Relationships Between Köhne Category/Baseline Tumor Load and Early Tumor Shrinkage, Depth of Response, and Outcomes in Metastatic Colorectal Cancer.

BACKGROUND: In metastatic colorectal cancer (mCRC), there are limited data on associations between early tumor shrinkage (ETS), depth of response (DpR), and patient characteristics. METHODS: Data from patients with RAS wild-type mCRC who had participated in the PRIME (NCT00364013) and PEAK (NCT00819780) studies were analyzed retrospectively. ETS and DpR were assessed by baseline Köhne category/BRAF status (PRIME) and baseline tumor load (pooled PRIME and PEAK). RESULTS: Analysis populations included 436 to 665 patients. Patients' chances of achieving ETS of 30% or greater were 63.8%, 50.4%, and 41.9% in the low-, medium-, and high-risk Köhne categories, and 21.7% in those with BRAF mutations. Corresponding percentages for the highest DpR classification (71%-100%) were 47.7% (low risk), 23.6% (medium risk), 10.0% (high risk), and 4.2% (BRAF mutant). No clear relationship was observed between baseline tumor load and ETS or DpR. An ETS of 30% or greater and higher DpR values were associated with statistically significant prolongation of median progression-free survival and overall survival. CONCLUSION: Patients with mCRC categorized at baseline by the Köhne criteria as high risk or with BRAF mutations have lower chances of achieving an ETS of 30% or greater or a high DpR. Baseline tumor load was not predictive of ETS or DpR. Favorable ETS or DpR is associated with improved progression-free and overall survival.

The evolving landscape of biomarker testing for non-small cell lung cancer in Europe.

The discovery of oncogenic driver mutations rendering non-small cell lung cancer (NSCLC) targetable by small-molecule inhibitors, and the development of immunotherapies, have revolutionised NSCLC treatment. Today, instead of non-selective chemotherapies, all patients with advanced NSCLC eligible for treatment (and increasing numbers with earlier, less extensive disease) require fast and comprehensive screening of biomarkers for first-line patient selection for targeted therapy, chemotherapy, or immunotherapy (with or without chemotherapy). To avoid unnecessary re-biopsies, biomarker screening before first-line treatment should also include markers that are actionable from second-line onwards; PD-L1 expression testing is also mandatory before initiating treatment. Population differences exist in the frequency of oncogenic driver mutations: EGFR mutations are more frequent in Asia than Europe, whereas the converse is true for KRAS mutations. In addition to approved first-line therapies, a number of emerging therapies are being investigated in clinical trials. Guidelines for biomarker testing vary by country, with the number of actionable targets and the requirement for extensive molecular screening strategies expected to increase. To meet diagnostic demands, rapid screening technologies for single-driver mutations have been implemented. Improvements in DNA- and RNA-based next-generation sequencing technologies enable analysis of a group of genes in one assay; however, turnaround times remain relatively long. Consequently, rapid screening technologies are being implemented alongside next-generation sequencing. Further challenges in the evolving landscape of biomarker testing in NSCLC are actionable primary and secondary resistance mechanisms to targeted therapies. Therefore, comprehensive testing on re-biopsies, collected at the time of disease progression, in combination with testing of circulating tumour DNA may provide important information to guide second- or third-line therapies. Furthermore, longitudinal biomarker testing can provide insights into tumour evolution and heterogeneity during the course of the disease. We summarise best practice strategies for Europe in the changing landscape of biomarker testing at diagnosis and during treatment.

Biomarker testing and mutation prevalence in metastatic colorectal cancer patients in five European countries using a large oncology database.

Background: The literature on biomarker testing for metastatic colorectal cancer (mCRC) in Europe is scarce. This study aimed to estimate the percentage of mCRC patients from five European countries tested for biomarkers over time. Materials & methods: An oncology database was retrospectively analyzed; evaluated biomarkers were RAS, BRAF and microsatellite instability (MSI). The patients were drug treated during 2018 and tested for relevant biomarkers in 2013-2018. Results: RAS testing was conducted in >90% of mCRC patients from 2014 onwards. BRAF testing increased from 31% of mCRC patients in 2013 to 67% in 2018. MSI testing increased from 10 to 41%. There was no notable trend over time for RAS and BRAF mutation or MSI-high prevalence. Conclusion: Biomarker testing among patients diagnosed with mCRC was increased over time. This study demonstrates the quick uptake of biomarker testing in clinical practice. These findings are significant as biomarker-based drugs are becoming more common.

Lay abstract Each patient's cancer is unique. To find the best medicine for each patient, doctors perform tests to look at the cancer's genes. It is unknown how often and how well these tests are done. We tried to find this out for patients with cancer of the bowel or rectum that has spread to other organs. We found that an important genetic test called RAS is done in most patients. Other tests, called BRAF and microsatellite instability, are also conducted increasingly frequently. This is important because the results of such tests allow doctors to decide which drug(s) should be the most effective depending on the patient's cancer genes.

Impact of biomarkers and primary tumor location on the metastatic colorectal cancer first-line treatment landscape in five European countries.

Background: Advances in therapies for patients with metastatic colorectal cancer (mCRC) and improved understanding of prognostic and predictive factors have impacted treatment decisions. Materials & methods: This study used a large oncology database to investigate patterns of monoclonal antibody (mAb) plus chemotherapy treatment in France, Germany, Italy, Spain and the UK in mCRC patients treated in first line in 2018. Results: Anti-EGFR mAbs were most often administered to patients with RAS wild-type mCRC and those with left-sided tumors, while anti-VEGF mAbs were preferred in RAS mutant and right-sided tumors. Adopted treatment strategies differed between countries, largely due to reimbursement. Conclusion: Biomarker status and primary tumor location steered treatment decisions in first line. Adopted treatment strategies differed between participating countries.

Lay abstract Each patient's cancer is unique. For example, colon cancer on the left side is different from colon cancer on the right side. Colon cancer is different from cancer of the rectum. Cancers also have changes in their genes, which means some treatments should work, while others may not. Doctors can select among different medicines to find the drug that works best for each patient. We looked at patients with cancer of the colon or rectum that has spread to other organs. We tried to find out how doctors in Europe select drugs for their patients after performing tests called RAS or BRAF. We found that doctors make different choices in different countries.

The Healthcare Professionals' Perspective on Impact and Actions Taken Following Severe Infusion Reaction Events in Oncology Centers in Europe.

PURPOSE: The study aim was to describe the management strategies used for severe infusion-related reactions (SIRs) and understand the impact of such events in oncology day hospitals in France, Germany, Spain, and the UK. METHODS: The study was based on qualitative telephone interviews and quantitative self-completion questionnaires and asked healthcare professionals about the impact of SIRs and consequent actions taken. RESULTS: The procedures to prevent and manage SIRs were similar across countries and settings. In all countries, they were part of a larger risk-assessment and adverse events-prevention process. Preventive measures included patient history, risk assessment, pre-medication, and close monitoring of high-risk patients. The management procedures comprised stopping the infusion, triggering of the emergency chain, administering corticosteroids ± antihistamines, and hospitalization if necessary. The recalled SIRs had important consequences to affected patients, healthcare providers, and hospital organizational plans. All affected patients needed to be monitored closely for a prolonged time, thus blocking hospital beds. 44% of patients needed to be hospitalized, 17% needed resuscitation, and one patient died of cardiac arrest immediately after the start of the infusion. Importantly, 82% of patients were not re-challenged with the presumedly SIR-causing regimen or re-challenged in a later line. CONCLUSION: SIRs are unpredictable in nature, may have an extremely rapid onset, and are potentially fatal. Such events have a profound impact on the affected and surrounding patients, the care team and the organizational plan of the day-hospitals. Specific tools to reliably identify high-risk patients and predict the occurrence of events are needed.

Management of EGFR Inhibitor-induced Skin Toxicity and Factors Impacting Patients' Adherence to Skin Toxicity Treatment: Health Care Provider and Patient Surveys in European Oncology Centers.

INTRODUCTION: This study aimed to provide a description of existing measures for the prevention and management of epidermal growth factor receptor inhibitor monoclonal antibody-induced skin toxicities and factors impacting patients' adherence to those measures in France, Germany, and Spain. MATERIALS AND METHODS: The study consisted of 2 separate surveys. Health care professionals (HCPs; oncologists and nurses) in France, Germany, and Spain were interviewed, and patients with metastatic colorectal cancer and head-and-neck cancer in France and Germany self-completed questionnaires. The study was conducted between February and July 2018. RESULTS: A total of 53 oncologists, 44 nurses, and 143 patients participated in the study. HCPs stated that skin toxicities moderately (52%) or severely (28%) impacted patient care. Ninety percent of HCPs reported routine provision of prophylactic measures. The great majority of patients self-reported adherence with the prophylactic (80% to 88% depending on the type of measures) and reactive (93% to drug prescription) skin toxicity recommendations. HCPs estimated patient adherence to be 45% for full adherence and 40% for partial adherence. Most HCPs reported a positive or very positive impact of preventive measures and recommendations on skin toxicity incidence and severity, patients' quality of life, and various aspects of quality of anti-cancer treatment. CONCLUSIONS: Skin toxicities are an important adversity negatively impacting on patient care. However, despite the positive perception of the effectiveness of skin toxicity prophylaxis, almost one-third of oncology centers did not provide formal guidelines, and 10% of HCPs did not provide routine prophylactic measures. Patient adherence appears to be high for epidermal growth factor receptor inhibitor monoclonal antibody-induced skin toxicity prevention measures.

Obligations in the Anthropocene.

The Anthropocene is a term described by Earth Systems Science to capture the recent rupture in the history of the Earth where human action has acquired the power to alter the Earth System as a whole. While normative conclusions cannot be logically derived from this descriptive fact, this paper argues that law and philosophy ought to develop responses that are ordered around human beings. Rather than arguing for legal rights or extending rights to nature, this paper focuses on obligations. Drawing on Hans Jonas, it argues that obligations are a more appropriate tool for cultivating human plurality, restraining human action and protecting future generations.

Relationship Between Tumor Response and Tumor-Related Symptoms in RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses From 3 Panitumumab Trials.

BACKGROUND: There is no standardized assessment of symptomatic events in metastatic colorectal cancer (mCRC) despite disease symptoms that affect treatment decisions. Data from 3 first-line panitumumab in mCRC trials were retrospectively analyzed to assess whether early tumor shrinkage (ETS) and depth of response (DpR) were associated with time to occurrence of tumor-related symptoms. PATIENTS AND METHODS: Patients with RAS wild-type mCRC from PRIME, PEAK, and Study 314 were included. ETS was defined as a reduction of ≥ 30% in the sum of the longest diameters of lesions at 8 weeks. DpR was calculated as maximum percentage change in tumor size from baseline to nadir. The proportion of patients who developed symptoms (including a composite symptomatic endpoint) during study treatment was calculated. This study was registered at ClinicalTrials.gov as PRIME (NCT00364013), PEAK (NCT00819780), and Study 314 (NCT00508404). RESULTS: Overall, data of 659 patients were analyzed. Onset of symptoms was delayed in patients with ETS ≥ 30% versus ETS < 30% and in patients with greater DpR. In patients with symptoms at baseline who experienced ETS ≥ 30%, overall survival was similar to that seen for patients without symptoms at baseline. CONCLUSION: Both ETS and DpR were associated with delayed onset of symptoms in RAS wild-type mCRC patients. Treatments with high cytoreductive potential may delay symptom development.

The Evolving Biomarker Landscape for Treatment Selection in Metastatic Colorectal Cancer.

The approval of targeted therapies for metastatic colorectal cancer (mCRC) has led to important improvements in patient outcomes. However, it is still necessary to increase individualisation of treatments based on tumour genetic profiles to optimise efficacy, while minimising toxicity. As such, there is currently great focus on the discovery and validation of further biomarkers in mCRC, with many new potential prognostic and predictive markers being identified alongside developments in patient molecular profiling technologies. Here, we review data for validated and emerging biomarkers impacting treatment strategies in mCRC. We completed a structured literature search of the PubMed database to identify relevant publications, limiting for English-language publications published between 1 January 2014 and 11 July 2018. In addition, we performed a manual search of the key general oncology and CRC-focused congresses to identify abstracts reporting emerging mCRC biomarker data, and of ClinicalTrials.gov to identify ongoing clinical trials investigating emerging biomarkers in mCRC and/or molecular-guided clinical trials. There is solid evidence supporting the use of BRAF status as a prognostic biomarker and DYPD, UGT1A1, RAS, and microsatellite instability as predictive biomarkers in mCRC. There are a number of emerging biomarkers that may prove to be clinically relevant in the future to have prognostic (HPP1 methylation), predictive (HER3, microRNAs, anti-angiogenic markers, and CRC intrinsic subtypes), or both prognostic and predictive values (HER2, CpG island methylator phenotype, tumour mutational load, gene fusions, and consensus molecular subtypes). As such, new biomarker-led treatment strategies in addition to anti-epidermal growth factor receptor and anti-angiogenetic treatments are being explored. Biomarkers that are not recommended to be tested in clinical practice or are unlikely to be imminently clinically relevant for mCRC include thymidylate transferase, ERCC1, PIK3CA, and PTEN. We highlight the clinical utility of existing and emerging biomarkers in mCRC and provide recommended treatment strategies according to the biomarker status. An update on ongoing molecular-guided clinical trials is also provided.

Relationships between tumour response and primary tumour location, and predictors of long-term survival, in patients with RAS wild-type metastatic colorectal cancer receiving first-line panitumumab therapy: retrospective analyses of the PRIME and PEAK clinical trials.

BACKGROUND: Data from two trials of panitumumab in metastatic colorectal cancer (mCRC) were retrospectively analysed to investigate the effects of primary tumour location on early-tumour shrinkage (ETS) and depth of response (DpR), and identify factors predicting long-term survival. METHODS: Patients with RAS wild-type mCRC from PRIME (NCT00364013) and PEAK (NCT00819780) were included. ETS was defined as a ≥30% reduction in the sum-of-the-longest-diameters of measurable target lesions at eight weeks. DpR was the maximum percentage change from baseline to nadir in patients with shrinkage. Univariate and multivariate logistic analyses of short- versus long-term survivor data were performed. RESULTS: A total of 435/559 (78%) patients had left-sided disease. Of these, a higher proportion of patients treated with panitumumab versus comparator achieved ETS (PRIME: 62% vs. 36%; PEAK: 58% vs. 41%); median DpR was also higher with panitumumab (PRIME: 59% vs. 49%; PEAK: 70% vs. 48%). In pooled analyses of the studies, more patients with right-sided disease achieved ETS if treated with panitumumab than comparator (39% vs. 29%). Panitumumab treatment consistently predicted long-term survival. CONCLUSIONS: First-line panitumumab was associated with improved ETS and DpR vs. comparator in patients with left-sided mCRC. ETS may identify a subgroup of patients with right-sided disease who might respond to panitumumab.

Migration across the sinusoidal endothelium regulates neutrophil mobilization in response to ELR + CXC chemokines.

An increase in circulating neutrophils is a characteristic feature of many inflammatory reactions and is a result of the rapid mobilization of neutrophils from the bone marrow, driven by inflammatory mediators, including the ELR + CXC chemokines. In this paper, using a combination of light and electron microscopy and an in situ perfusion system of the rat femoral bone marrow, we examined this mobilization process in detail. We show that mobilization of neutrophils stimulated by the CXC chemokine, rat MIP-2, involves neutrophil migration from the haematopoietic compartment of the bone marrow across the bone marrow sinusoidal endothelium via a transcellular route. The critical role of the bone marrow sinusoidal endothelium in regulating neutrophil mobilization was demonstrated by artificially disrupting the bone marrow endothelial barrier by treatment with cytochalasin D, which results in the non-selective release of leucocytes from the bone marrow. In contrast, inhibiting the activity of p38 mitogen-activated protein kinase, inhibited both MIP-2 stimulated chemotaxis of bone marrow neutrophils in vitro and neutrophil mobilization in situ while, a broad spectrum matrix metalloproteinase inhibitor, BB94, had no effect on neutrophil mobilization. These results support the hypothesis that neutrophil migration drives their mobilization and highlights the function of the sinusoidal endothelium in regulating this process.

The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner.

The acute release of neutrophils from the bone marrow is a critical step in their trafficking to sites of inflammation. This process is stimulated by systemically acting inflammatory mediators, such as the CXC chemokines. In this study we have used a novel in situ perfusion system of the rat femoral bone marrow to directly investigate the role of specific adhesion molecules in chemokine-stimulated neutrophil mobilization. We show here that neutrophils mobilized in response to rat macrophage inflammatory protein-2 (MIP-2) shed L-selectin and expressed significantly higher levels of CD11b and CD49d. However, inhibition of L-selectin sheddase activity with KD-IX-73-4 had no effect on the number of neutrophils mobilized in response to rat MIP-2. Blockade of CD18, using a neutralizing monoclonal antibody (mAb), did not inhibit neutrophil mobilization but unexpectedly increased the rate and number of neutrophils released from the bone marrow in response to chemokine, suggesting that CD18 could play a role in neutrophil retention within the bone marrow. Blockade of CD49d using either a selective mAb or a specific antagonist resulted in a dramatic inhibition (> 75%) of the chemokine-stimulated neutrophil mobilization from the bone marrow. These data reveal contrasting roles for CD18 and CD49d in the retention and release of neutrophils from the bone marrow.

Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence.

In this study we provide evidence that the SDF-1alpha/CXCR4 chemokine axis is involved in both the retention of neutrophils within the bone marrow and the homing of senescent neutrophils back to the bone marrow. We show that the functional responses of freshly isolated human and murine neutrophils to CXCR2 chemokines are significantly attenuated by SDF-1alpha, acting via CXCR4. As a consequence, the mobilization of neutrophils from the bone marrow in vivo by the CXCR2-chemokine, KC, was dramatically enhanced by blocking the effects of endogenous SDF-1alpha using a specific CXCR4 antagonist. As neutrophils age, they upregulate expression of CXCR4 and acquire the ability to migrate toward SDF-1alpha. We show here that these senescent CXCR4(high) neutrophils preferentially home to the bone marrow in vivo in a CXCR4-dependent manner, suggesting a previously undefined mechanism for the clearance of senescent neutrophils from the circulation.