Abstract
Background
KRAS and BRAF mutations are well-established predictive and prognostic factors in metastatic colorectal cancer; however, their impact in the adjuvant setting has not yet been ...established.
Methods
We performed a meta-analysis of adjuvant phase III trials in patients with stage II and III colon cancer with available data on the impact of KRAS or BRAF mutations on both disease-free survival (DFS) and overall survival (OS). Trials were subgrouped based on whether adjustment for microsatellite instability (MSI) was performed and the subgroup effect was analyzed through a meta-regression. To increase the precision of the estimates, a joint DFS–OS (so-called “multivariate”) meta-analysis was performed. All statistical tests were 2-sided.
Results
Nine trials were selected (QUASAR 2, PETACC-8, N0147, CALGB-89803, NSABP-C07, NSABP-C08, PETACC-3, QUASAR, MOSAIC) including a total of 10 893 patients. In the primary meta-analysis, KRAS mutation was associated with poor DFS (pooled hazard ratio HR = 1.36, 95% confidence interval CI = 1.15 to 1.61, P < .001) and OS (pooled HR = 1.27, 95% CI = 1.03 to 1.55, P = .03) and BRAF mutation was also associated with poor DFS (pooled HR = 1.33, 95% CI = 1.00 to 1.78, P = .05) and OS (pooled HR = 1.49, 95% CI = 1.31 to 1.70, P < .001). The effect of the mutations on outcome was enhanced in the MSI-adjusted subgroup for both the KRAS mutation (pooled HR for DFS = 1.43, 95% CI = 1.15 to 1.79, P = .001; and pooled HR for OS = 1.33, 95% CI = 1.03 to 1.71, P = .03) and the BRAF mutation (pooled HR for DFS = 1.59, 95% CI = 1.22 to 2.07, P = .001; and pooled HR for OS = 1.67, 95% CI = 1.37 to 2.04, P < .001). The interaction between BRAF and MSI adjustment was statistically significant for DFS (Pinteraction = .02). This interaction was even more pronounced in the DFS–OS multivariate meta-analysis.
Conclusions
Both KRAS and BRAF mutations were statistically significantly associated with both DFS and OS, with the mutation effect being enhanced by MSI adjustment. Effective adjuvant treatment for microsatellite-stable BRAF or KRAS-mutated colon cancer represents an unmet clinical need, and exploring the use of recently available BRAF and KRAS inhibitors in this setting would be highly desirable.
Obesity-associated diseases account for a large portion of public health challenges.Among obesity-related disorders,a direct and independent relationship has been ascertained for colorectal ...cancer(CRC).The evidence that adipocyte hypertrophy and excessive adipose tissue accumulation(mainly visceral)can promote pathogenic adipocyte and adipose tissue-related diseases,has led to formulate the concept of"adiposopathy",defined as adipocyte and adipose tissue dysfunction that contributes to metabolic syndrome.Adipose tissue can,indeed,be regarded as an important and highly active player of the innate immune response,in which cytokine/adipokine secretion is responsible for a paracrine loop between adipocytes and macrophages,thus contributing to the systemic chronic low-grade inflammation associated with visceral obesity,which represents a favorable niche for tumor development.The adipocyte itself participates as a central mediator of this inflammatory response in obese individuals by secreting hormones,growth factors and proinflammatory cytokines,which are of particular relevance for the pathogenesis of CRC.Among adipocyte-secreted hormones,the most relevant to colorectal tumorigenesis are adiponectin,leptin,resistin and ghrelin.All these molecules have been involved in cell growth and proliferation,as well as tumor angiogenesis and it has been demonstrated that their expression changes from normal colonic mucosa to adenoma and adenocarcinoma,suggesting their involvement in multistep colorectal carcinogenesis.These findings have led to the hypothesis that an unfavorable adipokine profile,with a reduction of those with an anti-inflammatory and anti-cancerous activity,might serve as a prognostic factor in CRC patients and that adipokines or their analogues/antagonists might become useful agents in the management or chemoprevention of CRC.
Renal cell carcinoma (RCC) associated with anaplastic lymphoma kinase (ALK) gene rearrangements (ALK-RCC) is currently considered an "emerging or provisional" tumor entity by the last World Health ...Organization classification published in 2016. Although several studies assessing ALK-RCC's clinical and histological characteristics have been published in recent years, only a few publications have evaluated the activity of ALK inhibitors (ALK-i) in this subgroup of patients. Considering the well-recognized efficacy of this evolving class of targeted therapies in other ALK-positive tumors, we conducted a systematic review to evaluate the reported activity of ALK-i in the ALK-RCC subtype. MEDLINE was searched from its inception to 7 January 2022 for case reports and case series on adult metastatic ALK-RCC patients treated with ALK-i whose therapeutic outcomes were available. A virtual cohort of ALK-RCC patients was created. Our results showed a favorable activity of first- and second-generation ALK-i in pretreated ALK-RCC patients in terms of either radiological response or performance status improvement. We hope that the present work will prompt the creation of large, multi-institutional clinical trials to confirm these promising early data.
Several markers have been associated with sarcopenia in the elderly, including bioelectrical indices. Phase angle (PhA) is an impedance parameter and it has been suggested as an indicator of cellular ...death. Thus, the relationship between PhA and muscle mass and strength was investigated in 207 consecutively elderly participants (mean age 76.2±6.7years) admitted for multidimensional geriatric evaluation. Muscle strength by grip strength using a hand-held dynamometer and muscle mass was measured by bioimpedentiometer. PhA was calculated directly with its arctangent (resistance/reactance×180°/π). Linear relationship among muscular mass and strength and with clinical and biochemical parameters, including PhA at uni- and multivariate analysis were performed. Linear regression analysis demonstrated that lower level of PhA is associated with reduction in grip strength (y=3.16+0.08x; r=0.49; p<0.001), and even more, with muscle mass (y=3.04+0.25x; r=0.60; p<0001). Multivariate analysis confirms these relationships (grip strength β=0.245, p=0.031; muscular mass β=0.623, p<0.01). Thus, PhA is inversely related to muscle mass and strength in elderly subjects and it may be considered a good bioelectrical marker to identify elderly patients at risk of sarcopenia.
•Phase angle is an impedance parameter and it has been suggested as an indicator of cellular death.•Phase angle is inversely related to muscle mass and strength in elderly subjects.•Phase angle may represent a new and inexpensive geriatric tool to identify elderly patients at risk of sarcopenia.
Machine learning (ML) has been recently introduced to develop prognostic classification models that can be used to predict outcomes in individual cancer patients. Here, we report the significance of ...an ML-based decision support system (DSS), combined with random optimization (RO), to extract prognostic information from routinely collected demographic, clinical and biochemical data of breast cancer (BC) patients. A DSS model was developed in a training set (
= 318), whose performance analysis in the testing set (
= 136) resulted in a C-index for progression-free survival of 0.84, with an accuracy of 86%. Furthermore, the model was capable of stratifying the testing set into two groups of patients with low- or high-risk of progression with a hazard ratio (HR) of 10.9 (
< 0.0001). Validation in multicenter prospective studies and appropriate management of privacy issues in relation to digital electronic health records (EHR) data are presently needed. Nonetheless, we may conclude that the implementation of ML algorithms and RO models into EHR data might help to achieve prognostic information, and has the potential to revolutionize the practice of personalized medicine.
The debate on the optimal drug combination for treating chemotherapy-nave patients with metastatic colorectal cancer has recently become particularly heated.The present editorial will review recent ...data on this topic.The FIRE-3 and PEAK trials have shown a 7.5 to 12 mo survival advantage with the use anti-epidermal growth factor receptor(anti-EGFR)antibodies.The CALGB 80405 has shown no difference between anti-EGFR and anti-vascular endothelial growth factor agents.All three trials have consistently shown a significant increase in objective response rate.These data suggest that there is a subset of metastatic colorectal cancer patients,rigorously selected by molecular profiling,who particularly benefit from an anti-EGFR-based regimen in the first-line setting.
The development of large language models (LLMs) is a recent success in the field of generative artificial intelligence (AI). They are computer models able to perform a wide range of natural language ...processing tasks, including content generation, question answering, or language translation. In recent months, a growing number of studies aimed to assess their potential applications in the field of medicine, including cancer care. In this mini review, we described the present published evidence for using LLMs in oncology. All the available studies assessed ChatGPT, an advanced language model developed by OpenAI, alone or compared to other LLMs, such as Google Bard, Chatsonic, and Perplexity. Although ChatGPT could provide adequate information on the screening or the management of specific solid tumors, it also demonstrated a significant error rate and a tendency toward providing obsolete data. Therefore, an accurate, expert-driven verification process remains mandatory to avoid the potential for misinformation and incorrect evidence. Overall, although this new generative AI-based technology has the potential to revolutionize the field of medicine, including that of cancer care, it will be necessary to develop rules to guide the application of these tools to maximize benefits and minimize risks.
Precision medicine has opened up a new era in the development of anti-cancer agents that is focused on identifying biomarkers predictive of treatment response regardless of tumor histology. Since ...2017, the Food and Drug Administration has approved six drugs with histology-agnostic indications: pembrolizumab (both for tumors with the mismatch-repair deficiency (dMMR)/high microsatellite instability (MSI-H) phenotype and for those with the high tumor mutational burden (TMB-H) phenotype), dostarlimab (for dMMR tumors), larotrectinib and entrectinib (for tumors harboring neurotrophic tyrosine receptor kinase (NTRK) fusions), and the combination of dabrafenib plus trametinib (for BRAF V600E-mutated tumors). The genomic alterations targeted by these antineoplastic agents are rare in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, only a small number of mCRPC patients were enrolled in the clinical trials that led to the approval of the above-mentioned drugs. Therefore, we critically reviewed the literature on the efficacy of histology-agnostic drugs in mCRPC patients. Although the available evidence derives from retrospective studies and case reports, our results confirmed the efficacy of pembrolizumab in dMMR/MSI-H mCRPC. In contrast, few data are available for dostarlimab, larotrectinib, entrectinib, and dabrafenib-trametinib in this subset of patients. Large, multi-institutional registries aimed at collecting real-world data are needed to better comprehend the role of tissue-agnostic drugs in mCRPC patients.
Cancer genomes have been explored from the early 2000s through massive exome sequencing efforts, leading to the publication of The Cancer Genome Atlas in 2013. Sequencing techniques have been ...developed alongside this project and have allowed scientists to bypass the limitation of costs for whole‐genome sequencing (WGS) of single specimens by developing more accurate and extensive cancer sequencing projects, such as deep sequencing of whole genomes and transcriptomic analysis. The Pan‐Cancer Analysis of Whole Genomes recently published WGS data from more than 2600 human cancers together with almost 1200 related transcriptomes. The application of WGS on a large database allowed, for the first time in history, a global analysis of features such as molecular signatures, large structural variations and noncoding regions of the genome, as well as the evaluation of RNA alterations in the absence of underlying DNA mutations. The vast amount of data generated still needs to be thoroughly deciphered, and the advent of machine‐learning approaches will be the next step towards the generation of personalized approaches for cancer medicine. The present manuscript wants to give a broad perspective on some of the biological evidence derived from the largest sequencing attempts on human cancers so far, discussing advantages and limitations of this approach and its power in the era of machine learning.
Since the publication of The Cancer Genome Atlas data in 2013, the advances in the sequencing techniques allowed us to study cancer through whole‐genome sequencing and multiomics approaches. The vast amount of data generated still needs to be thoroughly deciphered, and the advent of machine learning approaches will be the next step towards personalized approaches for cancer medicine.
Risk prediction of chemotherapy-associated venous thromboembolism (VTE) is a compelling challenge in contemporary oncology, as VTE may result in treatment delays, impaired quality of life, and ...increased mortality. Current guidelines do not recommend thromboprophylaxis for primary prevention, but assessment of the patient's individual risk of VTE prior to chemotherapy is generally advocated. In recent years, efforts have been devoted to building accurate predictive tools for VTE risk assessment in cancer patients. This review focuses on candidate biomarkers and prediction models currently under investigation, considering their advantages and disadvantages, and discussing their diagnostic performance and potential pitfalls.
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