopathological markers from the original patient sample. The BRAFV600E inhibitor encorafenib reduced cell viability of BRAFV600E PMP-PDO models. Proof-of-concept in vivo experiments showed that a systemic treatment with encorafenib significantly reduced tumor growth and prolonged survival in subcutaneous and orthotopic BRAFV600E-PMP-PDX mouse models. CONCLUSIONS: Our study demonstrates for the first time that systemic targeted therapies can effectively control PMP tumors. BRAF signaling pathway inhibition represents a new therapeutic opportunity for BRAFV600E PMP patients who have a poor prognosis. Importantly, our present data and collection of preclinical models pave the way for evaluating the efficacy of other systemic targeted therapies toward extending the promise of precision oncology to PMP patients.

Treatment of BRAF-V600E mutant metastatic colorectal cancer: new insights and biomarkers.

INTRODUCTION: The presence of a BRAF-V600E mutation in metastatic colorectal cancer (mCRC) is observed in approximately 12% of cases and is associated with poor prognosis and aggressive disease. Unlike melanoma, the development of successful BRAF blockade in colorectal cancer has been complex. The phase III BEACON trial made significant progress in the development of BRAF inhibitors by establishing encorafenib-cetuximab as the new standard of care for patients with mCRC who have progressed to one or two previous lines of treatment. Nonetheless, not all patients respond to encorafenib-based combinations, and some responses are short-lived. Identifying new strategies to boost antitumor activity and improve survival is paramount. AREAS COVERED: The development of targeted therapy for BRAF-V600E mCRC starting with BRAF inhibitors as monotherapy through novel combinations with anti-VEGF or anti-PD1 agents to enhance antitumor activity is reviewed, with a particular focus on the development of predictive and prognostic biomarkers. EXPERT OPINION: There is a crucial need to better understand tumor biology and develop accurate and reliable biomarkers to enhance the antitumor activity of encorafenib-based combinations. The RNF43 mutation is an accurate and reliable predictive biomarker of response, and combinations that target crosstalk between the MAPK pathway, the immune system, and WNT pathways seem promising.

Immunotherapy for Colorectal Cancer with High Microsatellite Instability: The Ongoing Search for Biomarkers.

Microsatellite instability (MSI) is a biological condition associated with inflamed tumors, high tumor mutational burden (TMB), and responses to immune checkpoint inhibitors. In colorectal cancer (CRC), MSI tumors are found in 5% of patients in the metastatic setting and 15% in early-stage disease. Following the impressive clinical activity of immune checkpoint inhibitors in the metastatic setting, associated with deep and long-lasting responses, the development of immune checkpoint inhibitors has expanded to early-stage disease. Several phase II trials have demonstrated a high rate of pathological complete responses, with some patients even spared from surgery. However, in both settings, not all patients respond and some responses are short, emphasizing the importance of the ongoing search for accurate biomarkers. While various biomarkers of response have been evaluated in the context of MSI CRC, including B2M and JAK1/2 mutations, TMB, WNT pathway mutations, and Lynch syndrome, with mixed results, liver metastases have been associated with a lack of activity in such strategies. To improve patient selection and treatment outcomes, further research is required to identify additional biomarkers and refine existing ones. This will allow for the development of personalized treatment approaches and the integration of novel therapeutic strategies for MSI CRC patients with liver metastases.

Advances in immune checkpoint inhibitor combination strategies for microsatellite stable colorectal cancer.

Immune checkpoint inhibitors have reshaped the prognostic of several tumor types, including metastatic colorectal tumors with microsatellite instability (MSI). However, 90-95% of metastatic colorectal tumors are microsatellite stable (MSS) in which immunotherapy has failed to demonstrate meaningful clinical results. MSS colorectal tumors are considered immune-cold tumors. Several factors have been proposed to account for this lack of response to immune checkpoint blockade including low levels of tumor infiltrating lymphocytes, low tumor mutational burden, a high rate of WNT/ß-catenin pathway mutations, and liver metastases which have been associated with immunosuppression. However, studies with novel combinations based on immune checkpoint inhibitors are showing promising activity in MSS colorectal cancer. Here, we review the underlying biological facts that preclude immunotherapy activity, and detail the different immune checkpoint inhibitor combinations evaluated, along with novel immune-based therapies, to overcome innate mechanisms of resistance in MSS colorectal cancer.