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Evidence indicates that combinations of anti‐EGFR antibodies and KRAS p.G12C (c.34G>T) inhibitors can be an effective treatment strategy for advanced colorectal cancer. We hypothesized that KRAS c.34G>T (p.G12C)‐mutated colorectal carcinoma might be a distinct tumor subtype. We utilized a prospective cohort incident tumor biobank (including 1347 colorectal carcinomas) and detected KRAS c.34G>T (p.G12C) mutation in 43 cases (3.2%) and other KRAS mutations (in codon 12, 13, 61, or 146) in 467 cases (35%). The CpG island methylator phenotype (CIMP)‐low prevalence was similarly higher in KRAS c.34G>T mutants (52%) and other KRAS mutants (49%) than in KRAS‐wild‐type tumors (31%). KRAS c.34G>T mutants showed higher CIMP‐high prevalence (14%) and lower CIMP‐negative prevalence (33%) compared with other KRAS mutants (6% and 45%, respectively; p = 0.0036). Similar to other KRAS mutants, KRAS c.34G>T‐mutated tumors were associated with cecal location, non‐microsatellite instability (MSI)‐high status, BRAF wild type, and PIK3CA mutation when compared with KRAS‐wild‐type tumors. Compared with BRAF‐mutated tumors, KRAS c.34G>T mutants showed more frequent LINE‐1 hypomethylation, a biomarker for early‐onset colorectal carcinoma. KRAS c.34G>T mutants were not associated with other features, including the tumor tissue abundance of Fusobacterium nucleatum (F. animalis), pks+Escherichia coli, Bifidobacterium, or (enterotoxigenic) Bacteroides fragilis. Among 1122 BRAF‐wild‐type colorectal carcinomas, compared with KRAS‐wild‐type tumors, multivariable‐adjusted colorectal cancer‐specific mortality hazard ratios (95% confidence interval) were 1.82 (1.05–3.17) in KRAS c.34G>T (p.G12C)‐mutated tumors (p = 0.035) and 1.57 (1.22–2.02) in other KRAS‐mutated tumors (p = 0.0004). Our study provides novel evidence for clinical and tumor characteristics of KRAS c.34G>T (p.G12C)‐mutated colorectal carcinoma. [ABSTRACT FROM AUTHOR]

Background: Survival differences between left‐sided colon cancer (LSCC) and right‐sided colon cancer (RSCC) has been previously reported with mixed results, with various study periods not accounting for other causes of mortality. Purpose: We sought to assess the trends in colon cancer cause‐ specific survival (CSS) and overall survival (OS) based on sidedness. Method: Fine‐Gray competing risk and Cox models were used to analyze Surveillance, Epidemiology, and End Results (SEER) population‐based cohort from 1975 to 2019. Various interval periods were identified based on the timeline of clinical adoption of modern chemotherapy (1975–1989, interval period A; 1990–2004, B; and 2005–2019, C). Results: Of the 227,637 patients, 50.1% were female and 46.2% were RSCC. RSCC was more common for African Americans (51.5%), older patients (age ≥65; 51.4%), females (50.4%), while LSCC was more common among Whites (53.1%; p < 0.001), younger patients (age 18–49, 64.6%; 50–64, 62.3%; p < 0.001), males (58.1%; p < 0.001). The Median CSS for LSCC and RCC were 19.3 and 16.7 years respectively for interval period A (1975–1989). Median CSS for interval periods B and C were not reached (more than half of the cohort was still living at the end of the follow‐up period). Adjusted CSS was superior for LSCC versus RSCC for the most recent interval period C (HR 0.89; 0.86–0.92; p < 0.001). LSCC consistently showed superior OS for all study periods. Stage stratification showed worse CSS for localized and regional LSCC in the earlier study periods, but the risk attenuated over time. However, left sided distant disease had superior CSS per stage for all interval periods. OS was better for LSCC irrespective of stage, with gradual improvement over time. Conclusion: LSCC was associated with superior survival compared to right sided tumors. With the adoption of modern chemotherapy regimens, prognosis between LSCC and RSCC became more divergent in favor of LSCC. Colon cancer clinical trials should strongly consider tumor sidedness as an enrollment factor. [ABSTRACT FROM AUTHOR]

Background: Emergence of novel immuno‐therapeutics has shown promising improvement in the clinical outcome of colorectal cancer (CRC). Objective: To identify robust immune checkpoints based on expression and immune infiltration profiles of clinical CRC samples. Methods: One dataset from The Cancer Genome Atlas database and two from Gene Expression Omnibus were independently employed for the analysis. Genes associated with overall survival were identified, and distribution of each immune checkpoint with respect to different clinical features was determined to explore key immune checkpoints. Multiple staining methods were used to verify the correlation between key immune checkpoint ICOS and clinical pathological features. Differentially expressed mRNA and long non‐coding RNA (lncRNA) were then detected for gene set enrichment analysis and gene set variation analysis to investigate the differentially enriched biological processes between low‐ and high‐expression groups. Significant immune‐related mRNAs and lncRNA were subjected to competing endogenous RNA (ceRNA) network analysis. Correlation of inducible T‐cell costimulator (ICOS) and top 10 genes in ceRNA network were further considered for validation. Results: ICOS was identified from 14 immune checkpoints as the most highly correlated gene with survival and clinical features in CRC. The expression of ICOS protein in the poorly differentiated group was lower than that in the moderately differentiated group, and the expression in different pathological stages was significant. In addition, the expressions of ICOS were negatively correlated with Ki67. A conspicuous number of immune‐related pathways were enriched in differentially expressed genes in the ICOS high‐ and low‐expression groups. Integration with immune infiltration data revealed a multitude of differentially expressed immune‐related genes enriched for ceRNA network. Furthermore, expression of top 10 genes investigated from ceRNA network showed high correlation with ICOS. Conclusion: ICOS might serve as a robust immune checkpoint for prognosis with several genes being potential targets of ICOS‐directed immunotherapy in CRC. [ABSTRACT FROM AUTHOR]

Aim: Immune checkpoint inhibitors (ICIs) are less effective in mismatch repair (MMR)‐proficient (pMMR) colorectal cancers (CRCs) than in MMR‐deficient CRCs. Here, we investigated changes in the tumor microenvironment after neoadjuvant chemotherapy (NAC) without radiotherapy in locally advanced rectal cancer (LARC) and the potential of ICIs as therapeutic agents for pMMR CRCs. Methods: This was an ad hoc analysis of a KSCC1301 randomized phase II trial in which patients with untreated resectable LARC were randomly assigned to receive S‐1 and oxaliplatin or folinic acid, 5‐fluorouracil, and oxaliplatin as NAC. Forty‐nine patients were studied in this ad hoc analysis. As a reference cohort, we assessed 25 rectal cancer patients who underwent surgery without NAC outside the randomized trial. Immune checkpoint molecules (ICMs; PD‐1, PD‐L1, CTLA‐4, LAG3), tumor‐infiltrating lymphocytes (TILs; CD8, FOXP3), and other related proteins were evaluated by immunohistochemistry. Next‐generation sequencing (NGS) using Oncomine™ Comprehensive Assay version 3 was conducted in 23 patients. Results: The expression levels of PD‐1, CTLA‐4, and LAG3 in the NAC group were significantly higher than in reference patients (p < 0.001). Additionally, the infiltration of CD8+ and FOXP3+ T cells, and the CD8/FOXP3 ratio were significantly higher in the NAC group than in reference patients (p < 0.0001). NGS analysis revealed no specific gene alteration related to TILs or ICMs. Conclusion: We demonstrated changes in the tumor immune microenvironment after NAC in pMMR rectal cancer. NAC was associated with increased expression of ICMs and TILs. Rectal cancer could be susceptible to combined immunotherapy with chemotherapy. [ABSTRACT FROM AUTHOR]

The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the prognostic impact of RAS mutations on the Japanese Society of Hepatobiliary and Pancreatic Surgeons (JSHBPS) nomogram score in patients with colorectal cancer liver metastasis (CRLM) following hepatectomy. Methods: We included 218 consecutive patients undergoing hepatectomy for CRLM between 2004 and 2020. The JSHBPS nomogram score was calculated using six preoperative clinical factors. The score ranged from 0 to 25, and higher scores indicated greater tumor burden. Associations of RAS mutations with disease‐free survival (DFS) and overall survival (OS) by the JSHBPS nomogram score were examined. Multivariable Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and confidence intervals (CIs). Results: RAS mutations were detected in 72 (33%) of the 218 patients. Multivariate analyses revealed that RAS mutations were independently associated with poor DFS (HR, 1.93; 95% CI: 1.20–3.10; p =.007) and OS (HR, 2.65; 95% CI: 1.59–4.71; p =.001) compared with wild‐type RAS with JSHBPS nomogram scores ≤ 10. However, in patients with scores ≥ 11, the association of RAS mutations with DFS or OS was not statistically significant (p >.08). Conclusion: RAS mutation status in combination with the JSHBPS nomogram may be useful for preoperatively identifying CRLM with high risk of recurrence and mortality after hepatectomy. [ABSTRACT FROM AUTHOR]

Aim: Total neoadjuvant treatment (TNT) is becoming standard in patients with locally advanced rectal carcinoma (LARC). Preoperative chemoradiotherapy (CRT) has proven side effects on bowel and genitourinary function. An early tumoral response to induction chemotherapy demonstrates its high prognostic value. Tailored management could be used as an alternative to systematic CRT. The GRECCAR 14 trial will attempt to personalize treatment strategy according to the patient's early tumour response to intensive chemotherapy with the aim of achieving the best toxicity–efficiency ratio. Method: GRECCAR 14 is a multicentric, randomized, two‐arm, phase II–III noninferiority trial. Patients with mid or low LARC with a predictive circumferential resection margin ≤2 mm or T3c‐d stage with extramural venous invasion will be included. Evaluation of the tumoral response will be performed after six courses of high‐dose FOLFIRINOX chemotherapy. Good responders (GRs) will be defined by a 60% decrease in tumoral volume on magnetic resonance imaging. Patients will be randomized to CRT before surgery. The primary endpoints will be R0 resection for phase II and the 3‐year disease‐free survival (DFS) for phase III. Results: Tailored management of LARC is becoming an exciting challenge for the modality of neoadjuvant treatment and for the type of surgery or its omission. Neoadjuvant FOLFIRINOX has established efficacy, with a significant increase in the 3‐year DFS. Better control of systemic disease must be accompanied by the same locoregional control, with the lowest morbidity. Our previous GRECCAR 4 trial demonstrated the high value of the early tumoral response after induction chemotherapy and the long‐term safety of tailored management for GRs. Conclusion: If GRECCAR 14 demonstrates the ability to tailor TNT for LARC, this could lead to changes in clinical practice. [ABSTRACT FROM AUTHOR]

The bone morphogenetic protein (BMP) pathway promotes differentiation and induces apoptosis in normal colorectal epithelial cells. However, its role in colorectal cancer (CRC) is controversial, where it can act as context‐dependent tumor promoter or tumor suppressor. Here we have found that CRC cells reside in a BMP‐rich environment based on curation of two publicly available RNA‐sequencing databases. Suppression of BMP using a specific BMP inhibitor, LDN193189, suppresses the growth of select CRC organoids. Colorectal cancer organoids treated with LDN193189 showed a decrease in epidermal growth factor receptor, which was mediated by protein degradation induced by leucine‐rich repeats and immunoglobulin‐like domains protein 1 (LRIG1) expression. Among 18 molecularly characterized CRC organoids, suppression of growth by BMP inhibition correlated with induction of LRIG1 gene expression. Notably, knockdown of LRIG1 in organoids diminished the growth‐suppressive effect of LDN193189. Furthermore, in CRC organoids, which are susceptible to growth suppression by LDN193189, simultaneous treatment with LDN193189 and trametinib, an FDA‐approved MEK inhibitor, resulted in cooperative growth inhibition both in vitro and in vivo. Taken together, the simultaneous inhibition of BMP and MEK could be a novel treatment option in CRC cases, and evaluating in vitro growth suppression and LRIG1 induction by BMP inhibition using patient‐derived organoids could offer functional biomarkers for predicting potential responders to this regimen. [ABSTRACT FROM AUTHOR]

Immunotherapy, especially with immune checkpoint inhibitors (ICIs), has shown advantages in cancer treatment and is a new hope for patients who have failed multiline therapy. However, in colorectal cancer (CRC), the benefit is limited to a small subset of patients with microsatellite instability‐high (MSI‐H) or mismatch repair‐deficient (dMMR) metastatic CRC (mCRC). In addition, 45% to 60% of dMMR/MSI‐H mCRC patients showed primary or acquired resistance to ICIs. This means that these patients may have potential unknown pathways mediating immune escape. Almost all mismatch repair‐proficient (pMMR) or microsatellite‐stable (MSS) mCRC patients do not benefit from ICIs. In this review, we discuss the mechanisms of action of ICIs and their current status in CRC. We then discuss the mechanisms of primary and acquired resistance to ICIs in CRC. Finally, we discuss promising therapeutic strategies to overcome resistance to ICIs in the clinic. [ABSTRACT FROM AUTHOR]

Background: Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient selection. TKI‐induced hypertension is reportedly a surrogate marker for treatment benefit for some tumor types. Our objective was to determine whether hypertension was associated with benefit in the context of CRC treatment, and also to gain insight on the pathogenesis of TKI‐induced hypertension by monitoring associated changes in the circulating metabolome. Patients and Methods: Clinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab ± the TKI brivanib (N = 750). Outcomes were evaluated as a function of treatment‐induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12 weeks after treatment initiation. Samples were submitted to gas chromatography–mass spectrometry to identify treatment‐related metabolomic changes associated with TKI‐induced hypertension, compared to pre‐treatment baseline. A model based on changes in metabolite concentrations was generated using orthogonal partial least squares discriminant analysis (OPLS‐DA). Results: In the brivanib treated group, 95 patients had treatment‐related hypertension within 12 weeks of initiating treatment. TKI‐induced hypertension was not associated with a significantly higher response rate, nor was it associated with improved progression‐free or overall survival. In metabolomic studies, 386 metabolites were identified. There were 29 metabolites that changed with treatment and distinguished patients with and without TKI‐induced hypertension. The OPLS‐DA model for brivanib‐induced hypertension was significant and robust (R2Y score = 0.89, Q2Y score = 0.70, CV‐ANOVA = 2.01 e‐7). Notable metabolomic features previously reported in pre‐eclampsia and associated with vasoconstriction were found. Conclusion: TKI‐induced hypertension was not associated with clinical benefit in metastatic CRC. We have identified changes in the metabolome that are associated with the development of worsening brivanib‐induced hypertension that may be useful in future efforts of characterizing this toxicity. [ABSTRACT FROM AUTHOR]

Aim: To clarify the incidence and risk factors of infusion‐related reactions (IRRs) caused by trastuzumab in breast cancer patients and verify the preventive effects of dexamethasone. Methods: All breast cancer patients newly treated with trastuzumab at the Osaka Medical and Pharmaceutical University Hospital from 1 January 2017 to 31 December 2020 were included. The electronic medical records were retrospectively reviewed. The outcome measure was the occurrence of IRRs of grade 1 or higher during trastuzumab infusion. Only dexamethasone and anticancer drugs administered concomitantly before trastuzumab were used as explanatory variables. Results: The 176 patients included in the study received 2320 infusions. Fifty‐eight patients (33.0%) experienced IRRs, and IRRs occurred in 80 (3.4%) of the total 2320 infusions. Owing to the hierarchical structure of the data, the independence of the observed values was evaluated using the intraclass correlation coefficient. Multivariate multilevel logistic regression analysis showed that premedication with dexamethasone lowered the risk of trastuzumab‐induced IRRs (mg, per 1 unit, odds ratio [OR] = 0.61, 95% confidence interval [95% CI] 0.43‐0.85, P =.003). In addition, preoperative status (OR = 38.9, 95% CI 5.4‐278.7, P <.001) and high‐dose trastuzumab (mg/kg, per 1 unit, OR = 60.6, 95% CI 20.1‐182.9, P <.001) were independent risk factors for IRRs. Conclusion: The results of this study suggest that premedication with dexamethasone exhibits preventive effects on trastuzumab‐induced IRRs in breast cancer patients. Future studies are needed to determine the optimal dose of dexamethasone to prevent IRRs and the impact of dexamethasone on the efficacy of trastuzumab in breast cancer. [ABSTRACT FROM AUTHOR]

Many research studies have investigated the relationship between baseline factors or exposures, such as patient demographic and disease characteristics, and study outcomes such as toxicities or quality of life, but results from most of these studies may be problematic because of potential confounding effects (eg, the imbalance in baseline factors or exposures). It is important to study whether the baseline factors or exposures have causal effects on the clinical outcomes, so that clinicians can have better understanding of the diseases and develop personalized medicine. Mendelian randomization (MR) provides an efficient way to estimate the causal effects using genetic instrumental variables to handle confounders, but most of the existing studies focus on a single outcome at a time and ignores the correlation structure of multiple outcomes. Given that clinical outcomes like toxicities and quality of life are usually a mixture of different types of variables, and multiple datasets may be available for such outcomes, it may be much more beneficial to analyze them jointly instead of separately. Some well‐established methods are available for building multivariate models on mixed outcomes, but they do not incorporate MR mechanism to deal with the confounders. To overcome these challenges, we propose a Bayesian‐based two‐stage multivariate MR method for mixed outcomes on multiple datasets, called BMRMO. Using simulation studies and clinical applications on the CO.17 and CO.20 studies, we demonstrate better performance of our approach compared to the commonly used univariate two‐stage method. [ABSTRACT FROM AUTHOR]

Rat sarcoma (RAS), as a frequently mutated oncogene, has been studied as an attractive target for treating RAS-driven cancers for over four decades. However, it is until the recent success of kirsten-RAS (KRAS)G12C inhibitor that RAS gets rid of the title "undruggable". It is worth noting that the therapeutic effect of KRASG12C inhibitors on different RAS allelicmutations or even different cancers with KRASG12C varies significantly. Thus, deep understanding of the characteristics of each allelic RAS mutation will be a prerequisite for developing new RAS inhibitors. In this review, the structural and biochemical features of different RASmutations are summarized and compared. Besides, the pathological characteristics and treatment responses of different cancers carrying RASmutations are listed based on clinical reports. In addition, the development of RAS inhibitors, either direct or indirect, that target the downstream components in RAS pathway is summarized as well. Hopefully, this review will broaden our knowledge on RAS-targeting strategies and trigger more intensive studies on exploiting new RAS allele-specific inhibitors. [ABSTRACT FROM AUTHOR]

We studied the prognostic value of primary tumor sidedness in metastatic colorectal cancer over time and across treatment lines. Population data on synchronous metastatic colorectal cancer patients were extracted from the Netherlands Cancer Registry and SEER database. Pubmed, EMBASE and Cochrane library were searched for prospective studies on metastatic colorectal cancer to conduct a meta‐analysis. Inclusion criteria consisted of metastatic disease, systemic treatment with palliative intent and specification of primary tumor location. Data were pooled using a random‐effects model. For the population‐based data, multivariable Cox models were constructed. The Grambsch‐Therneau test was conducted to evaluate the potential time‐varying nature of sidedness. Meta‐regression incorporating treatment‐line as variable was conducted to test the pre‐specified hypothesis that the prognostic value of sidedness varies over time. Analysis of 12 885 and 16 160 synchronous metastatic colorectal cancer patients registered in the Netherlands Cancer Registry and SEER database, respectively, indicated a time‐varying prognostic value of sidedness (P <.01). Thirty‐one studies were selected for the meta‐analysis (9558 patients for overall survival analysis). Pooled univariable hazard ratioleft‐sided/right‐sided for overall survival was 0.71 (95% CI: 0.65‐0.76) in 1st‐line, 0.76 (0.54‐1.06) in 2nd‐line and 1.01 (0.86‐1.19) in 3rd‐line studies. Hazard ratios were significantly influenced by treatment line (P =.035). The prognostic value of sidedness of the primary tumor in metastatic colorectal cancer patients treated with palliative systemic therapy decreases over time since diagnosis, suggesting that sidedness may not be a useful stratification factor in late‐line trials. This decrease in prognostic value should be taken into account when providing prognostic information to patients. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to define the gene signature associated with response to neoadjuvant chemoradiotherapy (nCRT), or chemoradiosensitivity (CRS) signature, in rectal cancer, and investigate the correlation between the CRS signature and characteristics of tumor. Materials and Methods: Three public microarray datasets of pre‐nCRT rectal cancer were used to discover and validate the CRS signature, and the pathway analysis of the CRS signature was performed. Patients in The Cancer Genome Atlas (TCGA) dataset were stratified according to the CRS signature enrichment score, and mutational profile and proportions of infiltrated immune cells were compared. Results: In the discovery dataset (GSE53781), 95 genes were upregulated in complete responders compared to non‐complete responders and defined as the CRS signature. Pathways regarding DNA replication and repair processes as well as inflammatory response were enriched in the CRS signature. In the validation datasets (GSE35452 and GSE45404), patients with favorable response to nCRT exhibited higher enrichment score of the CRS. In TCGA‐READ cohort, patients with high CRS signature harbored KRAS mutation in lower frequency than those with low CRS signature. In addition, proportions of proinflammatory immune cells were higher, but proportion of immunosuppressive M2 macrophages was lower in patients with high CRS signature than those with low CRS signature. Conclusions: The current integrative bioinformatic analysis suggests the CRS signature and showed that the CRS signature is associated with dissimilar mutational profile and increased immune response. The discovered CRS signature and related characteristics may serve as candidate of stratification factor in upcoming studies for rectal cancer. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the efficacy and safety of adding anti-epidermal growth factor receptor [EGFR] MoAbs to various chemotherapy regimens in patients with RAS wild-type metastasized colorectal cancer (RAS WT metastatic colorectal cancer [mCRC]) and to identify the optimal combination regimens., Methods: We searched MEDLINE, EMBASE, and CENTRAL from the inception date to 20th May 2019. Randomized clinical trials investigating chemotherapy with or without anti-EGFR MoAbs in treatment of patients with RAS WT mCRC were included., Results: Eighteen studies involving 8848 participants were eligible. Comparing with oxaliplatin-based chemotherapy, adding anti-EGFR MoAbs benefited only in progression-free survival (PFS) (hazard ratio [HR] = 0.80, 95% confidence interval [CI]: 0.67 to 0.94), but not in overall survival (OS) (HR = 0.89, 95% CI: 0.78 to 1.02). Further sensitivity analysis indicated that adding anti-EGFR MoAbs to FOLFOLX regimen as a first-line treatment showed benefits in both PFS and OS (PFS: HR = 0.74, 95% CI: 0.64 to 0.84; OS: HR = 0.83, 95% CI: 0.73 to 0.95, respectively). Comparing with irinotecan-based chemotherapy or best supportive care, adding anti-EGFR MoAbs revealed an improvement in both PFS (HR = 0.77, 95% CI: 0.69 to 0.86; HR = 0.46, 95% CI: 0.40 to 0.54, respectively) and OS (HR = 0.89, 95% CI: 0.80 to 0.98; HR = 0.65, 95% CI: 0.54 to 0.78, respectively)., Conclusion: Anti-EGFR MoAbs as a monotherapy or in combination with either irinotecan-based chemotherapy or FOLFOX in patients with RAS wild-type mCRC have better response and survival outcome, whereas OS does not benefit from adding anti-EGFR MoAbs to another oxaliplatin-based regimen. Anti-EGFR MoAbs have increased the risk of adverse effects than chemotherapy alone. More high-quality randomized controlled trials for RAS wild type are necessary., (© 2019 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.)

The systematic treatment of colorectal cancer (CRC) still has room for improvement. The efficacy of chemotherapy, that of anti‐vascular therapy, and that of immunotherapy have been unsatisfactory. In recent years, nanomaterials have been used as carriers to improve the bioavailability of anticancer drugs. For the treatment of colorectal cancer, nanodrugs increase the possibility of more precise targeted delivery. However, the actual benefits may cover more aspects. Nanocarriers can produce synergistic effects with anticancer drugs, including the scavenging of reactive oxygen species and co‐delivery of a variety of drugs. Currently, immunotherapy has very limited clinical applications in CRC. Modified nanocarriers can activate the immune microenvironment, which can be used for staging antigen recognition or the immune response. Cancer vaccines based on nanomaterials and modified immune checkpoint inhibitors have shown therapeutic potential in animal models. Considering the direct or indirect relationship between the intestinal microflora and CRC, a variety of nanodrugs that regulate microbial function have been explored as an anticancer strategy, and the special structure of microorganisms can also be used as a basis for improving the delivery of traditional nanoparticles (NPs). This review summarizes recent research performed on nanocarriers in in vivo and in vitro models and the synergistic anticancer effects of nanocarriers, focusing on the interaction between NPs and the body, resulting in enhanced efficacy and immune activation. Furthermore, this review describes the current trend of NPs used in the treatment of CRC. [ABSTRACT FROM AUTHOR]

Introduction: Analyzing longitudinal cancer quality‐of‐life (QoL) measurements and their impact on clinical outcomes may improve our understanding of patient trajectories during systemic therapy. We applied an unsupervised growth mixture modeling (GMM) approach to identify unobserved subpopulations ("patient clusters") in the CO.20 clinical trial longitudinal QoL data. Classes were then evaluated for differences in clinico‐epidemiologic characteristics and overall survival (OS). Methods and Materials: In CO.20, 750 chemotherapy‐refractory metastatic colorectal cancer (CRC) patients were randomized to receive Brivanib+Cetuximab (n = 376, experimental arm) versus Cetuximab+Placebo (n = 374, standard arm) for 16 weeks. EORTC‐QLQ‐C30 QoL summary scores were calculated for each patient at seven time points, and GMM was applied to identify patient clusters (termed "classes"). Log‐rank/Kaplan–Meier and multivariable Cox regression analyses were conducted to analyze the survival performance between classes. Cox analyses were used to explore the relationship between baseline QoL, individual slope, and the quadratic terms from the GMM output with OS. Results: In univariable analysis, the linear mixed effect model (LMM) identified sex and ECOG Performance Status as strongly associated with the longitudinal QoL score (p < 0.01). The patients within each treatment arm were clustered into three distinct QoL‐based classes by GMM, respectively. The three classes identified in the experimental (log‐rank p‐value = 0.00058) and in the control arms (p < 0.0001) each showed significantly different survival performance. The GMM's baseline, slope, and quadratic terms were each significantly associated with OS (p < 0.001). Conclusion: GMM can be used to analyze longitudinal QoL data in cancer studies, by identifying unobserved subpopulations (patient clusters). As demonstrated by CO.20 data, these classes can have important implications, including clinical prognostication. [ABSTRACT FROM AUTHOR]

Background: RAS mutation testing now routinely informs the optimal management of metastatic colorectal cancer (mCRC), specifically the finding of a RAS mutation defines patients who will not benefit from treatment with an epidermal growth factor receptor inhibitor. Over time more RAS genes have been tested and more sensitive techniques used. Aims: To review routine care RAS testing and results over time. Methods: A retrospective analysis of the molecular data collected prospectively in the multi‐site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry from 2009 to 2018 was undertaken. Patients with RAS data were further analyzed. In parallel, the RAS mutation status of patients enrolled in the Test Tailor Treat (TTT) program was examined for 2011–2018. Results: Of 2908 patients in the TRACC registry, 1892 (65%) were tested, with 898 (47%) of tested patients found to be RAS mutant (RASmt). RAS data were available for 5935 TTT patients. Of the tested TRACC patients diagnosed in 2009 and 2010, 38% were RASmt. For each 2‐year period from 2011/2012 through to 2017/2018, the prevalence of RASmt in TRACC and TTT was 42% and 40% (2011/2012), 52% and 40% (2013/2014), 47% and 49% (2015/2016), and 47% and 49% (2017/2018). Conclusions: Based on both TRACC and TTT data, the proportion of patients reported to have a RAS mutation increased from 2009 to 2015 but has remained relatively stable in recent years. The increased proportion of RASmt patients observed over time is likely largely driven by the uptake of extended RAS testing. [ABSTRACT FROM AUTHOR]

Colon adenocarcinoma (COAD) has a high incidence and death rate. Despite the fact that change in fatty acid metabolism promotes tumor growth and metastasis to the greatest degree among metabolite profiles, a thorough investigation on the involvement of fatty acid metabolism‐related genes (FAMRGs) in COAD has yet not been conducted. Here, the clinical data as well as the gene expression profiles were extracted from The Cancer Genome Atlas (TCGA) database. Based on the FAMRG expression data and clinical information, a FAMRG risk signature was developed using LASSO as well as multivariate and univariate Cox regression analyses. Then, the nomogram was used to create a customized prognostic prediction model, and the calibration and receiver operating characteristic curves were used to evaluate the nomogram's prediction performance and discriminative capability. Lastly, a number of studies were conducted to assess the influence of independent FAMRGs on COAD, including unsupervised cluster analysis, functional analysis, and drug sensitivity analysis. Three hundred and sixty‐seven patients were included in this study, and a 12‐FAMRG risk signature was discovered in the training cohort based on a detailed examination of the FAMRGs expression data and clinical information. After that, risk scores were computed to classify patients into low or high‐risk groups, and the Kaplan–Meier curve analysis revealed that patients in the low‐risk group exhibited an elevated overall survival (OS) rate. The FAMRG was shown to be substantially correlated with prognosis in multivariate Cox regression analysis and was validated using the validation dataset. Then, using the clinical variables and risk signature, we developed and validated a prediction nomogram for OS. Functional characterization showed a strong correlation between this signature and immune cell infiltration and immune modulation. Additionally, by evaluating the GDSC database, it was determined that the high‐risk group exhibited medication resistance to many chemotherapeutic and targeted medicines, including VX.680, gemcitabine, doxorubicin, and paclitaxel. Overall, we have revealed the significance of a FAMRG risk signature for predicting the prognosis and response to immunotherapy in COAD, and our findings might contribute to an enhanced comprehension of metabolic pathways and the future development of innovative COAD therapeutic methods. [ABSTRACT FROM AUTHOR]

Despite recent advances in the systemic treatment of gastrointestinal tumors, pancreatic adenocarcinoma (PDAC) remains a challenging disease, with 5‐year survival just over 10%. Pancreatectomy in patients meeting defined anatomic criteria can result in cure; however, perioperative morbidity and mortality, as well as high rates of both local and distant recurrence even after "potentially curative" resection, have limited survival. Although perioperative chemotherapy has been shown to improve patients' longevity and chance for cure, debate continues about whether the preoperative or adjuvant approach is most effective in treatment of localized PDAC. Large, randomized multicenter trials in patients with resectable and borderline resectable PDAC have evaluated an evolving therapeutic landscape with mixed results. Importantly, these landmark studies share the fundamentally flawed assumption that tumor anatomical characteristics are an indicator of behavior and natural history. Concurrent biologic and translational research has revealed that rather than a single disease, PDAC represents a phenotypically variable group of malignancies arising in physiologically diverse patients. Ongoing novel trials have begun to capture this heterogeneity both in patient selection as well as the measurement of response by using genomic, transcriptional and radiomic markers. By moving away from classic anatomic descriptors to a more nuanced landscape of biomarkers predictive of tumor behavior and response, we can further refine the questions asked in preoperative trials and translate the answers to clinically meaningful precision therapy in localized PDAC. The concurrent evolution of perioperative therapy, surgery and multidisciplinary care have resulted in hard‐fought gains in survival for patients with pancreatic cancer. In the management of localized PDAC, the focus on classic anatomic descriptors of tumor resectability must yield to a more nuanced focus on biomarkers of cancer behavior and response. [ABSTRACT FROM AUTHOR]

Background: Plant‐based foods have been recommended for health. However, not all plant foods are healthy, and little is known about the association between plant‐based diets and specific molecular subtypes of colorectal cancer (CRC). We examined the associations of healthy and unhealthy plant‐based diets with the incidence of CRC and its molecular subtypes. Methods: While 123 773 participants of the Nurses' Health Study and the Health Professionals Follow‐up Study had been followed up (3 143 158 person‐years), 3077 of them had developed CRC. Healthy and unhealthy plant‐based diet indices (hPDI and uPDI, respectively) were calculated using repeated food frequency questionnaire data. We determined the tumoural status of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and BRAF and KRAS mutations. Results: Higher hPDI was associated with lower CRC incidence (multivariable hazard ratio [HR] comparing extreme quartiles, 0.86, 95% confidence interval [CI]: 0.77, 0.96; P‐trend =.04), whereas higher uPDI was associated with higher CRC incidence (multivariable HR comparing extreme quartiles, 1.16, 95% CI: 1.04, 1.29; P‐trend =.005). The association of hPDI significantly differed by KRAS status (P‐heterogeneity =.003) but not by other tumour markers. The hPDI was associated with lower incidence of KRAS‐wildtype CRC (multivariable HR comparing extreme quartiles, 0.74, 95% CI: 0.57, 0.96; P‐trend =.004) but not KRAS‐mutant CRC (P‐trend =.22). Conclusions: While unhealthy plant‐based diet enriched with refined grains and sugar is associated with higher CRC incidence, healthy plant‐based diet rich in whole grains, fruits and vegetables is associated with lower incidence of CRC, especially KRAS‐wildtype CRC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a genetically heterogeneous disease with its pathogenesis often driven by varying genetic or epigenetic alterations. This has led to a substantial number of patients developing chemoresistance and treatment failure, resulting in a high mortality rate for advanced disease. Deep molecular analysis has allowed for the discovery of key intestinal signaling pathways which impacts colonic epithelial cell fate, and the integral role of the tumor microenvironment on cancer growth and dissemination. Through transitioning pre‐clinical knowledge in research into clinical practice, many potential druggable targets within these pathways have been discovered in the hopes of overcoming the roadblocks encountered by conventional therapies. A personalized approach tailoring treatment according to the histopathological and molecular features of individual tumors can hopefully translate to better patient outcomes, and reduce the rate of recurrence in patients with advanced CRC. Herein, the latest understanding on the molecular science behind CRC tumorigenesis, and the potential treatment targets currently at the forefront of research are summarized. [ABSTRACT FROM AUTHOR]

Background and Aim: It remains unclear whether immunotherapy, which is not generally considered for microsatellite stable (MSS) colorectal cancer (CRC), can be used to effectively treat select CRC patients. We investigated the feasibility of obesity‐associated MSS CRC patients for immunotherapy based on genomic alterations. Methods: We evaluated differences in genomic alteration types and immune signatures between obese and non‐obese patients with MSS CRC. We performed genomic analyses using 434 CRC patients from The Cancer Genome Atlas (TCGA). Patients with MSS CRC were stratified into subgroups based on their BMI and numbers of nonsynonymous single nucleotide variants (nsSNVs) and frameshift insertions and deletions (fs INDELs) using machine learning. Results: The obese subgroup showed higher incidences of single nucleotide variants (SNV) and insertions and deletions (INDELs) in comparison with healthy weight patients with MSS CRC. The subgroup, who had higher numbers of nsSNVs and fs INDLEs, exhibited increased immune signatures, increased number of SNV‐derived neoantigens, and had up‐regulated two immune checkpoint genes in comparison with healthy weight patients with MSS CRC, reflecting interactions between the cancer genome and immune system. Conclusions: This study suggests that immunotherapy may be suitable for some obesity‐associated CRC patients. [ABSTRACT FROM AUTHOR]

Introduction: Colorectal cancer (CRC) is driven by a small set of oncogenic and tumour suppressor mutations. However, different combinations of mutations often lead to poor tumour responses to individual anticancer drugs. We have investigated the antiproliferative and in vitro cytotoxic activity of pair‐wise combinations of inhibitors which target specific signalling pathways in colon cancer cells. Objectives: To target specific signaling pathways pairwise with inhibitors in order to kill colon cancer cells. Methods: The effects of different concentrations of two inhibitors on the proliferation and viability of colon cancer cell lines were measured using cell titre glow and cytotoxic assays in 2D and 3D cell micro‐cultures. One successful drug combination was used to treat a colon cancer cell line growing as a xenograft in nude mice. Results: Colon cancer cells in non‐adherent cultures were killed more effectively by combinations of pyrvinium pamoate (a Wnt pathway inhibitor) and ABT263 (a pro‐apoptotic Bcl‐2 family inhibitor) or Ly29004 (a PI3kinase inhibitor). However, in a mouse xenograft model, the formulation and toxicity of the ABT737/PP combination prevent the use of these drugs for treatment of tumours. Fortunately, oral analogues of PP (pyrvinium phosphate, PPh) and ABT737(ABT263) have equivalent activity and can be used for treatment of mice carrying SW620 colorectal cancer xenografts. The PPh/ABT263 induced SW620 tumour cell apoptosis and reduced the rate of SW620 tumour growth. Conclusion: By combining a Wnt signaling inhibitor (pyrvinium phosphate) and a pro‐survival inhibitor (ABT263) colon cancer cells can be killed. Combinations of Wnt signalling inhibitors with an inhibitor of the Bcl pro‐survival protein family should be considered for the treatment of patients with precancerous colon adenomas or advanced colorectal cancers with APC mutations. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine‐based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC. CA Cancer J Clin. 2022;72:000‐000. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, discovered in the cytoplasm of almost all types of mammalian cells, plays a significant role in biological functions. The duration of STAT3 activation in normal tissues is a transient event and is strictly regulated. However, in cancer tissues, STAT3 is activated in an aberrant manner and is induced by certain cytokines. The continuous activation of STAT3 regulates the expression of downstream proteins associated with the formation, progression, and metastasis of cancers. Thus, elucidating the mechanisms of STAT3 regulation and designing inhibitors targeting the STAT3 pathway are considered promising strategies for cancer treatment. This review aims to introduce the history, research advances, and prospects concerning the STAT3 pathway in cancer. We review the mechanisms of STAT3 pathway regulation and the consequent cancer hallmarks associated with tumor biology that are induced by the STAT3 pathway. Moreover, we summarize the emerging development of inhibitors that target the STAT3 pathway and novel drug delivery systems for delivering these inhibitors. The barriers against targeting the STAT3 pathway, the focus of future research on promising targets in the STAT3 pathway, and our perspective on the overall utility of STAT3 pathway inhibitors in cancer treatment are also discussed. [ABSTRACT FROM AUTHOR]

Aim: We sought to identify genetic differences between right‐ and left‐sided colon cancers and using these differences explain lower survival in right‐sided cancers. Method: A retrospective review of patients diagnosed with colon cancer was performed using The Cancer Genome Atlas, a cancer genetics registry with patient and tumour data from 20 North American institutions. The primary outcome was 5‐year overall survival. Predictors for survival were identified using directed acyclic graphs and Cox proportional hazards models. Results: A total of 206 right‐ and 214 left‐sided colon cancer patients with 84 recorded deaths were identified. The frequency of mutated alleles differed significantly in 12 of 25 genes between right‐ and left‐sided tumours. Right‐sided tumours had worse survival with a hazard ratio of 1.71 (95% confidence interval 1.10–2.64, P = 0.017). The total effect of the genetic loci on survival showed five genes had a sizeable effect on survival: DNAH5, MUC16, NEB, SMAD4, and USH2A. Lasso‐penalized Cox regression selected 13 variables for the highest‐performing model, which included cancer stage, positive resection margin, and mutated alleles at nine genes: MUC16, USH2A, SMAD4, SYNE1, FLG, NEB, TTN, OBSCN, and DNAH5. Post‐selection inference demonstrated that mutations in MUC16 (P = 0.01) and DNAH5 (P = 0.02) were particularly predictive of 5‐year overall survival. Conclusions: Our study showed that genetic mutations may explain survival differences between tumour sites. Further studies on larger patient populations may identify other genes, which could form the foundation for more precise prognostication and treatment decisions beyond current rudimentary TNM staging. [ABSTRACT FROM AUTHOR]

DNA methylation status correlates with clinical outcomes of anti‐epidermal growth factor receptor (EGFR) treatment. There is a strong need to develop a simple assay for measuring DNA methylation status for the clinical application of drug selection based on it. In this study, we collected data from 186 patients with metastatic colorectal cancer (mCRC) who had previously received anti‐EGFR treatment. We modified MethyLite to develop a novel assay to classify patients as having highly methylated colorectal cancer (HMCC) or low‐methylated colorectal cancer (LMCC) based on the methylation status of 16 CpG sites of tumor‐derived genomic DNA in the development cohort (n = 30). Clinical outcomes were then compared between the HMCC and LMCC groups in the validation cohort (n = 156). The results showed that HMCC had a significantly worse response rate (4.2% vs 33.3%; P =.004), progression‐free survival (median: 2.5 vs 6.6 mo, P <.001, hazard ratio [HR] = 0.22), and overall survival (median: 5.6 vs 15.5 mo, P <.001, HR = 0.23) than did LMCC in patients with RAS wild‐type mCRC who were refractory or intolerable to oxaliplatin‐ and irinotecan‐based chemotherapy (n = 101). The DNA methylation status was an independent predictive factor and a more accurate biomarker than was the primary site of anti‐EGFR treatment. In conclusion, our novel DNA methylation measurement assay based on MethyLight was simple and useful, suggesting its implementation as a complementary diagnostic tool in a clinical setting. [ABSTRACT FROM AUTHOR]

Background: Development of a pragmatic pathologic classifier of pancreatic ductal adenocarcinoma (PDAC) that reflects biological behavior is needed. Methods: The tumor epithelial and stromal features of PDAC and molecular subtype‐related markers were evaluated in three independent cohorts. Results: In the non‐neoadjuvant therapy cohort (n = 108), regarding tumor‐epithelial feature, non‐gland‐forming type showed worse prognosis compared to gland‐forming type (P <.001). For tumor‐stromal feature, in gland‐forming type, the prognosis was good in order of inactivated stroma‐rich, stroma‐poor, and activated stroma‐rich (P =.027). Whereas, non‐gland‐forming type revealed no difference of prognosis according to tumor stroma. Of molecular subtype‐related markers, keratin 81 expression was correlated with non‐gland‐forming type and poor prognosis (P =.005 and P =.021, respectively). Other markers (HNF1A, c‐MET, and p53) showed no significant differences in prognosis. In the neoadjuvant therapy cohort (n = 68), non‐gland‐forming type was correlated with high residual tumor volume (≥20%) (P <.001) and gland‐forming/stroma‐poor type was not present. In the next‐generation sequencing cohort (n = 55), non‐gland‐forming type was correlated with a higher number of the KRAS, TP53, CDKN2A, and SMAD4 mutations (P =.038). Conclusion: Combined tumor epithelial and stromal histopathology with keratin 81 expression is suggested to be useful for predicting prognosis of PDAC. [ABSTRACT FROM AUTHOR]

Aim: Microscopically positive (R1) margins are associated with poorer outcomes in patients with colorectal cancer. However, little is known of the differential impact of subdivisions of R1 margins, be they to the primary tumour (R1tumour) or to lymph node metastases/tumour deposits (R1LNM). Methods: Patients treated for Stage III colorectal cancer from 1 January 2016 to 31 December 2019 were identified from the Danish national cancer registry. Patients were stratified into three groups according to margin status (R0 vs. R1tumour vs. R1LNM). The primary outcome was overall survival. Results: In all, 4186 patients were included, comprising 3012 patients with colon cancer and 1174 patients with rectal cancer. The R1 resection rates were 16.5% and 18.2% in patients with colon and rectum cancer, respectively. In colon cancers, 3‐year overall survival was reduced in patients with R1LNM (65.7%, 95% CI 62.8–68.6) or R1tumour margins (51.8%, 95% CI 47.3–56.3) compared with R0 resections (80.8%, 95% CI 79.9–81.6, P < 0.001). A similar impact on survival was seen in rectal cancers (R0, 84.2%, 95% CI 82.9–85.5; R1LNM, 72.2%, 95% CI 67.8–76.6; R1tumour, 56.6%, 95% CI 50.0–63.2, P < 0.001). Margin status was independently prognostic of survival in both colon (R1tumour, hazard ratio 2.08, 95% CI 1.50–2.89, P < 0.001; R1LNM, hazard ratio 1.48, 95% CI 1.11–1.97, P = 0.008) and rectal cancers (R1tumour, hazard ratio 2.35, 95% CI 1.42–3.90, P < 0.001; R1LNM, hazard ratio 1.54, 95% CI 0.95–2.48, P = 0.077). Conclusion: R1 subdivisions have distinct impacts on survival in Stage III colorectal cancer. Further focused research in these patient subgroups is warranted. [ABSTRACT FROM AUTHOR]

Checkpoint‐blockade therapy (CBT) is approved for select colorectal cancer (CRC) patents, but additional immunotherapeutic options are needed. We hypothesized that vaccination with carcinoembryonic antigen (CEA) and Her2/neu (Her2) peptides would be immunogenic and well tolerated by participants with advanced CRC. A pilot clinical trial (NCT00091286) was conducted in HLA‐A2+ or ‐A3+ Stage IIIC‐IV CRC patients. Participants were vaccinated weekly with CEA and Her2 peptides plus tetanus peptide and GM‐CSF emulsified in Montanide ISA‐51 adjuvant for 3 weeks. Adverse events (AEs) were recorded per NIH Common Terminology Criteria for Adverse Events version 3. Immunogenicity was evaluated by interferon‐gamma ELISpot assay of in vitro sensitized peripheral blood mononuclear cells and lymphocytes from the sentinel immunized node. Eleven participants were enrolled and treated; one was retrospectively found to be ineligible due to HLA type. All 11 participants were included in AEs and survival analyses, and the 10 eligible participants were evaluated for immunogenicity. All participants reported AEs: 82% were Grade 1‐2, most commonly fatigue or injection site reactions. Two participants (18%) experienced treatment‐related dose‐limiting Grade 3 AEs; both were self‐limiting. Immune responses to Her2 or CEA peptides were detected in 70% of participants. Median overall survival (OS) was 16 months; among those enrolled with no evidence of disease (n = 3), median OS was not reached after 10 years of follow‐up. These data demonstrate that vaccination with CEA or Her2 peptides is well tolerated and immunogenic. Further study is warranted to assess potential clinical benefits of vaccination in advanced CRC either alone or in combination with CBT. What's new? Carcinoembryonic antigen (CEA) and human epidermal growth factor receptor (Her2) are cancer‐associated antigens that are overexpressed in most colorectal cancer cases, making them promising targets for vaccine‐based immunotherapy. Here, the authors show that vaccination with HLA‐A2‐ and HLA‐A3‐restricted CEA and Her2 peptides is well‐tolerated by patients with advanced colorectal cancer. Immunogenicity was equivalent or superior to more costly vaccination strategies. These data encourage further evaluation of clinical benefits from CEA and Her2 vaccination and support the possibility that cancer‐associated peptide vaccination may enhance responses to checkpoint blockade therapy in patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

What is known and Objective: Cancer drug treatment is often discontinued because of skin disorder aggravation. However, information on risk factors for skin disorders caused by anti‐epidermal growth factor receptor (EGFR) antibody drugs is limited. The aim of this study was to analyse the factors associated with skin disorders caused by anti‐EGFR antibody drugs and establish a method to minimize such aggravations. Methods: We retrospectively examined 67 colorectal cancer patients treated with anti‐EGFR antibody drugs for the first time. Results and discussion: A higher proportion of males than females experienced drug withdrawal, dose reduction or treatment discontinuation. The multiple logistic regression analysis revealed body weight as a risk factor affecting drug withdrawal, dose reduction or treatment discontinuation because of an acneiform rash. An examination of methods to avoid the aggravation of skin disorders revealed the acneiform rash grade in patients who received prophylactic minocycline was significantly lower than that in patients who did not receive prophylactic minocycline. Furthermore, among patients with grade 1 acneiform rash at the initiation of minocycline, the proportion of those who withdrew, required dose reduction or discontinued treatment was lower than that among patients with grade 2 acneiform rash. What is new and Conclusion: High body weight was identified as a novel factor for skin disorder aggravation caused by anti‐EGFR antibody drugs. The aggravation of skin disorders during cancer treatment with anti‐EGFR antibody drugs can potentially be avoided by carefully observing the onset of acneiform rash in affected patients with high body weight and using minocycline prophylactically or as an early‐stage intervention. [ABSTRACT FROM AUTHOR]

Detection of tumour‐specific circulating cell‐free DNA in plasma (ctDNA) fails in a significant number of cases depending on the clinical context. The primary aim was to investigate clinicopathological factors associated with detection of ctDNA in patients with RAS‐/BRAF‐mutated metastatic colorectal cancer (mCRC) prior to first‐line therapy. A secondary aim was to evaluate the prognostic impact of ctDNA compared to other biomarkers. Patients were included from the NORDIC‐VII study (N = 253). ctDNA was sampled prior to treatment and analysed for hotspot tissue mutations (KRAS, NRAS, and BRAF) using droplet digital PCR. Multivariable regression models were constructed to predict the probability of mutation detection and survival. Increasing radiological size of target lesions by increments of 1 cm (odds ratio [OR] = 1.18; 95% confidence interval [CI] 1.09‐1.27; P <.001), intact primary tumour (OR = 3.17; 95% CI 1.22‐8.22; P =.018) and more than one metastatic site (OR = 3.08; 95% CI 1.32‐7.19; P =.009) were associated with mutation detection in plasma. Metastatic involvement of the lung was associated with non‐detection (OR = 0.26; 95% CI 0.12‐0.58; P =.001). Preanalytical and analytical factors modulated detection. High allele frequencies of ctDNA indicated poor prognosis independently of CEA and CA19‐9 (hazard ratio [HR] = 2.38; 95% CI 1.74‐3.26; P <.001; N = 206). Clinicopathological characteristics should be carefully considered when evaluating ctDNA results from mCRC patients, especially when confronted with a plasma negative result. ctDNA may prove to be a clinically useful marker in the evaluation of mCRC treatment. What's new? In a "liquid biopsy", plasma samples that contain cell‐free DNA from a tumor (ctDNA) are analyzed. While promising, this technique isn't always reliable. Are there factors that affect the ability to detect tumour‐specific mutations in the plasma of cancer patients? In this study, the authors identified several such factors in patients with metastatic colorectal cancer (mCRC). They also found that ctDNA outperformed CEA and CA19‐9 when used to predict prognosis. With some caveats, ctDNA may thus provide a clinically useful biomarker for evaluating mCRC treatment and prognosis. [ABSTRACT FROM AUTHOR]

The advent of the genomic age has created a rapid increase in complexity for the development and selection of drug treatments. A key component of precision medicine is the use of genetic information to improve therapeutic effectiveness of drugs and prevent potential adverse drug reactions. Pharmacoepidemiology, as a field, uses observational methods to evaluate the safety and effectiveness of drug treatments in populations. Pharmacoepidemiology by virtue of its focus, tradition, and research orientation can provide appropriate study designs and analysis methods for precision medicine. The objective of this manuscript is to demonstrate how pharmacoepidemiology can impact and shape precision medicine and serve as a reference for pharmacoepidemiologists interested in contributing to the science of precision medicine. This paper depicts the state of the science with respect to the need for pharmacoepidemiology and pharmacoepidemiological methods, tools and approaches for precision medicine; the need for and how pharmacoepidemiologists use their skills to engage with the precision medicine community; and recommendations for moving the science of precision medicine pharmacoepidemiology forward. We propose a new integrated multidisciplinary approach dedicated to the emerging science of precision medicine pharmacoepidemiology. [ABSTRACT FROM AUTHOR]

Background: To describe ocular adverse events and retinal changes during fibroblast growth factor receptor (FGFR) inhibitor (AZD4547) anticancer therapy. Methods: This is a sub‐study examining ocular adverse effects from AZD4547 therapy (single‐centre, open‐label, single arm phase II clinical trial). Comprehensive ocular examinations were performed 3 weekly in 24 patients. Macular optical coherence tomography (OCT) scan (300 × 250) was obtained at each visit and OCT parameters [central 1 mm retinal thickness (CRT) and total macular volume in central 6 mm] extracted. OCT scans were subdivided into outer (ELM to RPE) and inner (ELM to ILM) layers to compare outer and inner retinal changes. Results: In 24 patients, AZD4547 was associated with eyelash elongation (n = 5, 21%) and punctate corneal erosion (n = 2, 8%). One patient developed clinically significant posterior capsular opacification during the study. OCT data were available in 23 patients, retinal changes ranged from an asymptomatic increased visibility of the interdigitation zone (IDZ) (n = 10, 43%) to multilobular subretinal fluid pockets (n = 5, 22%), which was associated with mild visual acuity loss. In a subset of patients (n = 9) with pre‐AZD4547 dosing OCT baseline, CRT increased by mean (SD) of 9 (4) μm in those with IDZ change only compared with 64 (38) μm in those with other retinal changes. Retinal changes tended to be bilateral, self‐limiting and improved over time without medical intervention. Conclusions: The ocular signs and symptoms did not result in dose cessation. Posteriorly, FGFR inhibition leads to outer retinal changes ranging from increased visibility of IDZ to distinct, multiple fluid pockets. [ABSTRACT FROM AUTHOR]

Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug‐drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1‐11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug‐drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration–time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%‐141.4%]), intravenous midazolam (118% [94.4%‐147.3%]), repaglinide (127% [104.7%‐153.3%]), and rosuvastatin (213% [42.5%‐1068.3%]) and decreased the area under the plasma concentration–time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%‐108.3%]), bupropion (79% [64.6%‐97.0%]), and hydroxybupropion (45% [15.7%‐129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree. [ABSTRACT FROM AUTHOR]

Background: Surgery is an important component in the treatment of esophageal cancer. For patients not eligible for R0 resection, defined as locally advanced unresectable esophageal cancer, a new approach is to transform the cancer into a resectable state by preoperative treatment. However, preoperative chemo/radiation is unsatisfactory. Therefore, the aim of this study was to assess the safety and efficacy of chemo/radiotherapy combined with a programmed cell death protein 1 (PD‐1) inhibitor in the preoperative transformation of unresectable esophageal cancer. Methods: Patients were evaluated as having unresectable, locally advanced esophageal cancer at baseline and were re‐evaluated as possible R0 resection candidates after PD‐1 inhibitor treatment. Patient data were derived from the prospective database of Peking University Cancer Hospital Thoracic Surgery I. Preoperative chemotherapy plus PD‐1 inhibitor treatment was defined as "transformation treatment." The objective response rate, operation rate (proportion of patients who underwent surgery), R0 rate, and treatment safety were analyzed retrospectively. Results: A total of 36 patients were enrolled into the study, and 94.4% (34/36) completed the planned transformation treatment. The objective response rate was 71.4% (25/35), and 75% (27/36) of the patients who completed transformation treatment underwent surgery. For these surgical patients, 81.5% (22/27) obtained R0 resection, and 22.2% (6/22) had pathological complete response (pCR). During transformation treatment, 22.2% (8/36) patients had ≥ grade 3 complications. There were no reoperations or perioperative deaths. After surgery, 29.6% (8/27) had ≥ grade 3 complications. Conclusions: Esophagectomy after immunotherapy is safe with acceptable complications. Compared with chemotherapy alone, chemotherapy combined with immunotherapy had a more favorable transformation effect for patients with unresectable esophageal cancer. [ABSTRACT FROM AUTHOR]

Big data in drug development may not satisfactorily address the demands of precision medicine in a rare disease population, making the use of smaller clinical trials necessary. Consequently, the use of innovative design and analysis of these clinical trials using model-informed approaches have become indispensable. This requires informative exposure-outcome analysis, together with formal statistical analysis, which should include the strength of evidence for a study outcome. We demonstrate how knowledge can be gained, with supporting strength of evidence, from a small (data) clinical trial with a low dose of blarcamesine in the treatment of Rett syndrome. Based on a small data paradigm, pharmacometrics item response theory modelling and Bayes factor analysis were used to demonstrate the efficacy of blarcamesine in Rett syndrome., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)