While various studies have highlighted the prognostic significance of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAT), the impact of additional adjuvant therapy after pCR is ...not known.
PubMed was searched for studies with NAT for breast cancer and individual patient-level data was extracted for analysis using plot digitizer software. HRs, with 95% probability intervals (PI), measuring the association between pCR and overall survival (OS) or event-free survival (EFS), were estimated using Bayesian piece-wise exponential proportional hazards hierarchical models including pCR as predictor.
Overall, 52 of 3,209 publications met inclusion criteria, totaling 27,895 patients. Patients with a pCR after NAT had significantly better EFS (HR = 0.31; 95% PI, 0.24-0.39), particularly for triple-negative (HR = 0.18; 95% PI, 0.10-0.31) and HER2
(HR = 0.32; 95% PI, 0.21-0.47) disease. Similarly, pCR after NAT was also associated with improved survival (HR = 0.22; 95% PI, 0.15-0.30). The association of pCR with improved EFS was similar among patients who received subsequent adjuvant chemotherapy (HR = 0.36; 95% PI, 0.19-0.67) and those without adjuvant chemotherapy (HR = 0.36; 95% PI, 0.27-0.54), with no significant difference between the two groups (
= 0.60).
Achieving pCR following NAT is associated with significantly better EFS and OS, particularly for triple-negative and HER2
breast cancer. The similar outcomes with or without adjuvant chemotherapy in patients who attain pCR likely reflects tumor biology and systemic clearance of micrometastatic disease, highlighting the potential of escalation/deescalation strategies in the adjuvant setting based on neoadjuvant response.
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Immune checkpoint inhibitors (ICIs) initiate antitumor immunity by blocking the action of immune inhibitor‐signaled cytotoxic proteins, such as cytotoxic T‐lymphocyte‐associated protein 4, programmed ...cell death protein 1, and programmed cell death ligand 1. However, in rare cases (∼1%–12% of patients), ICI treatment causes neurologic immune‐related adverse events (irAEs). These include, but are not limited to, headache, encephalitis, neuropathies, myasthenia gravis, and myositis. The symptoms associated with irAEs can range from mild (grade 1–2) to severe (grade 3–4); however, they are often challenging to diagnose because they may present as generalized symptoms, such as fatigue and weakness, that can also be caused by the cancer itself. Here, we present an illustrative case of a 67‐year‐old woman who presented with signs of a neurologic irAE, including progressive dysphagia and weakness leading to falls, which started during treatment with pembrolizumab and worsened following initiation of ipilimumab. Following neurological and pathological evaluation, she was diagnosed with myositis. She was treated with steroids and improved rapidly. In this article, we review previous literature to provide guidance to frequently asked questions concerning the diagnosis and management of neurologic irAEs in patients with advanced cancer. With prompt and effective treatment, most patients will achieve a complete recovery.
Key Points
Neurologic immune‐related adverse events (irAEs) affect approximately 1% of patients treated with immune checkpoint inhibitor (ICI) monotherapy and 2%‐3% treated with combination therapy. These irAEs can affect any portion of the nervous system, although peripheral nerve system manifestations are most common. Overlap syndromes with multiple neurologic irAEs or other affected organ systems frequently exist.
Diagnosis of neurologic irAEs can be challenging. Routine testing may be unremarkable and symptoms frequently mimic those from cancer or side effects of other therapies. Optimal management is currently unknown. A systematic, highly coordinated, and multidisciplinary approach is critical.
Outcomes from neurologic irAEs are typically favorable with the current practice of holding the ICI and starting corticosteroids. Some patients are even successfully retreated with an ICI. A subset of patients, however, have a fulminant and potentially fatal course.
Improved risk assessments and targeted therapies are needed.
In some cases, immune checkpoint inhibitor treatment causes neurologic immune‐related adverse events that can be challenging to diagnose and treat. This article provides a current approach to the evaluation and management of neurologic immune‐related adverse events in patients with advanced cancer through an illustrative case and review of the literature.
Abstract
The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and ...management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.
Graphical Abstract
Graphical Abstract
Outline of the five focus areas of cardiovascular toxicities covered in this definitions document. HF, heart failure.
Expanding use of immune‐checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune‐related adverse events (irAE‐N). We evaluate the ...real‐world frequency, phenotypes, co‐occurring immune‐related adverse events (irAEs), and long‐term outcomes of severe, grade III to V irAE‐N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE‐N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE‐N reporting are outlined. ANN NEUROL 2020;87:659–669
Purpose of Review
While immune checkpoint inhibitor (ICI) therapy has improved melanoma patient outcomes, it has also resulted in the rise of unique immune-related adverse events (irAEs). Here, we ...review and synthesize irAE management recommendations from several oncological societies into a streamlined format to aid in diagnosis and management. We also include clinical pearls highlighting several recent research studies in this field.
Recent Findings
Knowledge of immunotherapy toxicity has continually evolved, and several major oncologic societies have recently released new or updated guidelines.
Summary
Keeping up with the evolving field of immunotherapy and related toxicities is crucial, because ICI use, in combination with other agents, will only continue to increase and likely result in new and different patterns of irAEs. Providing clear and concise references for clinicians will help ensure proper irAE evaluation and management going forward. We present one such reference here, covering management of common and/or serious irAEs.
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies directed at negative regulatory components on T cells, such as cytotoxic T lymphocyte‐associated antigen 4, programmed cell death‐1 ...(PD‐1), and its ligand, programmed cell death ligand‐1. ICIs initate antitumor immunity; however, these agents are associated with immune‐related adverse events (irAEs) that may affect a variety of organs. Renal irAEs most commonly present with asymptomatic acute kidney injury (AKI), which is often detected by routine laboratory testing. The severity of AKI associated with irAEs ranges from mild (grade 1–2) to severe (grade 3–4). It is often challenging to diagnose because this group of patients often have multiple reasons to have AKI (dehydration, sepsis, or nephrotoxic medication exposure). We present an illustrative case of a 60‐year‐old man with metastatic melanoma who presented with AKI during treatment with nivolumab and review the literature to address frequently asked questions concerning the diagnosis and management of renal irAEs in patients with advanced cancer. Importantly, most patients will recover completely, and some may tolerate a rechallenge of ICI therapy, with prompt and effective treatment.
Key Points
Renal immune‐related adverse events (irAEs) are less frequently reported than other irAEs; however, it is possible that available data underestimate their true incidence because of missed diagnoses and under‐reporting. Although severe renal irAEs are more easily detected, smaller rises in creatinine may not be appreciated or may be attributed to other causes, because the differential diagnosis of acute kidney injury (AKI) in patients with cancer is broad.
Baseline creatinine should be established prior to beginning immune checkpoint inhibitorss (ICIs), and it should be monitored with every cycle. If a patient develops AKI, the ICI should be held while the evaluation is pursued. A thorough workup of suspected renal irAEs must exclude other potential causes of AKI such as infection, dehydration, urinary tract obstruction, and nephrotoxin exposure.
Acute kidney injury after ICI therapy does not appear to be more common in patients with baseline estimated glomerular filtration rate <60 mL per min per 1.73 m. One particular concern, however, is that those with baseline renal disease have less “renal reserve,” and repeated AKI events may push a patient closer to end‐stage renal disease. Thus, clinicians must exert caution when rechallenging patients with pre‐existing renal disease with ICI therapy in the event of a prior AKI from ICI‐related allergic interstitial nephritis.
Oncologists treating immune checkpoint inhibitor‐exposed patients often face challenging questions during the evaluation of renal immune‐related adverse events. This review addresses frequently asked questions to assist in the recognition and management of these conditions
Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized.
The authors sought to understand the ...presentation and clinical course of ICI-associated myocarditis.
After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block.
The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates.
Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.
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Our understanding of gene regulation in plants is constrained by our limited knowledge of plant cis-regulatory DNA and its dynamics. We mapped DNase I hypersensitive sites (DHSs) in A. thaliana ...seedlings and used genomic footprinting to delineate ∼700,000 sites of in vivo transcription factor (TF) occupancy at nucleotide resolution. We show that variation associated with 72 diverse quantitative phenotypes localizes within DHSs. TF footprints encode an extensive cis-regulatory lexicon subject to recent evolutionary pressures, and widespread TF binding within exons may have shaped codon usage patterns. The architecture of A. thaliana TF regulatory networks is strikingly similar to that of animals in spite of diverged regulatory repertoires. We analyzed regulatory landscape dynamics during heat shock and photomorphogenesis, disclosing thousands of environmentally sensitive elements and enabling mapping of key TF regulatory circuits underlying these fundamental responses. Our results provide an extensive resource for the study of A. thaliana gene regulation and functional biology.
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•A. thaliana regulatory DNA, TF footprints, and cis-regulatory lexicon are elucidated•TF binding in protein-coding exons may have shaped A. thaliana codon usage•A. thaliana TF network architecture is strikingly similar to human•Light- and heat-cued regulatory DNA dynamics and TF network remodeling are revealed
Our understanding of plant gene regulation is constrained by our limited knowledge of plant cis-regulatory DNA and its dynamics in response to environmental cues. Sullivan et al. now establish nucleotide-resolution regulatory DNA landscapes for A. thaliana seedlings before and after exposure to light and heat, key environmental cues shaping plant growth and development. This study generates genome-wide, condition- and tissue-specific maps of TF occupancy, constructs condition-specific TF networks, and identifies hundreds of de novo TF motif models.
BACKGROUND:Immune checkpoint inhibitors (ICI) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. ...Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events.
METHODS:The study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls, matched by age, a history of cardiovascular events and cancer type. In a second design, a case-crossover analysis was performed with an “at-risk period” defined as the two-year period after and the “control period” as the two-year prior to treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. Additionally, in an imaging sub-study (n=40), the rate of atherosclerotic plaque progression was compared from before and after starting an ICI. All study measures and outcomes were blindly adjudicated.
RESULTS:In the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (HR, 3.3 95% CI, 2.0-5.5; P<0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at two years (adjusted HR, 4.8 95% CI, 3.5-6.5; P<0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/year pre-to 6.7%/year post). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids.
CONCLUSIONS:Cardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk, prior to, during and after treatment, should be considered among patients on an ICI.
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